Academic Appointments

Research & Scholarship

Current Research and Scholarly Interests

Abnormalities in brain structure and function in healthy aging, alcoholism, HIV infection, and Alzheimer's Disease; diffusion tensor imaging of white matter microstructure in alcoholism; spectroscopic analysis of brain brain metabolite concentrations in alcoholism and HIV infection; functional neuroimaging of cognitive networks in alcoholism.


Journal Articles

  • A mechanism of rapidly reversible cerebral ventricular enlargement independent of tissue atrophy. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Zahr, N. M., Mayer, D., Rohlfing, T., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2013; 38 (6): 1121-1129


    Ventricular enlargement, a common in vivo marker of aging, disease, and insult, is presumed to reflect atrophy of surrounding brain regions. Pathological mechanisms underlying ventricular enlargement, however, are likely specific to the condition under investigation. Here, multimodal imaging, incorporating structural magnetic resonance imaging (MRI), MR spectroscopy (MRS), and diffusion weighted imaging (DWI), was used in rats exposed to binge ethanol (EtOH) to provide insight into a mechanism of reversible ventricular enlargement. During intoxication, MRI revealed expansion of ventricles, but volume changes in dorsal or ventral hippocampi, caudate-putamen, or thalamus were not detectible. MRS of whole-brain parenchyma showed decreases in N-acetylasparate (NAA) and tissue water T2, and increases in choline-containing compounds (Cho). DWI showed decreased diffusivity selective to the thalamus. All MR parameters returned to baseline with 7 days of recovery. Rapid recovery of ventricular volume and the absence of detectable tissue volume reductions in brain regions adjacent to ventricles argue against atrophy as a mechanism of ventricular expansion. Decreased tissue water T2 and decreased thalamic diffusivity suggest lower tissue water content and a role for both NAA and Cho, as osmolytes is proposed. Together, these data support a model of fluid redistribution during acute EtOH intoxication and recovery to account for rapid ventricular volume changes.

    View details for DOI 10.1038/npp.2013.11

    View details for PubMedID 23306181

  • In vivo glutamate measured with magnetic resonance spectroscopy: behavioral correlates in aging NEUROBIOLOGY OF AGING Zahr, N. M., Mayer, D., Rohlfing, T., Chanraud, S., Gu, M., Sullivan, E. V., Pfefferbaum, A. 2013; 34 (4): 1265-1276


    Altered availability of the brain biochemical glutamate might contribute to the neural mechanisms underlying age-related changes in cognitive and motor functions. To investigate the contribution of regional glutamate levels to behavior in the aging brain, we used an in vivo magnetic resonance spectroscopy protocol optimized for glutamate detection in 3 brain regions targeted by cortical glutamatergic efferents-striatum, cerebellum, and pons. Data from 61 healthy men and women ranging in age from 20 to 86 years were used. Older age was associated with lower glutamate levels in the striatum, but not cerebellum or pons. Older age was also predictive of poorer performance on tests of visuomotor skills and balance. Low striatal glutamate levels were associated with high systolic blood pressure and worse performance on a complex visuomotor task, the Grooved Pegboard. These findings suggest that low brain glutamate levels are related to high blood pressure and that changes in brain glutamate levels might mediate the behavioral changes noted in normal aging.

    View details for DOI 10.1016/j.neurobiolaging.2012.09.014

    View details for Web of Science ID 000314708000027

    View details for PubMedID 23116877

  • Variation in longitudinal trajectories of regional brain volumes of healthy men and women (ages 10 to 85 years) measured with atlas-based parcellation of MRI NEUROIMAGE Pfefferbaum, A., Rohlfing, T., Rosenbloom, M. J., Chu, W., Colrain, I. M., Sullivan, E. V. 2013; 65: 176-193


    Numerous cross-sectional MRI studies have characterized age-related differences in regional brain volumes that differ with structure and tissue type. The extent to which cross-sectional assumptions about change are accurate depictions of actual longitudinal measurement remains controversial. Even longitudinal studies can be limited by the age range of participants, sex distribution of the samples, and scan intervals. To address these issues, we calculated trajectories of regional brain volume changes from T1-weighted (SPGR) MRI data, quantified with our automated, unsupervised SRI24 atlas-based registration and parcellation method. Longitudinal MRIs were acquired at 3T in 17 boys and 12 girls, age 10 to 14 years, and 41 men and 41 women, age 20 to 85 years at first scan. Application of a regression-based correction function permitted merging of data acquired at 3T field strength with data acquired at 1.5T from additional subjects, thereby expanding the sample to a total of 55 men and 67 women, age 20 to 85 years at first scan. Adjustment for individual supratentorial volume removed regional volume differences between men and women due to sex-related differences in head size. Individual trajectories were computed from data collected on 2 to 6 MRIs at a single field strength over a ~1 to 8 year interval. Using linear mixed-effects models, the pattern of trajectories over age indicated: rises in ventricular and Sylvian fissure volumes, with older individuals showing faster increases than younger ones; declines in selective cortical volumes with faster tissue shrinkage in older than younger individuals; little effect of aging on volume of the corpus callosum; more rapid expansion of CSF-filled spaces in men than women after age 60 years; and evidence for continued growth in central white matter through early adulthood with accelerated decline in senescence greater in men than women.

    View details for DOI 10.1016/j.neuroimage.2012.10.008

    View details for Web of Science ID 000312283900016

    View details for PubMedID 23063452

  • Regional Brain Structural Dysmorphology in Human Immunodeficiency Virus Infection: Effects of Acquired Immune Deficiency Syndrome, Alcoholism, and Age BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Rosenbloom, M. J., Sassoon, S. A., Kemper, C. A., Deresinski, S., Rohlfing, T., Sullivan, E. V. 2012; 72 (5): 361-370


    Human immunodeficiency virus (HIV) infection and alcoholism each carries liability for disruption of brain structure and function integrity. Despite considerable prevalence of HIV-alcoholism comorbidity, few studies examined the potentially heightened burden of disease comorbidity.Participants were 342 men and women: 110 alcoholics, 59 with HIV infection, 65 with HIV infection and alcoholism, and 108 healthy control subjects. This design enabled examination of independent and combined effects of HIV infection and alcoholism along with other factors (acquired immune deficiency syndrome [AIDS]-defining events, hepatitis C infection, age) on regional brain volumes derived from T1-weighted magnetic resonance images.Brain volumes, expressed as Z scores corrected for intracranial volume and age, were measured in 20 tissue and 5 ventricular and sulcal regions. The most profound and consistent volume deficits occurred with alcohol use disorders, notable in the cortical mantle, insular and anterior cingulate cortices, thalamus, corpus callosum, and frontal sulci. The HIV-only group had smaller thalamic and larger frontal sulcal volumes than control subjects. HIV disease-related factors associated with greater volume abnormalities included CD4 cell count nadir, clinical staging, history of AIDS-defining events, infection age, and current age. Longer sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities in both alcohol groups.Having HIV infection with alcoholism and AIDS had an especially poor outcome on brain structures. That longer periods of sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities encourages the inclusion of alcohol recovery efforts in HIV/AIDS therapeutic settings.

    View details for DOI 10.1016/j.biopsych.2012.02.018

    View details for Web of Science ID 000307308100006

    View details for PubMedID 22458948

  • Fast volumetric imaging of ethanol metabolism in rat liver with hyperpolarized [1-13C]pyruvate NMR IN BIOMEDICINE Josan, S., Spielman, D., Yen, Y., Hurd, R., Pfefferbaum, A., Mayer, D. 2012; 25 (8): 993-999


    Rapid volumetric imaging of hyperpolarized (13) C compounds allows the real-time measurement of metabolic activity and can be useful in distinguishing between normal and diseased tissues. This work extends a fast two-dimensional undersampled spiral MRSI sequence to provide volumetric coverage, acquiring a 16 × 16 × 12 matrix with a nominal isotropic resolution of 5 mm in 4.5 s. The rapid acquisition enables a high temporal resolution for dynamic imaging. This dynamic three-dimensional MRSI method was used to investigate hyperpolarized [1-(13) C]pyruvate metabolism modulated by the administration of ethanol in rat liver. A significant increase in the pyruvate to lactate conversion was observed in the liver as a result of the greater availability of NADH (nicotinamide adenine dinucleotide, reduced form) from ethanol metabolism.

    View details for DOI 10.1002/nbm.2762

    View details for Web of Science ID 000306178400005

    View details for PubMedID 22331837

  • Combining atlas-based parcellation of regional brain data acquired across scanners at 1.5 T and 3.0 T field strengths NEUROIMAGE Pfefferbaum, A., Rohlfing, T., Rosenbloom, M. J., Sullivan, E. V. 2012; 60 (2): 940-951


    Longitudinal brain morphometric studies designed for data acquisition at a single MRI field strength can be seriously limited by system replacements from lower to higher field strength. Merging data across field strengths has not been endorsed for a variety of reasons, yet the ability to combine such data would broaden longitudinal investigations. To determine whether structural T1-weighted MRI data acquired across MR field strengths could be merged, parcellations of archival SPGR data acquired in 114 individuals at 1.5 T and at 3.0 T within 3 weeks of each other were compared. The first set of analyses examined 1) the correspondence between regional tissue volumes derived from data collected at 1.5 T and 3.0 T and 2) whether there were systematic differences for which a correction factor could be determined and applied to improve measurement agreement. Comparability of regional volume determination at 1.5 T and 3.0 T was assessed with intraclass correlation (ICC) computed on volumes derived from the automated and unsupervised SRI24 atlas registration and parcellation method. A second set of analyses measured the reliability of the registration and quantification using the same approach on longitudinal data acquired in 69 healthy adults at a single field strength, 1.5 T, at an interval < 2 years. The mainstay of the analyses was based on the SRI24 method; to examine the potential of merging data across field strengths and across image analysis packages, a secondary set of analyses used FreeSurfer instead of the SRI24 method. For both methods, a regression-based linear correction function significantly improved correspondence. The results indicated high correspondence between most selected cortical, subcortical, and CSF-filled spaces; correspondence was lowest in the globus pallidus, a region rich in iron, which in turn has a considerable field-dependent effect on signal intensity. Thus, the application of a regression-based correction function that improved the correspondence in regional volume estimations argues well for the proposition that selected T1-weighted regional anatomical brain data can be reliably combined across 1.5 T and 3.0 T field strengths with the application of an appropriate correction procedure.

    View details for DOI 10.1016/j.neuroimage.2012.01.092

    View details for Web of Science ID 000303272300012

    View details for PubMedID 22297204

  • A selective insular perfusion deficit contributes to compromised salience network connectivity in recovering alcoholic men. Biological psychiatry Sullivan, E. V., Müller-Oehring, E., Pitel, A., Chanraud, S., Shankaranarayanan, A., Alsop, D. C., Rohlfing, T., Pfefferbaum, A. 2013; 74 (7): 547-555


    BACKGROUND: Alcoholism can disrupt neural synchrony between nodes of intrinsic functional networks that are maximally active when resting relative to engaging in a task, the default mode network (DMN) pattern. Untested, however, are whether the DMN in alcoholics can rebound normally from the relatively depressed task state to the active resting state and whether local perfusion deficits could disrupt network synchrony when switching from conditions of rest to task to rest, thereby indicating a physiological mechanism of neural network adaptation capability. METHODS: Whole-brain, three-dimensional pulsed-continuous arterial spin labeling provided measurements of regional cerebral blood flow (CBF) in 12 alcoholics and 12 control subjects under three conditions: pretask rest, spatial working-memory task, and posttask rest. RESULTS: With practice, alcoholics and control subjects achieved similar task accuracy and reaction times. Both groups exhibited a high-low-high pattern of perfusion levels in DMN regions during the rest-task-rest runs and the opposite pattern in posterior and cerebellar regions known to be associated with spatial working memory. Alcoholics showed selective differences from control subjects in the rest-task-rest CBF pattern in the anterior precuneus and CBF level in the insula, a hub of the salience network. Connectivity analysis identified activation synchrony from an insula seed to salience nodes (parietal, medial frontal, anterior cingulate cortices) in control subjects only. CONCLUSIONS: We propose that attenuated insular CBF is a mechanism underlying compromised connectivity among salience network nodes. This local perfusion deficit in alcoholics has the potential to impair ability to switch from cognitive states of interoceptive cravings to cognitive control for curbing internal urges.

    View details for DOI 10.1016/j.biopsych.2013.02.026

    View details for PubMedID 23587427

  • Midbrain-driven emotion and reward processing in alcoholism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Müller-Oehring, E. M., Jung, Y., SULLIVAN, E. V., Hawkes, W. C., Pfefferbaum, A., Schulte, T. 2013; 38 (10): 1844-1853


    Alcohol dependence is associated with impaired control over emotionally motivated actions, possibly associated with abnormalities in the frontoparietal executive control network and midbrain nodes of the reward network associated with automatic attention. To identify differences in the neural response to alcohol-related word stimuli, 26 chronic alcoholics (ALC) and 26 healthy controls (CTL) performed an alcohol-emotion Stroop Match-to-Sample task during functional MR imaging. Stroop contrasts were modeled for color-word incongruency (eg, word RED printed in green) and for alcohol (eg, BEER), positive (eg, HAPPY) and negative (eg, MAD) emotional word content relative to congruent word conditions (eg, word RED printed in red). During color-Stroop processing, ALC and CTL showed similar left dorsolateral prefrontal activation, and CTL, but not ALC, deactivated posterior cingulate cortex/cuneus. An interaction revealed a dissociation between alcohol-word and color-word Stroop processing: ALC activated midbrain and parahippocampal regions more than CTL when processing alcohol-word relative to color-word conditions. In ALC, the midbrain region was also invoked by negative emotional Stroop words thereby showing significant overlap of this midbrain activation for alcohol-related and negative emotional processing. Enhanced midbrain activation to alcohol-related words suggests neuroadaptation of dopaminergic midbrain systems. We speculate that such tuning is normally associated with behavioral conditioning to optimize responses but here contributed to automatic bias to alcohol-related stimuli.Neuropsychopharmacology advance online publication, 29 May 2013; doi:10.1038/npp.2013.102.

    View details for DOI 10.1038/npp.2013.102

    View details for PubMedID 23615665

  • In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-C-13]pyruvate NMR IN BIOMEDICINE Josan, S., Xu, T., Yen, Y., Hurd, R., Ferreira, J., Chen, C., Mochly-Rosen, D., Pfefferbaum, A., Mayer, D., Spielman, D. 2013; 26 (6): 607-612


    To date, measurements of the activity of aldehyde dehydrogenase-2 (ALDH2), a critical mitochondrial enzyme for the elimination of certain cytotoxic aldehydes in the body and a promising target for drug development, have been largely limited to in vitro methods. Recent advancements in MRS of hyperpolarized (13) C-labeled substrates have provided a method to detect and image in vivo metabolic pathways with signal-to-noise ratio gains greater than 10 000-fold over conventional MRS techniques. However aldehydes, because of their toxicity and short T1 relaxation times, are generally poor targets for such (13) C-labeled studies. In this work, we show that dynamic MRSI of hyperpolarized [1-(13) C]pyruvate and its conversion to [1-(13) C]lactate can provide an indirect in vivo measurement of ALDH2 activity via the concentration of NADH (nicotinamide adenine dinucleotide, reduced form), a co-factor common to both the reduction of pyruvate to lactate and the oxidation of acetaldehyde to acetate. Results from a rat liver ethanol model (n = 9) show that changes in (13) C-lactate labeling following the bolus injection of hyperpolarized pyruvate are highly correlated with changes in ALDH2 activity (R(2)  = 0.76). Copyright © 2012 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.2897

    View details for Web of Science ID 000318231700002

    View details for PubMedID 23225495

  • Modulation of limbic-cerebellar functional connectivity enables alcoholics to recognize who is who BRAIN STRUCTURE & FUNCTION Pitel, A., Chanraud, S., Mueller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2013; 218 (3): 683-695


    Chronic alcoholism is known to disrupt functions served by distributed brain systems, including limbic and frontocerebellar circuits involved in resting-state and task-activated networks subserving component processes of memory often affected in alcoholics. Using an fMRI paradigm, we investigated whether memory performance by alcoholics on a face-name association test previously observed to be problematic for alcoholics could be explained by desynchronous activity between nodes of these specific networks. While in the scanner, 18 alcoholics and 15 controls performed a face-name associative learning task with different levels of processing at encoding. This task was designed to activate the hippocampus, cerebellum, and frontal cortex. Alcoholics and controls were also scanned at rest. Twelve alcoholics and 12 controls were selected to be matched on face-name recognition performance. Task-related fMRI analysis indicated that alcoholics had preserved limbic activation but lower cerebellar activation (Crus II) than the controls in the face-name learning task. Crus II was, therefore, chosen as a seed for functional connectivity MRI analysis. At rest, the left hippocampus and left Crus II had positively synchronized activity in controls, while hippocampal and cerebellar activities were negatively synchronized in alcoholics. Task engagement resulted in hippocampal-cerebellar desynchronization in both groups. We speculate that atypical cerebello-hippocampal activity synchronization during rest in alcoholics was reset to the normal pattern of asynchrony by task engagement. Aberrations from the normal pattern of resting-state default mode synchrony could be interpreted as enabling preserved face-name associative memory in alcoholism.

    View details for DOI 10.1007/s00429-012-0421-6

    View details for Web of Science ID 000318310600005

  • Quantification of glutamate and glutamine using constant-time point-resolved spectroscopy at 3 T NMR IN BIOMEDICINE Gu, M., Zahr, N. M., Spielman, D. M., Sullivan, E. V., Pfefferbaum, A., Mayer, D. 2013; 26 (2): 164-172


    Separate quantification of glutamate (Glu) and glutamine (Gln) using conventional MRS on clinical scanners is challenging. In previous work, constant-time point-resolved spectroscopy (CT-PRESS) was optimized at 3 T to detect Glu, but did not resolve Gln. To quantify Glu and Gln, a time-domain basis set was constructed taking into account metabolite T(2) relaxation times and dephasing from B(0) inhomogeneity. Metabolite concentrations were estimated by fitting the basis one-dimensional CT-PRESS diagonal magnitude spectra to the measured spectrum. This method was first validated using seven custom-built phantoms containing variable metabolite concentrations, and then applied to in vivo data acquired in rats exposed to vaporized ethanol and controls. Separate metabolite quantification revealed increased Gln after 16 weeks and increased Glu after 24 weeks of vaporized ethanol exposure in ethanol-treated compared with control rats. Without separate quantification, the signal from the combined resonances of Glu and Gln (Glx) showed an increase at both 16 and 24 weeks in ethanol-exposed rats, precluding the determination of the independent and differential contribution of each metabolite at each time.

    View details for DOI 10.1002/nbm.2831

    View details for Web of Science ID 000313886500007

  • Remapping the Brain to Compensate for Impairment in Recovering Alcoholics CEREBRAL CORTEX Chanraud, S., Pitel, A., Mueller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2013; 23 (1): 97-104


    Abnormal brain activity may reflect compensation when observed in patients who perform normally on tests requiring functions usually observed as impaired. Operational criteria defining compensation have been described and aid in distinguishing compensatory from chance events. Here, we tested whether previously published functional magnetic resonance imaging data acquired in 15 recovering alcoholics and 15 controls at rest and while performing a spatial working memory task would fulfill criteria defining functional compensation. Multivariate analysis tested how well abnormal activation in the affected group predicted normal performance, despite low or no activation in brain regions invoked by controls to accomplish the same task. By identifying networks that uniquely and positively correlated with good performance, we provide evidence for compensatory recruitment of cerebellar-based functional networks by alcoholics. Whereas controls recruited prefrontal-cerebellar regions VI/Crus I known to subserve working memory, alcoholics recruited 2 other parallel frontocerebellar loops: dorsolateral prefrontal cortex (DLPFC)-cerebellar VIII system during rest and DLPFC-cerebellar VI system while task engaged. Greater synchronous activity between cerebellar lobule VIII and DLPFC at rest and greater activation within cerebellar lobule VI and DLPFC during task predicted better working memory performance. Thus, higher intrinsic cerebellar activity in alcoholics was an adequate condition for triggering task-relevant activity in the frontal cortex required for normal working memory performance.

    View details for DOI 10.1093/cercor/bhr381

    View details for Web of Science ID 000312106300010

  • Differential Effect of Alcoholism and HIV Infection on Visuomotor Procedural Learning and Retention ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Rosenbloom, M. J., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2012; 36 (10): 1738-1747


    Selective declarative memory processes are differentially compromised in chronic alcoholism (ALC) and HIV infection (HIV) and likely reflect neuropathology associated with each condition: frontocerebellar dysfunction in ALC and frontostriatal dysfunction in HIV infection. Evidence for disease overlap derives from observed exacerbated impairments in these declarative memory processes in ALC-HIV comorbidity. Less is known about nondeclarative memory processes in these disease conditions. Examination of visuomotor learning in chronic ALC and HIV infection could provide insight into the differential and combined contribution of selective disease-related injury to visuomotor procedural memory processes.We examined component processes of visuomotor learning and retention on the rotary pursuit task in 29 ALC, 23 HIV, 28 ALC + HIV, and 20 control subjects. Participants were given 4 rotary pursuit learning sessions over 2 testing days, typically separated by 1 week, to assess visuomotor learning and retention patterns. Ancillary measures of simple motor, psychomotor, explicit memory, and balance abilities were administered to test which component processes independently predicted visuomotor learning.All clinical groups showed visuomotor learning across rotary pursuit testing sessions, despite impairment in visuomotor speed in the HIV groups and impairment in explicit memory and psychomotor speed in the alcohol groups. The 2 alcoholic groups showed retention and consolidation over time (i.e., improved performance without further training), whereas the HIV-infected group showed learning and retention but no consolidation effect. The comorbid group shared impairments associated with the ALC-only group (explicit memory and psychomotor speed) and the HIV-only group (visuomotor speed), although there was no clear compounded effect of alcohol and HIV infection on visuomotor learning performance.This study supports the hypothesis that ALC and HIV infection exert differential effects on components of visuomotor procedural learning. Further, the results provide behavioral evidence for dissociable influences of frontocerebellar and frontostriatal disruption to visuomotor procedural learning and retention.

    View details for DOI 10.1111/j.1530-0277.2012.01790.x

    View details for Web of Science ID 000309390800009

    View details for PubMedID 22823125

  • Face-Name Association Learning and Brain Structural Substrates in Alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pitel, A., Chanraud, S., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2012; 36 (7): 1171-1179


    Associative learning is required for face-name association and is impaired in alcoholism, but the cognitive processes and brain structural components underlying this deficit remain unclear. It is also unknown whether prompting alcoholics to implement a deep level of processing during face-name encoding would enhance performance.Abstinent alcoholics and controls performed a levels-of-processing face-name learning task. Participants indicated whether the face was that of an honest person (deep encoding) or that of a man (shallow encoding). Retrieval was examined using an associative (face-name) recognition task and a single-item (face or name only) recognition task. Participants also underwent 3T structural MRI.Compared with controls, alcoholics had poorer associative and single-item learning and performed at similar levels. Level of processing at encoding had little effect on recognition performance but affected reaction time (RT). Correlations with brain volumes were generally modest and based primarily on RT in alcoholics, where the deeper the processing at encoding, the more restricted the correlations with brain volumes. In alcoholics, longer control task RTs correlated modestly with smaller tissue volumes across several anterior to posterior brain regions; shallow encoding correlated with calcarine and striatal volumes; deep encoding correlated with precuneus and parietal volumes; and associative recognition RT correlated with cerebellar volumes. In controls, poorer associative recognition with deep encoding correlated significantly with smaller volumes of frontal and striatal structures.Despite prompting, alcoholics did not take advantage of encoding memoranda at a deep level to enhance face-name recognition accuracy. Nonetheless, conditions of deeper encoding resulted in faster RTs and more specific relations with regional brain volumes than did shallow encoding. The normal relation between associative recognition and corticostriatal volumes was not present in alcoholics. Rather, their speeded RTs occurred at the expense of accuracy and were related most robustly to cerebellar volumes.

    View details for DOI 10.1111/j.1530-0277.2011.01731.x

    View details for Web of Science ID 000306219400009

    View details for PubMedID 22509954

  • Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic C-13 MRSI NMR IN BIOMEDICINE Xu, T., Mayer, D., Gu, M., Yen, Y., Josan, S., Tropp, J., Pfefferbaum, A., Hurd, R., Spielman, D. 2011; 24 (8): 997-1005


    With signal-to-noise ratio enhancements on the order of 10,000-fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1-(13)C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1-(13)C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time-to-peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small-flip-angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral-based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo (13)C labeling of lactate and alanine after a bolus injection of [1-(13)C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis-Menten-like formulation, with the resulting estimated apparent maximal reaction velocity V(max) and apparent Michaelis constant K(M) being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis-Menten kinetics, it is conceptually different. In this study, we focus on the (13)C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process.

    View details for DOI 10.1002/nbm.1719

    View details for Web of Science ID 000295293900009

    View details for PubMedID 21538639

  • Disruption of Functional Connectivity of the Default-Mode Network in Alcoholism CEREBRAL CORTEX Chanraud, S., Pitel, A., Pfefferbaum, A., Sullivan, E. V. 2011; 21 (10): 2272-2281


    The default mode network (DMN) comprises brain structures maximally active at rest. Disturbance of network nodes or their connections occurs with some neuropsychiatric conditions and may underlie associated dysfunction. DMN connectivity has not been examined in alcoholism, which is marked by compromised DMN nodes and impaired spatial working memory. To test whether performance would be related to DMN integrity, we examined DMN functional connectivity using functional magnetic resonance imaging (fMRI) data and graph theory analysis. We assumed that disruption of short paths between network nodes would attenuate processing efficiency. Alcoholics and controls were scanned at rest and during a spatial working memory task. At rest, the spontaneous slow fluctuations of fMRI signals in the posterior cingulate and cerebellar regions in alcoholics were less synchronized than in controls, indicative of compromised functional connectivity. Graph theory analysis indicated that during rest, alcoholics had significantly lower efficiency indices than controls between the posterior cingulate seed and multiple cerebellar sites. Greater efficiency in several connections correlated with longer sobriety in alcoholics. During the task, on which alcoholics performed on par with controls, connectivity between the left posterior cingulate seed and left cerebellar regions was more robust in alcoholics than controls and suggests compensatory networking to achieve normal performance.

    View details for DOI 10.1093/cercor/bhq297

    View details for Web of Science ID 000294808800007

    View details for PubMedID 21368086

  • Ethanol-induced changes in the expression of proteins related to neurotransmission and metabolism in different regions of the rat brain PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR Zahr, N. M., Bell, R. L., Ringham, H. N., Sullivan, E. V., Witzmann, F. A., Pfefferbaum, A. 2011; 99 (3): 428-436


    Despite extensive description of the damaging effects of chronic alcohol exposure on brain structure, mechanistic explanations for the observed changes are just emerging. To investigate regional brain changes in protein expression levels following chronic ethanol treatment, one rat per sibling pair of male Wistar rats was exposed to intermittent (14 h/day) vaporized ethanol, the other to air for 26 weeks. At the end of 24 weeks of vapor exposure, the ethanol group had blood ethanol levels averaging 450 mg%, had not experienced a protracted (> 16 h) withdrawal from ethanol, and revealed only mild evidence of hepatic steatosis. Extracted brains were micro-dissected to isolate the prefrontal cortex (PFC), dorsal striatum (STR), corpus callosum genu (CCg), CC body (CCb), anterior vermis (AV), and anterior dorsal lateral cerebellum (ADLC) for protein analysis with two-dimensional gel electrophoresis. Expression levels for 54 protein spots were significantly different between the ethanol- and air-treated groups. Of these 54 proteins, tandem mass spectroscopy successfully identified 39 unique proteins, the levels of which were modified by ethanol treatment: 13 in the PFC, 7 in the STR, 2 in the CCg, 7 in the CCb, 7 in the AV, and 5 in the ADLC. The functions of the proteins altered by chronic ethanol exposure were predominantly associated with neurotransmitter systems in the PFC and cell metabolism in the STR. Stress response proteins were elevated only in the PFC, AV, and ADLC perhaps supporting a role for frontocerebellar circuitry disruption in alcoholism. Of the remaining proteins, some had functions associated with cytoskeletal physiology (e.g., in the CCb) and others with transcription/translation (e.g., in the ADLC). Considered collectively, all but 4 of the 39 proteins identified in the present study have been previously identified in ethanol gene- and/or protein-expression studies lending support for their role in ethanol-related brain alterations.

    View details for DOI 10.1016/j.pbb.2011.03.002

    View details for Web of Science ID 000293371100020

    View details for PubMedID 21397625

  • Developmental change in regional brain structure over 7 months in early adolescence: Comparison of approaches for longitudinal atlas-based parcellation NEUROIMAGE Sullivan, E. V., Pfefferbaum, A., Rohlfing, T., Baker, F. C., Padilla, M. L., Colrain, I. M. 2011; 57 (1): 214-224


    Early adolescence is a time of rapid change in neuroanatomy and sexual development. Precision in tracking changes in brain morphology with structural MRI requires image segmentation with minimal error. Here, we compared two approaches to achieve segmentation by image registration with an atlas to quantify regional brain structural development over a 7-month interval in normal, early adolescent boys and girls. Adolescents were scanned twice (average interval=7.3 months), yielding adequate data for analysis in 16 boys (baseline age 10.9 to 13.9 years; Tanner Stage=1 to 4) and 12 girls (baseline age=11.2 to 13.7 years; Tanner Stage=3 to 4). Brain volumes were derived from T1-weighted (SPGR) images and dual-echo Fast Spin-Echo (FSE) images collected on a GE 3T scanner with an 8-channel phased-array head coil and analyzed by registration-based parcellation using the SRI24 atlas. The "independent" method required two inter-subject registrations: both baseline (MRI 1) to atlas and follow-up (MRI 2) to the atlas. The "sequential" method required one inter-subject registration, which was MRI 1 to the atlas, and one intra-subject registration, which was MRI 2 to MRI 1. Gray matter/white matter/CSF were segmented in both MRI-1 and MRI-2 using FSL FAST with tissue priors also based on the SRI24 atlas. Gray matter volumes were derived for 10 cortical regions, gray+white matter volumes for 5 subcortical structures, and CSF volumes for 4 ventricular regions and the cortical sulci. Across the 15 tissue regions, the coefficient of variation (CV) of change scores across individuals was significantly lower for the sequential method (CV=3.02), requiring only one inter-subject registration, than for the independent method (CV=9.43), requiring two inter-subject registrations. Volume change based on the sequential method revealed that total supratentorial and CSF volumes increased, while cortical gray matter volumes declined significantly (p<0.01) in anterior (lateral and medial frontal, anterior cingulate, precuneus, and parietal) but not posterior (occipital, calcarine) cortical regions. These volume changes occurred in all boys and girls who advanced a step in Tanner staging. Subcortical structures did not show consistent changes. Thus, longitudinal MRI assessment using robust registration methods is sufficiently sensitive to identify significant regional brain changes over a 7-month interval in boys and girls in early adolescence. Increasing the temporal resolution of the retest interval in longitudinal developmental studies could increase accuracy in timing of peak growth of regional brain tissue and refine our understanding of the neural mechanisms underlying the dynamic changes in brain structure throughout adolescence.

    View details for DOI 10.1016/j.neuroimage.2011.04.003

    View details for Web of Science ID 000291624100025

    View details for PubMedID 21511039

  • In vivo MRSI of hyperpolarized [1-C-13]pyruvate metabolism in rat hepatocellular carcinoma NMR IN BIOMEDICINE Darpolor, M. M., Yen, Y., Chua, M., Xing, L., Clarke-Katzenberg, R. H., Shi, W., Mayer, D., Josan, S., Hurd, R. E., Pfefferbaum, A., Senadheera, L., So, S., Hofmann, L. V., Glazer, G. M., Spielman, D. M. 2011; 24 (5): 506-513


    Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1-(13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1-(13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n?=?7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors.

    View details for DOI 10.1002/nbm.1616

    View details for Web of Science ID 000291597200009

    View details for PubMedID 21674652

  • Dynamic and High-Resolution Metabolic Imaging of Hyperpolarized [1-C-13]-Pyruvate in the Rat Brain Using a High-Performance Gradient Insert MAGNETIC RESONANCE IN MEDICINE Mayer, D., Yen, Y., Takahashi, A., Josan, S., Tropp, J., Rutt, B. K., Hurd, R. E., Spielman, D. M., Pfefferbaum, A. 2011; 65 (5): 1228-1233


    Fast chemical shift imaging (CSI) techniques are advantageous in metabolic imaging of hyperpolarized compounds due to the limited duration of the signal amplification. At the same time, reducing the acquisition time in hyperpolarized imaging does not necessarily lead to the conventional penalty in signal-to-noise ratio that occurs in imaging at thermal equilibrium polarization levels. Here a high-performance gradient insert was used in combination with undersampled spiral CSI to increase either the imaging speed or the spatial resolution of hyperpolarized (13)C metabolic imaging on a clinical 3T MR scanner. Both a single-shot sequence with a total acquisition time of 125 ms and a three-shot sequence with a nominal in-plane resolution of 1.5 mm were implemented. The k-space trajectories were measured and then used during image reconstruction. The technique was applied to metabolic imaging of the rat brain in vivo after the injection of hyperpolarized [1-(13)C]-pyruvate. Dynamic imaging afforded the measurement of region-of-interest-specific time courses of pyruvate and its metabolic products, while imaging at high spatial resolution was used to better characterize the spatial distribution of the metabolite signals.

    View details for DOI 10.1002/mrm.22707

    View details for Web of Science ID 000289760800003

    View details for PubMedID 21500253

  • Application of double spin echo spiral chemical shift imaging to rapid metabolic mapping of hyperpolarized [1-C-13]-pyruvate JOURNAL OF MAGNETIC RESONANCE Josan, S., Yen, Y., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2011; 209 (2): 332-336


    Undersampled spiral CSI (spCSI) using a free induction decay (FID) acquisition allows sub-second metabolic imaging of hyperpolarized ¹³C. Phase correction of the FID acquisition can be difficult, especially with contributions from aliased out-of-phase peaks. This work extends the spCSI sequence by incorporating double spin echo radiofrequency (RF) pulses to eliminate the need for phase correction and obtain high quality spectra in magnitude mode. The sequence also provides an added benefit of attenuating signal from flowing spins, which can otherwise contaminate signal in the organ of interest. The refocusing pulses can potentially lead to a loss of hyperpolarized magnetization in dynamic imaging due to flow of spins through the fringe field of the RF coil, where the refocusing pulses fail to provide complete refocusing. Care must be taken for dynamic imaging to ensure that the spins remain within the B?-homogeneous sensitive volume of the RF coil.

    View details for DOI 10.1016/j.jmr.2011.01.010

    View details for Web of Science ID 000289270900030

    View details for PubMedID 21316280

  • Pontocerebellar contribution to postural instability and psychomotor slowing in HIV infection without dementia BRAIN IMAGING AND BEHAVIOR Sullivan, E. V., Rosenbloom, M. J., Rohlfing, T., Kemper, C. A., Deresinski, S., Pfefferbaum, A. 2011; 5 (1): 12-24


    Postural instability occurs in HIV infection, but quantitative balance tests in conjunction with neuroimaging are lacking. We examined whether infratentorial brain tissue volume would be deficient in nondemented HIV-infected individuals and whether selective tissue deficits would be related to postural stability and psychomotor speed performance. The 123 participants included 28 men and 12 women with HIV infection without dementia or alcohol use disorders, and 40 men and 43 women without medical or psychiatric conditions. Participants completed quantitative balance testing, Digit Symbol test, and a test of finger movement speed and dexterity. An infratentorial brain region, supratentorial ventricular system, and corpus callosum were quantified with MRI-derived atlas-based parcellation, and together with archival DTI-derived fiber tracking of pontocerebellar and internal and external capsule fiber systems, brain measures were correlated with test performance. The tissue ratio of the infratentorium was ~3% smaller in the HIV than control group. The HIV group exhibited performance deficits in balancing on one foot, walking toe-to-heel, Digit Symbol substitution task, and time to complete all Digit Symbol grid boxes. Total infratentorial tissue ratio was a significant predictor of balance and Digit Symbol scores. Balance scores did not correlate significantly with ventricular volumes, callosal size, or internal or external capsule fiber integrity but did so with indices of pontocerebellar tract integrity. HIV-infected individuals specifically recruited to be without complications from alcohol use disorders had pontocerebellar tissue volume deficits with functional ramifications. Postural stability and psychomotor speed were impaired and attributable, at least in part, to compromised infratentorial brain systems.

    View details for DOI 10.1007/s11682-010-9107-y

    View details for Web of Science ID 000286464700002

    View details for PubMedID 20872291

  • Remote Semantic Memory for Public Figures in HIV Infection, Alcoholism, and Their Comorbidity ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Rosenbloom, M. J., Sassoon, S. A., Thompson, M. A., Pfefferbaum, A., Sullivan, E. V. 2011; 35 (2): 265-276


    Impairments in component processes of working and episodic memory mark both HIV infection and chronic alcoholism, with compounded deficits often observed in individuals comorbid for these conditions. Remote semantic memory processes, however, have only seldom been studied in these diagnostic groups. Examination of remote semantic memory could provide insight into the underlying processes associated with storage and retrieval of learned information over extended time periods while elucidating spared and impaired cognitive functions in these clinical groups.We examined component processes of remote semantic memory in HIV infection and chronic alcoholism in 4 subject groups (HIV, ALC, HIV + ALC, and age-matched healthy adults) using a modified version of the Presidents Test. Free recall, recognition, and sequencing of presidential candidates and election dates were assessed. In addition, component processes of working, episodic, and semantic memory were assessed with ancillary cognitive tests.The comorbid group (HIV + ALC) was significantly impaired on sequencing of remote semantic information compared with age-matched healthy adults. Free recall of remote semantic information was also modestly impaired in the HIV + ALC group, but normal performance for recognition of this information was observed. Few differences were observed between the single diagnosis groups (HIV, ALC) and healthy adults, although examination of the component processes underlying remote semantic memory scores elicited differences between the HIV and ALC groups. Selective remote memory processes were related to lifetime alcohol consumption in the ALC group and to viral load and depression level in the HIV group. Hepatitis C diagnosis was associated with lower remote semantic memory scores in all 3 clinical groups. Education level did not account for group differences reported.This study provides behavioral support for the existence of adverse effects associated with the comorbidity of HIV infection and chronic alcoholism on selective component processes of memory function, with untoward effects exacerbated by Hepatitis C infection. The pattern of remote semantic memory function in HIV + ALC is consistent with those observed in neurological conditions primarily affecting frontostriatal pathways and suggests that remote memory dysfunction in HIV + ALC may be a result of impaired retrieval processes rather than loss of remote semantic information per se.

    View details for DOI 10.1111/j.1530-0277.2010.01342.x

    View details for Web of Science ID 000286510000010

    View details for PubMedID 21121935

  • Signs of Preclinical Wernicke's Encephalopathy and Thiamine Levels as Predictors of Neuropsychological Deficits in Alcoholism without Korsakoff's Syndrome NEUROPSYCHOPHARMACOLOGY Pitel, A., Zahr, N. M., Jackson, K., Sassoon, S. A., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2011; 36 (3): 580-588


    The purpose of this study was to determine whether meeting historical criteria for unsuspected Wernicke's encephalopathy (WE), largely under-diagnosed in vivo, explains why some alcoholics have severe neuropsychological deficits, whereas others, with a similar drinking history, exhibit preserved performance. Demographic, clinical, alcohol related, and neuropsychological measures were collected in 56 abstinent alcoholics and 38 non-alcohol-dependent volunteers. Alcoholics were classified using the clinical criteria established by Caine et al (1997) and validated in their neuropathological study of alcoholic cases. Our alcoholics who met a single criterion were considered 'at risk for WE' and those with two or more criteria with 'signs of WE'. Whole blood thiamine was also measured in 22 of the comparison group and 28 alcoholics. Of the alcoholics examined, 27% met no criteria, 57% were at risk for WE, and 16% had signs of WE. Neuropsychological performance of the alcoholic subgroups was graded, with those meeting zero criteria not differing from controls, those meeting one criterion presenting mild-to-moderate deficits on some of the functional domains, and those meeting two or more criteria having the most severe deficits on each of the domains examined. Thiamine levels were selectively related to memory performance in the alcoholics. Preclinical signs of WE can be diagnosed in vivo, enabling the identification of ostensibly 'uncomplicated' alcoholics who are at risk for neuropsychological complications. The graded effects in neuropsychological performance suggest that the presence of signs of WE explains, at least partially, the heterogeneity of alcoholism-related cognitive and motor deficits.

    View details for DOI 10.1038/npp.2010.189

    View details for Web of Science ID 000286176700004

    View details for PubMedID 20962766

  • Fiber tracking functionally distinct components of the internal capsule NEUROPSYCHOLOGIA Sullivan, E. V., Zahr, N. M., Rohlfing, T., Pfefferbaum, A. 2010; 48 (14): 4155-4163


    The internal capsule conveys information from primary and supplementary motor areas, frontopontine and thalamic peduncles to brain stem and cerebellar regions, and from thalamus to prefrontal cortex. Neurological accidents involving the internal capsule indicate differential functional correlates with its sectors. To examine the microstructural condition of this fiber system and to test functional correlates of its sectors in health and aging, 12 younger and 12 older adults were examined with diffusion tensor imaging (DTI) fiber tracking and neuropsychological tests. Greater age-related degradation was evident in the anterior than posterior limb and in the superior than inferior division of the internal capsule. The superior division age effect was especially notable in axial and radial diffusivity. Fractional anisotropy (FA) across the three (anterior, genu, posterior) fiber bundles of the inferior division accounted for 27-73% of the variance for each neuropsychological domain. Identification of a triple dissociation indicated selective correlations between anterior FA and set shifting, genu FA and motor skills, and posterior FA and fluency. Quantitative fiber tracking combined with assessment of cognitive and motor functions enabled the identification of selective brain structure-function relations in healthy adults without lesions that were previously observed only in patients with lesions of the internal capsule.

    View details for DOI 10.1016/j.neuropsychologia.2010.10.023

    View details for Web of Science ID 000285668200019

    View details for PubMedID 20974161

  • Measurement of Serum, Liver, and Brain Cytokine Induction, Thiamine Levels, and Hepatopathology in Rats Exposed to a 4-Day Alcohol Binge Protocol ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Zahr, N. M., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2010; 34 (11): 1858-1870


    ?In rodent and human studies, ethanol (EtOH) exposure is associated with elevated brain levels of the magnetic resonance spectroscopy (MRS) signal representing choline-containing compounds (Cho). One interpretation of elevated brain Cho is that it is a marker of neuroinflammation, and some evidence suggests that EtOH exposure promotes neuroinflammation. This study aimed to determine whether binge EtOH exposure (intragastric 3 g/kg 25% EtOH every 8 hours for 4 days) would induce the expression of certain cytokines in blood, liver, or brain, thereby supporting the neuroinflammation hypothesis of elevated Cho.Ten of 18 wild-type male Wistar rats (~322 g at baseline) were exposed to EtOH and attained average blood alcohol levels of ~315 mg/dl across 4 days. Blood for cytokine immunoassays was collected at baseline, after 5 doses of EtOH (binge), and immediately preceding euthanasia either 4 or 24 hours after the last dose of EtOH. Blood was additionally assayed for the levels of thiamine and liver enzymes; liver histopathology was performed postmortem; and tissue from liver and 6 brain regions was assayed for the potential induction of 7 cytokines.There were no group effects on the levels of thiamine or its phosphate derivatives, thiamine monophosphate or thiamine diphosphate. ANOVAs of liver enzyme levels indicated that only alkaline phosphatase (ALP) levels were higher in the EtOH group than in control group at binge; ALP elevations, however, are difficult to explain in the absence of changes in the levels of additional liver enzymes. Postmortem liver pathology provided evidence for minimal microvesicular lipidosis and portocentric fibrosis in the EtOH group. Group effects on the levels of the measured cytokines in the blood (TNF-?, IFN-?, IL-1?, IL-4, IL-5, IL-13, and GRO/CXCL1) were not significant. Similarly, postmortem evaluation of liver cytokines did not reveal group effects. Postmortem evaluation of the 7 cytokines in 6 brain regions (anterior cerebellar vermis, cingulate cortex, frontal cortex, hippocampus, hypothalamus, striatum) also failed to identify group effects.A single 4-day bout of binge EtOH exposure alone was insufficient to induce the expression of 7 cytokines in blood, liver, or 6 brain regions of wild-type Wistar rats. Alternative interpretations for elevations in brain Cho in response to a 4-day binge EtOH treatment are therefore necessary and may include induction of cytokines not measured herein or other noninflammatory mechanisms.

    View details for DOI 10.1111/j.1530-0277.2010.01274.x

    View details for Web of Science ID 000283594000005

    View details for PubMedID 20662804

  • Callosal microstructural abnormalities in Alzheimer's disease and alcoholism: same phenotype, different mechanisms PSYCHIATRY RESEARCH-NEUROIMAGING Pitel, A., Chanraud, S., Sullivan, E. V., Pfefferbaum, A. 2010; 184 (1): 49-56


    Magnetic resonance (MRI) and diffusion tensor imaging (DTI) data were acquired in 13 Alzheimer's disease (AD) patients, 15 elderly alcoholics, and 32 elderly controls. Midsagittal area, length, dorsoventral height, fractional anisotropy (FA), and mean diffusivity (MD) of the total corpus callosum and volume of the lateral ventricles were measured; area, FA, and MD were also determined for the callosal genu, body, and splenium. On DTI, both patient groups had lower FA and higher MD than controls in all callosal regions. On MRI, both patient groups had smaller genu than controls; additional size deficits were present in the alcoholism group's callosal body and the AD group's splenium. The callosal arch was higher in the AD but not the alcoholic group compared with controls. The two patient groups had larger ventricles than controls, and the AD group had larger ventricles than the alcoholic group. Callosal area correlated with its height, and callosal FA and MD correlated with ventricular volume in AD, whereas callosal area correlated only with FA in alcoholics. In AD, the disruption of the callosal integrity, which was associated with distorted callosal shape, was related to ventricular dilation, which has been shown in twin studies to be under a multitude of genetic, polygenetic, and environmental influences. Conversely, in alcoholism, disruption of callosal microstructural integrity was related to shrinkage of the corpus callosum itself.

    View details for DOI 10.1016/j.pscychresns.2010.07.006

    View details for Web of Science ID 000283406100007

    View details for PubMedID 20832253

  • White Matter Fiber Degradation Attenuates Hemispheric Asymmetry When Integrating Visuomotor Information JOURNAL OF NEUROSCIENCE Schulte, T., Mueller-Oehring, E. M., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2010; 30 (36): 12168-12178


    Degradation of white matter fibers can affect the transmission of signals in brain circuits that normally enable integration of highly lateralized visual and motor processes. Here, we used diffusion tensor imaging tractography in combination with functional magnetic resonance imaging to examine the specific contributions of interhemispheric and intrahemispheric white matter fibers to functional measures of hemispheric transfer and parallel information processing using bilateral and unilateral left and right visual field stimulation in normal and compromised systems. In healthy adults, a greater degree of bilateral processing advantage with the left (nondominant) hand correlated with higher integrity of callosal fibers connecting occipital cortices, whereas less unilateral processing advantage with the right hand correlated with higher integrity of left-hemispheric posterior cingulate fibers. In contrast, alcoholics who have compromised callosal integrity showed less bilateral processing advantage than controls when responding with the left hand and greater unilateral processing advantage when responding with the right hand. We also found degraded left posterior cingulate and posterior callosal fibers in chronic alcoholics, which is consistent with functional imaging results of less left posterior cingulate and extrastriate cortex activation in alcoholics than controls when processing bilateral compared with unilateral visual field stimulation. Together, our results demonstrated that interhemispheric and intrahemispheric white matter fiber pathways mediate visuomotor integration asymmetrically and that subtle white matter fiber degradation in alcoholism attenuated the normal pattern of hemispheric asymmetry, which may have ramifications for the efficiency of visual information processing and fast response execution.

    View details for DOI 10.1523/JNEUROSCI.2160-10.2010

    View details for Web of Science ID 000281768000028

    View details for PubMedID 20826679

  • Dual Tasking and Working Memory in Alcoholism: Relation to Frontocerebellar Circuitry NEUROPSYCHOPHARMACOLOGY Chanraud, S., Pitel, A., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2010; 35 (9): 1868-1878


    Controversy exists regarding the role of cerebellar systems in cognition and whether working memory compromise commonly marking alcoholism can be explained by compromise of nodes of corticocerebellar circuitry. We tested 17 alcoholics and 31 age-matched controls with dual-task, working memory paradigms. Interference tasks competed with verbal and spatial working memory tasks using low (three item) or high (six item) memory loads. Participants also underwent structural MRI to obtain volumes of nodes of the frontocerebellar system. On the verbal working memory task, both groups performed equally. On the spatial working memory with the high-load task, the alcoholic group was disproportionately more affected by the arithmetic distractor than were controls. In alcoholics, volumes of the left thalamus and left cerebellar Crus I volumes were more robust predictors of performance in the spatial working memory task with the arithmetic distractor than the left frontal superior cortex. In controls, volumes of the right middle frontal gyrus and right cerebellar Crus I were independent predictors over the left cerebellar Crus I, left thalamus, right superior parietal cortex, or left middle frontal gyrus of spatial working memory performance with tracking interference. The brain-behavior correlations suggest that alcoholics and controls relied on the integrity of certain nodes of corticocerebellar systems to perform these verbal and spatial working memory tasks, but that the specific pattern of relationships differed by group. The resulting brain structure-function patterns provide correlational support that components of this corticocerebellar system not typically related to normal performance in dual-task conditions may be available to augment otherwise dampened performance by alcoholics.

    View details for DOI 10.1038/npp.2010.56

    View details for Web of Science ID 000279924400005

    View details for PubMedID 20410871

  • Transcallosal White Matter Degradation Detected With Quantitative Fiber Tracking in Alcoholic Men and Women: Selective Relations to Dissociable Functions ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Rosenbloom, M. J., Fama, R., Sassoon, S. A., Sullivan, E. V. 2010; 34 (7): 1201-1211


    Excessive alcohol consumption can adversely affect white matter fibers and disrupt transmission of neuronal signals. Here, we examined six anatomically defined transcallosal white matter fiber bundles and asked whether any bundle was specifically vulnerable to alcohol, what aspect of white matter integrity was most affected, whether women were more vulnerable than men, and whether evidence of compromise in specific bundles was associated with deficits in balance, sustained attention, associative learning, and psychomotor function, commonly affected in alcoholics.Diffusion tensor imaging quantitative fiber tracking assessed integrity of six transcallosal white matter bundles in 87 alcoholics (59 men, 28 women) and 88 healthy controls (42 men, 46 women). Measures included orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, quantified separately for axial (longitudinal; lambdaL) and radial (transverse; lambdaT) diffusivity. The Digit Symbol Test and a test of ataxia were also administered.Alcoholism negatively affected callosal FA and lambdaT of all but the sensory-motor bundle. Women showed no evidence for greater vulnerability to alcohol than men. Multiple regression analyses confirmed a double dissociation: higher diffusivity in sensory-motor and parietal bundles was associated with poorer balance but not psychomotor speed, whereas higher diffusivity in prefrontal and temporal bundles was associated with slower psychomotor speed but not balance.This study revealed stronger alcohol effects for FA and radial diffusivity than axial diffusivity, suggesting myelin degradation, but no evidence for greater vulnerability to alcohol in women than men. The presence of brain-behavior relationships provides support for the role of alcoholism-related commissural white matter degradation as a substrate of cognitive and motor impairment. Identification of a double dissociation provides further support for the role of selective white matter integrity in specific domains of performance.

    View details for DOI 10.1111/j.1530-0277.2010.01197.x

    View details for Web of Science ID 000279122600009

    View details for PubMedID 20477772

  • Volumetric cerebral perfusion imaging in healthy adults: Regional distribution, laterality, and repeatability of pulsed continuous arterial spin labeling (PCASL) PSYCHIATRY RESEARCH-NEUROIMAGING Pfefferbaum, A., Chanraud, S., Pitel, A., Shankaranarayanan, A., Alsop, D. C., Rohlfing, T., Sullivan, E. V. 2010; 182 (3): 266-273


    The regional distribution, laterality, and reliability of volumetric pulsed continuous arterial spin labeling (PCASL) measurements of cerebral blood flow (CBF) in cortical, subcortical, and cerebellar regions were determined in 10 normal volunteers studied on two occasions separated by 3 to 7 days. Regional CBF, normalized for global perfusion, was highly reliable when measured on separate days. Several regions showed significant lateral asymmetry; notably, in frontal regions CBF was greater in the right than left hemisphere, whereas left was greater than right in posterior regions. There was considerable regional variability across the brain, whereby the posterior cingulate and central and posterior precuneus cortices had the highest perfusion and the globus pallidus the lowest gray matter perfusion. The latter may be due to iron-induced T1 shortening affecting labeled spins and computed CBF signal. High CBF in the posterior cingulate and posterior and central precuneus cortices in this task-free acquisition suggests high activity in these principal nodes of the "default mode network."

    View details for DOI 10.1016/j.pscychresns.2010.02.010

    View details for Web of Science ID 000279521300012

    View details for PubMedID 20488671

  • In vivo application of sub-second spiral chemical shift imaging (CSI) to hyperpolarized C-13 metabolic imaging: Comparison with phase-encoded CSI JOURNAL OF MAGNETIC RESONANCE Mayer, D., Yen, Y., Levin, Y. S., Tropp, J., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2010; 204 (2): 340-345


    A fast spiral chemical shift imaging (CSI) has been developed to address the challenge of the limited acquisition window in hyperpolarized (13)C metabolic imaging. The sequence exploits the sparsity of the spectra and prior knowledge of resonance frequencies to reduce the measurement time by undersampling the data in the spectral domain. As a consequence, multiple reconstructions are necessary for any given data set as only frequency components within a selected bandwidth are reconstructed "in-focus" while components outside that band are severely blurred ("spectral tomosynthesis"). A variable-flip-angle scheme was used for optimal use of the longitudinal magnetization. The sequence was applied to sub-second metabolic imaging of the rat in vivo after injection of hyperpolarized [1-(13)C]-pyruvate on a clinical 3T MR scanner. The comparison with conventional CSI based on phase encoding showed similar signal-to-noise ratio (SNR) and spatial resolution in metabolic maps for the substrate and its metabolic products lactate, alanine, and bicarbonate, despite a 50-fold reduction in scan time for the spiral CSI acquisition. The presented results demonstrate that dramatic reductions in scan time are feasible in hyperpolarized (13)C metabolic imaging without a penalty in SNR or spatial resolution.

    View details for DOI 10.1016/j.jmr.2010.03.005

    View details for Web of Science ID 000278162300021

    View details for PubMedID 20346717

  • MR Diffusion Tensor Imaging: A Window into White Matter Integrity of the Working Brain NEUROPSYCHOLOGY REVIEW Chanraud, S., Zahr, N., Sullivan, E. V., Pfefferbaum, A. 2010; 20 (2): 209-225


    As Norman Geschwind asserted in 1965, syndromes resulting from white matter lesions could produce deficits in higher-order functions and "disconnexion" or the interruption of connection between gray matter regions could be as disruptive as trauma to those regions per se. The advent of in vivo diffusion tensor imaging, which allows quantitative characterization of white matter fiber integrity in health and disease, has served to strengthen Geschwind's proposal. Here we present an overview of the principles of diffusion tensor imaging (DTI) and its contribution to progress in our current understanding of normal and pathological brain function.

    View details for DOI 10.1007/s11065-010-9129-7

    View details for Web of Science ID 000278470400008

    View details for PubMedID 20422451

  • Brain Injury and Recovery Following Binge Ethanol: Evidence from In Vivo Magnetic Resonance Spectroscopy BIOLOGICAL PSYCHIATRY Zahr, N. M., Mayer, D., Rohlfing, T., Hasak, M. P., Hsu, O., Vinco, S., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2010; 67 (9): 846-854


    The binge-drinking model in rodents using intragastric injections of ethanol (EtOH) for 4 days results in argyrophilic corticolimbic tissue classically interpreted as indicating irreversible neuronal degeneration. However, recent findings suggest that acquired argyrophilia can also identify injured neurons that have the potential to recover. The current in vivo magnetic resonance (MR) imaging and spectroscopy study was conducted to test the hypothesis that binge EtOH exposure would injure but not cause the death of neurons as previously ascertained postmortem.After baseline MR scanning, 11 of 19 rats received a loading dose of 5 g/kg EtOH via oral gavage, then a maximum of 3 g/kg every 8 hours for 4 days, for a total average cumulative EtOH dose of 43 +/- 1.2 g/kg and average blood alcohol levels of 258 +/- 12 mg/dL. All animals were scanned after 4 days of gavage (post-gavage scan) with EtOH (EtOH group) or dextrose (control [Con] group) and again after 7 days of abstinence from EtOH (recovery scan).Tissue shrinkage at the post-gavage scan was reflected by significantly increased lateral ventricular volume in the EtOH group compared with the Con group. At the post-gavage scan, the EtOH group had lower dorsal hippocampal N-acetylaspartate and total creatine and higher choline-containing compounds than the Con group. At the recovery scan, neither ventricular volume nor metabolite levels differentiated the groups.Rapid recovery of ventricular volume and metabolite levels with removal of the causative agent argues for transient rather than permanent effects of a single EtOH binge episode in rats.

    View details for DOI 10.1016/j.biopsych.2009.10.028

    View details for Web of Science ID 000277064100008

    View details for PubMedID 20044076

  • Callosal degradation in HIV-1 infection predicts hierarchical perception: A DTI study NEUROPSYCHOLOGIA Mueller-Oehring, E. M., Schulte, T., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2010; 48 (4): 1133-1143


    HIV-1 infection affects white matter circuits linking frontal, parietal, and subcortical regions that subserve visuospatial attention processes. Normal perception requires the integration of details, preferentially processed in the left hemisphere, and the global composition of an object or scene, preferentially processed in the right hemisphere. We tested whether HIV-related callosal white matter degradation contributes to disruption of selective lateralized visuospatial and attention processes. A hierarchical letter target detection paradigm was devised, where large (global) letters were composed of small (local) letters. Participants were required to identify target letters among distractors presented at global, local, both or neither level. Attention was directed to one (global or local) or both levels. Participants were 21 HIV-1 infected and 19 healthy control men and women who also underwent Diffusion Tensor Imaging (DTI). HIV-1 participants showed impaired hierarchical perception owing to abnormally enhanced global facilitation effects but no impairment in attentional control on local-global feature selection. DTI metrics revealed poorer fiber integrity of the corpus callosum in HIV-1 than controls that was more pronounced in posterior than anterior regions. Analysis revealed a double dissociation of anterior and posterior callosal compromise in HIV-1 infection: compromise in anterior but not posterior callosal fiber integrity predicted response conflict elicited by global targets, whereas compromise in posterior but not anterior callosal fiber integrity predicted response facilitation elicited by global targets. We conclude that component processes of visuospatial perception are compromised in HIV-1 infection attributable, at least in part, to degraded callosal microstructural integrity relevant for local-global feature integration.

    View details for DOI 10.1016/j.neuropsychologia.2009.12.015

    View details for Web of Science ID 000275933500033

    View details for PubMedID 20018201

  • Diffusion tensor imaging of deep gray matter brain structures: Effects of age and iron concentration NEUROBIOLOGY OF AGING Pfefferbaum, A., Adalsteinsson, E., Rohlfing, T., Sullivan, E. V. 2010; 31 (3): 482-493


    Diffusion tensor imaging (DTI) of the brain has become a mainstay in the study of normal aging of white matter, and only recently has attention turned to the use of DTI to examine aging effects in gray matter structures. Of the many changes in the brain that occur with advancing age is increased presence of iron, notable in selective deep gray matter structures. In vivo detection and measurement of iron deposition is possible with magnetic resonance imaging (MRI) because of iron's effect on signal intensity. In the process of a DTI study, a series of diffusion-weighted images (DWI) is collected, and while not normally considered as a major dependent variable in research studies, they are used clinically and they reveal striking conspicuity of the globus pallidus and putamen caused by signal loss in these structures, presumably due to iron accumulation with age. These iron deposits may in turn influence DTI metrics, especially of deep gray matter structures. The combined imaging modality approach has not been previously used in the study of normal aging. The present study used legacy DTI data collected in 10 younger (22-37 years) and 10 older (65-79 years) men and women at 3.0T and fast spin-echo (FSE) data collected at 1.5T and 3.0T to derive an estimate of the field-dependent relaxation rate increase (the "FDRI estimate") in the putamen, caudate nucleus, globus pallidus, thalamus, and a frontal white matter sample comparison region. The effect of age on the diffusion measures in the deep gray matter structures was distinctly different from that reported in white matter. In contrast to lower anisotropy and higher diffusivity typical in white matter of older relative to younger adults observed with DTI, both anisotropy and diffusivity were higher in the older than younger group in the caudate nucleus and putamen; the thalamus showed little effect of age on anisotropy or diffusivity. Signal intensity measured with DWI was lower in the putamen of elderly than young adults, whereas the opposite was observed for the white matter region and thalamus. As a retrospective study based on legacy data, the FDRI estimates were based on FSE sequences, which underestimated the classical FDRI index of brain iron. Nonetheless, the differential effects of age on DTI metrics in subcortical gray matter structures compared with white matter tracts appears to be related, at least in part, to local iron content, which in the elderly of the present study was prominent in the FDRI estimate of the putamen and visibly striking in the diffusion-weighted image of the basal ganglia structures.

    View details for DOI 10.1016/j.neurobiolaging.2008.04.013

    View details for Web of Science ID 000276759600012

    View details for PubMedID 18513834

  • Mechanisms of Postural Control in Alcoholic Men and Women: Biomechanical Analysis of Musculoskeletal Coordination During Quiet Standing ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Rose, J., Pfefferbaum, A. 2010; 34 (3): 528-537


    Excessive sway during quiet standing is a common sequela of chronic alcoholism even with prolonged sobriety. Whether alcoholic men and women who have remained abstinent from alcohol for weeks to months differ from each other in the degree of residual postural instability and biomechanical control mechanisms has not been directly tested.We used a force platform to characterize center-of-pressure biomechanical features of postural sway, with and without stabilizing conditions from touch, vision, and stance, in 34 alcoholic men, 15 alcoholic women, 22 control men, and 29 control women. Groups were matched in age (49.4 years), general intelligence, socioeconomic status, and handedness. Each alcoholic group was sober for an average of 75 days.Analysis of postural sway when using all 3 stabilizing conditions versus none revealed diagnosis and sex differences in ability to balance. Alcoholics had significantly longer sway paths, especially in the anterior-posterior direction, than controls when maintaining erect posture without balance aids. With stabilizing conditions the sway paths of all groups shortened significantly, especially those of alcoholic men, who demonstrated a 3.1-fold improvement in sway path difference between the easiest and most challenging conditions; the remaining 3 groups, each showed a approximately 2.4-fold improvement. Application of a mechanical model to partition sway paths into open-loop and closed-loop postural control systems revealed that the sway paths of the alcoholic men but not alcoholic women were characterized by greater short-term (open-loop) diffusion coefficients without aids, often associated with muscle stiffening response. With stabilizing factors, all 4 groups showed similar long-term (closed loop) postural control. Correlations between cognitive abilities and closed-loop sway indices were more robust in alcoholic men than alcoholic women.Reduction in sway and closed-loop activity during quiet standing with stabilizing factors shows some differential expression in men and women with histories of alcohol dependence. Nonetheless, enduring deficits in postural instability of both alcoholic men and alcoholic women suggest persisting liability for falling.

    View details for DOI 10.1111/j.1530-0277.2009.01118.x

    View details for Web of Science ID 000275142100017

    View details for PubMedID 20028360

  • Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: Relations to timed performance NEUROBIOLOGY OF AGING Sullivan, E. V., Rohlfing, T., Pfefferbaum, A. 2010; 31 (3): 464-481


    The integrity of white matter, as measured in vivo with diffusion tensor imaging (DTI), is disrupted in normal aging. A current consensus is that in adults advancing age affects anterior brain regions disproportionately more than posterior regions; however, the mainstay of studies supporting this anterior-posterior gradient is based primarily on measures of the corpus callosum. Using our quantitative fiber tracking approach, we assessed fiber tract integrity of samples of major white matter cortical, subcortical, interhemispheric, and cerebellar systems (11 bilateral and 2 callosal) on DTI data collected at 1.5T magnet strength. Participants were 55 men (age 20-78 years) and 65 women (age 28-81 years), deemed healthy and cognitively intact following interview and behavioral testing. Fiber integrity was measured as orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, which was quantified separately for longitudinal diffusivity (lambdaL), an index of axonal length or number, and transverse diffusivity (lambdaT), an index of myelin integrity. Aging effects were more evident in diffusivity than FA measures. Men and women, examined separately, showed similar age-related increases in longitudinal and transverse diffusivity in fibers of the internal and external capsules bilaterally and the fornix. FA was lower and diffusivity higher in anterior than posterior fibers of regional paired comparisons (genu versus splenium and frontal versus occipital forceps). Diffusivity with older age was generally greater or FA lower in the superior than inferior fiber systems (longitudinal fasciculi, cingulate bundles), with little to no evidence for age-related degradation in pontine or cerebellar systems. The most striking sex difference emerged for the corpus callosum, for which men showed significant decline in FA and increase in longitudinal and transverse diffusivity in the genu but not splenium. By contrast, in women the age effect was present in both callosal regions, albeit modestly more so in the genu than splenium. Functional meaningfulness of these age-related differences was supported by significant correlations between DTI signs of white matter degradation and poorer performance on cognitive or motor tests. This survey of multiple fiber systems throughout the brain revealed a differential pattern of age's effect on regional FA and diffusivity and suggests mechanisms of functional degradation, attributed at least in part to compromised fiber microstructure affecting myelin and axonal morphology.

    View details for DOI 10.1016/j.neurobiolaging.2008.04.007

    View details for Web of Science ID 000276759600011

    View details for PubMedID 18495300

  • Pontocerebellar volume deficits and ataxia in alcoholic men and women: no evidence for "telescoping" PSYCHOPHARMACOLOGY Sullivan, E. V., Rohlfing, T., Pfefferbaum, A. 2010; 208 (2): 279-290


    Brain volume shrinkage is common in treatment-seeking patients with alcohol use disorders. Whether women are more vulnerable to brain dysmorphology than men despite lower alcohol consumption levels or shorter dependency ("telescoping effect") remains controversial and has not been considered with respect to infratentorial structures or their potential contribution to ataxia.The 200 participants included 64 men and 31 women with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence and 105 controls. An infratentorial region (pons, cerebellar hemispheres, vermis (anterior, posterior, and inferior sectors), fissures, cisterns, fourth ventricle) was quantified with atlas-based parcellation. To enable comparison of men and women, regional tissue volumes were expressed as ratios of tissue in the volume. Participants also completed quantitative ataxia testing.Total infratentorial and vermian tissue ratios were significantly smaller in alcoholics than controls; alcoholic women did not show disproportionately greater volume deficits than alcoholic men. A re-analysis including alcoholic men and women matched in alcohol consumption, onset age, abstinence duration, and age revealed again that alcoholic women did not have disproportionately greater regional vermian volume deficits than alcoholic men. Alcoholic men and women were impaired in all measures of ataxia, which correlated with low infratentorial tissue ratios in men.Alcoholic men showed deficits of pontocerebellar volume ratios, yet alcoholic women did not display signs of "telescoping". Further, alcoholic men and women both showed signs of ataxia of gait and balance, related to affected pontocerebellar systems in the men but not the women, suggesting the need to consider other neural substrates for ataxia in women.

    View details for DOI 10.1007/s00213-009-1729-7

    View details for Web of Science ID 000273097300011

    View details for PubMedID 19943036

  • Longitudinal Study of Callosal Microstructure in the Normal Adult Aging Brain Using Quantitative DTI Fiber Tracking DEVELOPMENTAL NEUROPSYCHOLOGY Sullivan, E. V., Rohlfing, T., Pfefferbaum, A. 2010; 35 (3): 233-256


    We present a review of neuroimaging studies of normal adult aging conducted with diffusion tensor imaging (DTI) and data from one of the first longitudinal studies using DTI to study normal aging. To date, virtually all DTI studies of normal adult aging have been cross-sectional and have identified several patterns of white matter microstructural sparing and compromise that differentiate regional effects, fiber type, and diffusivity characteristics: (1) fractional anisotropy (FA) is lower and mean diffusivity is higher in older than younger adults, (2) aging is characterized by an anterior-to-posterior gradient of greater-to-lesser compromise also seen in superior-to-inferior fiber systems, and (3) association fibers connecting cortical sites appear to be more vulnerable to aging than projection fibers. The results of this longitudinal study of the macrostructure and microstructure of the corpus callosum yielded a consistent pattern of differences between healthy, young (20s to 30s) and elderly (60s to 70s) men and women without change over 2 years. We then divided the fibers of the corpus callosum into the midsagittal strip and the lateral distal fibers in an attempt to identify the locus of the age-related differences. The results indicated that, on average, mean values of FA and longitudinal diffusivity (lambdaL) were lower in the distal than midsagittal fibers in both groups, but the age effects and the anterior-to-posterior gradients were more pronounced for the distal than midsagittal fibers and extended more posteriorly in the distal than midsagittal fibers. Despite lack of evidence for callosal aging over 2 years, ventricular enlargement occurred and was disproportionately greater in the elderly relative to the young group, being 8.2% in the elderly but only 1.2% in the young group. Thus, different brain regions can express different rates of change with aging. Our longitudinal DTI data indicate that normal aging is associated with declining FA and increasing diffusivity in both lambdaL (longitudinal diffusivity) and lambdaT (transverse diffusivity), perhaps defining the normal ontological condition rather than a pathological one, which can be marked by low FA and low diffusivity.

    View details for DOI 10.1080/87565641003689556

    View details for Web of Science ID 000277518100002

    View details for PubMedID 20446131

  • Physiological and Focal Cerebellar Substrates of Abnormal Postural Sway and Tremor in Alcoholic Women BIOLOGICAL PSYCHIATRY Sullivan, E. V., Rose, J., Pfefferbaum, A. 2010; 67 (1): 44-51


    Posturography analysis of static balance reveals marked sway and tremor in sober alcoholic men related to anterior vermis volume but can be attenuated by simple visual or tactile cues or alterations in stance. Whether alcoholic women, whose ataxia can persist with prolonged sobriety, exhibit the same physiological signature of balance instability and relation to cerebellar vermian volume as alcoholic men or can benefit from stabilizing factors is unknown.Groups comprised 15 alcohol-dependent women, alcohol-free (median 3 months) and 29 control women. Groups were matched in age, demographic features, and finger movement speed and underwent balance platform testing and magnetic resonance imaging scanning.Alcoholic women exhibited excessive sway path length (.6 SD), more dramatic in the anterior-posterior than medial-lateral direction. Truncal tremor, measured as peak sway velocity frequency, was disproportionately great in the 5 Hz to 7 Hz band of alcoholics. Control subjects and alcoholics exhibited sway and tremor reduction with visual, tactile, or stance-stabilizing conditions, which aided both groups equally well; thus, alcoholic women never achieved normal stability. Smaller anterior vermian volumes selectively correlated with longer sway path and higher 5 Hz to 7 Hz peak sway velocity.Sway and tremor abnormalities and the selective relations between greater sway and 5 Hz to 7 Hz tremor and smaller volumes of the anterior vermis had not heretofore been described in abstinent alcoholic women. Reduction in sway and tremor with stabilizing factors indicate that adaptive mechanisms involving sensorimotor integration can be invoked to compensate for vermian-related dysfunction.

    View details for DOI 10.1016/j.biopsych.2009.08.008

    View details for Web of Science ID 000272858600006

    View details for PubMedID 19782966

  • In vivo glutamate decline associated with kainic acid-induced status epilepticus BRAIN RESEARCH Zahr, N. M., Crawford, E. L., Hsu, O., Vinco, S., Mayer, D., Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. 2009; 1300: 65-78


    Neurophysiological, biochemical, and anatomical evidence implicates glutamatergic mechanisms in epileptic seizures. Until recently, however, longitudinal characterization of in vivo glutamate dynamics was not possible. Here, we present data using in vivo magnetic resonance spectroscopy (MRS) optimized for the detection of glutamate to identify changes that evolve following kainic acid (KA)-induced status epilepticus. Wild-type male Wistar rats underwent whole-brain MR imaging and single-voxel MRS on a clinical 3 T scanner equipped with a high-strength insert gradient coil. Scanning took place before and then 3 days, 28-32 days, and 42-50 days after induction of status epilepticus. Analyses compared 5 seizure (Sz), 5 no-seizure (NoSz; received KA but did not exhibit seizures), and 6 control (Con) animals. This longitudinal study demonstrated reduced glutamate levels in vivo in the dorsal hippocampus 3 days and 1 month following status epilepticus in Sz animals compared with Con animals. Additionally, previous results were replicated: in the Sz group, computed T2 was higher in the ventral hippocampus and limbic cortex 3 days after seizure activity compared with baseline but resolved in both regions at the 1 month scan, suggesting a transient edema. Three days following seizure activity, N-acetylaspartate (NAA) declined and lactate increased in the dorsal hippocampus of the Sz group compared with the Con and NoSz group; both metabolites approached baseline levels by the third scan. Taken together, these results support the conclusion that seizure activity following KA infusion causes loss of glutamatergic neurons.

    View details for DOI 10.1016/j.brainres.2009.08.060

    View details for Web of Science ID 000271819200008

    View details for PubMedID 19715683

  • Frontostriatal fiber bundle compromise in HIV infection without dementia AIDS Pfefferbaum, A., Rosenbloom, M. J., Rohlfing, T., Kemper, C. A., Deresinski, S., Sullivan, E. V. 2009; 23 (15): 1977-1985


    Quantitative fiber tracking derived from diffusion tensor imaging (DTI) was used to determine whether white matter association, projection, or commissural tracts are affected in nondemented individuals with HIV infection and to identify the regional distribution of sparing and impairment of fiber systems.DTI measured fractional anisotropy and diffusivity, quantified separately for longitudinal (lambdaL) diffusivity (index of axonal injury) and transverse (lambdaT) diffusivity (index of myelin injury), in 11 association and projection white matter tracts and six commissural tracts in 29 men and 13 women with HIV infection and 88 healthy, age-matched controls (42 men and 46 women).The total group of HIV-infected individuals had higher diffusivity (principally longitudinal) than controls in the posterior sectors of the corpus callosum, internal and external capsules, and superior cingulate bundles. High longitudinal diffusivity, indicative of axonal compromise, was especially prominent in posterior callosal sectors, fornix, and superior cingulate bundle in HIV with AIDS. Unmedicated patients had notably high transverse diffusivity, indicative of myelin compromise, in the occipital forceps, inferior cingulate bundle, and superior longitudinal fasciculus. Pontocerebellar projection fibers were resistant to HIV effects as were commissural fibers coursing through premotor and sensorimotor callosal sectors.This quantitative survey of brain fiber tract integrity indicates that even nondemented HIV patients can have neuroradiological evidence for damage to association and commissural tracts. These abnormalities were vulnerable to exacerbation with AIDS and possibly mitigated by HAART.

    View details for DOI 10.1097/QAD.0b013e32832e77fe

    View details for Web of Science ID 000270475400006

    View details for PubMedID 19730350

  • Application of Subsecond Spiral Chemical Shift Imaging to Real-Time Multislice Metabolic Imaging of the Rat In Vivo after Injection of Hyperpolarized C-13(1)-Pyruvate MAGNETIC RESONANCE IN MEDICINE Mayer, D., Yen, Y., Tropp, J., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2009; 62 (3): 557-564


    Dynamic nuclear polarization can create hyperpolarized compounds with MR signal-to-noise ratio enhancements on the order of 10,000-fold. Both exogenous and normally occurring endogenous compounds can be polarized, and their initial concentration and downstream metabolic products can be assessed using MR spectroscopy. Given the transient nature of the hyperpolarized signal enhancement, fast imaging techniques are a critical requirement for real-time metabolic imaging. We report on the development of an ultrafast, multislice, spiral chemical shift imaging sequence, with subsecond acquisition time, achieved on a clinical MR scanner. The technique was used for dynamic metabolic imaging in rats, with measurement of time-resolved spatial distributions of hyperpolarized (13)C(1)-pyruvate and metabolic products (13)C(1)-lactate and (13)C(1)-alanine, with a temporal resolution of as fast as 1 s. Metabolic imaging revealed different signal time courses in liver from kidney. These results demonstrate the feasibility of real-time, hyperpolarized metabolic imaging and highlight its potential in assessing organ-specific kinetic parameters.

    View details for DOI 10.1002/mrm.22041

    View details for Web of Science ID 000269404900001

    View details for PubMedID 19585607

  • MRI estimates of brain iron concentration in normal aging: Comparison of field-dependent (FDRI) and phase (SWI) methods NEUROIMAGE Pfefferbaum, A., Adalsteinsson, E., Rohlfing, T., Sullivan, E. V. 2009; 47 (2): 493-500


    Different brain structures accumulate iron at different rates throughout the adult life span. Typically, striatal and brain stem structures are higher in iron concentrations in older than younger adults, whereas cortical white matter and thalamus have lower concentrations in the elderly than young adults. Brain iron can be measured in vivo with MRI by estimating the relaxivity increase across magnetic field strengths, which yields the Field-Dependent Relaxation Rate Increase (FDRI) metric. The influence of local iron deposition on susceptibility, manifests as MR phase effects, forms the basis for another approach for iron measurement, Susceptibility-Weighted Imaging (SWI), for which imaging at only one field strength is sufficient. Here, we compared the ability of these two methods to detect and quantify brain iron in 11 young (5 men, 6 women; 21 to 29 years) and 12 elderly (6 men, 6 women; 64 to 86 years) healthy adults. FDRI was acquired at 1.5 T and 3.0 T, and SWI was acquired at 1.5 T. The results showed that both methods detected high globus pallidus iron concentration regardless of age and significantly greater iron in putamen with advancing age. The SWI measures were more sensitive when the phase signal intensities themselves were used to define regions of interest, whereas FDRI measures were robust to the method of region of interest selection. Further, FDRI measures were more highly correlated than SWI iron estimates with published postmortem values and were more sensitive than SWI to iron concentration differences across basal ganglia structures. Whereas FDRI requires more imaging time than SWI, two field strengths, and across-study image registration for iron concentration calculation, FDRI appears more specific to age-dependent accumulation of non-heme brain iron than SWI, which is affected by heme iron and non-iron source effects on phase.

    View details for DOI 10.1016/j.neuroimage.2009.05.006

    View details for Web of Science ID 000267756900009

    View details for PubMedID 19442747

  • In Vivo Measurement of Ethanol Metabolism in the Rat Liver Using Magnetic Resonance Spectroscopy of Hyperpolarized [1-C-13]Pyruvate MAGNETIC RESONANCE IN MEDICINE Spielman, D. M., Mayer, D., Yen, Y., Tropp, J., Hurd, R. E., Pfefferbaum, A. 2009; 62 (2): 307-313


    [1-(13)C]pyruvate is a readily polarizable substrate that has been the subject of numerous magnetic resonance spectroscopy (MRS) studies of in vivo metabolism. In this work (13)C-MRS of hyperpolarized [1-(13)C]pyruvate was used to interrogate a metabolic pathway involved in neither aerobic nor anaerobic metabolism. In particular, ethanol consumption leads to altered liver metabolism, which when excessive is associated with adverse medical conditions including fatty liver disease, hepatitis, cirrhosis, and cancer. Here we present a method for noninvasively monitoring this important process in vivo. Following the bolus injection of hyperpolarized [1-(13)C]pyruvate, we demonstrate a significantly increased rat liver lactate production rate with the coadministration of ethanol (P = 0.0016 unpaired t-test). The affect is attributable to increased liver nicotinamide adenine dinucleotide (NADH) associated with ethanol metabolism in combination with NADH's role as a coenzyme in pyruvate-to-lactate conversion. Beyond studies of liver metabolism, this novel in vivo assay of changes in NADH levels makes hyperpolarized [1-(13)C]pyruvate a potentially viable substrate for studying the multiple in vivo metabolic pathways that use NADH (or NAD(+)) as a coenzyme, thus broadening the range of applications that have been discussed in the literature to date.

    View details for DOI 10.1002/mrm.21998

    View details for Web of Science ID 000268432400005

    View details for PubMedID 19526498

  • In Vivo Evidence for Alcohol-Induced Neurochemical Changes in Rat Brain Without Protracted Withdrawal, Pronounced Thiamine Deficiency, or Severe Liver Damage NEUROPSYCHOPHARMACOLOGY Zahr, N. M., Mayer, D., Vinco, S., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2009; 34 (6): 1427-1442


    Magnetic resonance spectroscopy (MRS) studies in human alcoholics report decreases in N-acetylaspartate (NAA) and choline-containing (Cho) compounds. Whether alterations in brain metabolite levels are attributable to alcohol per se or to physiological effects of protracted withdrawal or impaired nutritional or liver status remains unclear. Longitudinal effects of alcohol on brain metabolites measured in basal ganglia with single-voxel MRS were investigated in sibling pairs of wild-type Wistar rats, with one rat per pair exposed to escalating doses of vaporized alcohol, the other to vapor chamber air. MRS was conducted before alcohol exposure and twice during exposure. After 16 weeks of alcohol exposure, rats achieved average blood alcohol levels (BALs) of approximately 293 mg per 100 ml and had higher Cho and a trend for higher glutamine+glutamate (Glx) than controls. After 24 weeks of alcohol exposure, BALs rose to approximately 445 mg per 100 ml, and alcohol-exposed rats had higher Cho, Glx, and glutamate than controls. Thiamine and thiamine monophosphate levels were significantly lower in the alcohol than the control group but did not reach levels low enough to be considered clinically relevant. Histologically, livers of alcohol-exposed rats exhibited greater steatosis and lower glycogenosis than controls, but were not cirrhotic. This study demonstrates a specific pattern of neurobiochemical changes suggesting excessive membrane turnover or inflammation, indicated by high Cho, and alterations to glutamate homeostasis in the rat brain in response to extended vaporized alcohol exposure. Thus, we provide novel in vivo evidence for alcohol exposure as causing changes in brain chemistry in the absence of protracted withdrawal, pronounced thiamine deficiency, or severe liver damage.

    View details for DOI 10.1038/npp.2008.119

    View details for Web of Science ID 000265221000007

    View details for PubMedID 18704091

  • Postural sway reduction in aging men and women: Relation to brain structure, cognitive status, and stabilizing factors NEUROBIOLOGY OF AGING Sullivan, E. V., Rose, J., Rohlfing, T., Pfefferbaum, A. 2009; 30 (5): 793-807


    Postural stability becomes compromised with advancing age, but the neural mechanisms contributing to instability have not been fully explicated. Accordingly, this quantitative physiological and MRI study of sex differences across the adult age range examined the association between components of postural control and the integrity of brain structure and function under different conditions of sensory input and stance stabilization manipulation. The groups comprised 28 healthy men (age 30-73 years) and 38 healthy women (age 34-74 years), who completed balance platform testing, cognitive assessment, and structural MRI. The results supported the hypothesis that excessive postural sway would be greater in older than younger healthy individuals when standing without sensory or stance aids, and that introduction of such aids would reduce sway in both principal directions (anterior-posterior and medial-lateral) and in both the open-loop and closed-loop components of postural control even in older individuals. Sway reduction with stance stabilization, that is, standing with feet apart, was greater in men than women, probably because older men were less stable than women when standing with their feet together. Greater sway was related to evidence for greater brain structural involutional changes, indexed as ventricular and sulcal enlargement and white matter hyperintensity burden. In women, poorer cognitive test performance related to less sway reduction with the use of sensory aids. Thus, aging men and women were shown to have diminished postural control, associated with cognitive and brain structural involution, in unstable stance conditions and with diminished sensory input.

    View details for DOI 10.1016/j.neurobiolaging.2007.08.021

    View details for Web of Science ID 000265018700012

    View details for PubMedID 17920729

  • Degradation of Association and Projection White Matter Systems in Alcoholism Detected with Quantitative Fiber Tracking BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Rosenbloom, M., Rohlfing, T., Sullivan, E. V. 2009; 65 (8): 680-690


    Excessive alcohol use can cause macrostructural tissue shrinkage with regional preference for frontal systems. The extent and locus of alcoholism's effect on white matter microstructure is less known.Quantitative fiber tracking derived from diffusion tensor imaging (DTI) assessed the integrity of samples of 11 major white matter bundles in 87 alcoholics (59 men, 28 women) and 88 healthy control subjects (42 men, 46 women). Fiber integrity was expressed as fractional anisotropy (FA) and apparent diffusion coefficient (ADC), quantified separately for longitudinal diffusivity (lambdaL), a putative index of axonal integrity, and transverse diffusivity (lambdaT), a putative index of myelin integrity.Alcoholism affected FA and diffusivity, particularly lambdaT, of several fiber bundles. Frontal and superior sites (frontal forceps, internal and external capsules, fornix, and superior cingulate and longitudinal fasciculi) showed greatest abnormalities in alcoholics relative to control subjects. More posterior and inferior bundles were relatively spared. Lifetime alcohol consumption correlated with regional DTI measures in alcoholic men but not women. When matched for alcohol exposure, alcoholic women showed more DTI signs of white matter degradation than alcoholic men in several fiber bundles. Among all alcoholics, poorer performance on speeded tests correlated with DTI signs of regional white matter degradation.This survey of multiple brain fiber systems revealed a differential pattern of alcoholism's effect on regional FA and diffusivity with functional consequences attributable in part to compromised fiber microstructure with prominence in signs of myelin degradation. Sex-based differences suggest that women are at enhanced risk for alcoholism-related degradation in selective white matter systems.

    View details for DOI 10.1016/j.biopsych.2008.10.039

    View details for Web of Science ID 000264857400007

    View details for PubMedID 19103436

  • Global-Local Interference is Related to Callosal Compromise in Alcoholism: A Behavior-DTI Association Study ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Mueller-Oehring, E. M., Schulte, T., Fama, R., Pfefferbaum, A., Sullivan, E. V. 2009; 33 (3): 477-489


    Visuospatial ability is a multifactorial process commonly impaired in chronic alcoholism. Identification of which features of visuospatial processing are affected and which are spared in alcoholism, however, has not been clearly determined. We used a global-local paradigm to assess component processes of visuospatial ability and MR diffusion tensor imaging (DTI) to examine whether alcoholism-related microstructural degradation of the corpus callosum contributes to disruption of selective lateralized visuospatial and attention processes.A hierarchical letter paradigm was devised, where large global letters were composed of small local letters. The task required identification of target letters among distractors presented at global, local, both, or neither level. Attention was either selectively directed to global or local levels or divided between levels. Participants were 18 detoxified chronic alcoholics and 22 age-matched healthy controls. DTI provided quantitative assessment of the integrity of corpus callosal white matter microstructure.Alcoholics generally had longer reaction times than controls but obtained similar accuracy scores. Both groups processed local targets faster than global targets and showed interference from targets at the unattended level. Alcoholics exhibited moderate compromise in selectively attending to the global level when the global stimuli were composed of local targets. Such local interference was less with longer abstinence. Callosal microstructural integrity compromise predicted degree of interference from stimulus incongruency in the alcoholic group. This relationship was not observed for lateral or third ventricular volumes, which are measures of nonspecific cortical volume deficits.Global-local feature perception was generally spared in abstinent chronic alcoholics, but impairments were observed when directing attention to global features and when global and local information interfered at stimulus or response levels. Furthermore, the interference-callosal integrity relationship in alcoholics indicates that compromised visuospatial functions include those requiring bilateral integration of information.

    View details for DOI 10.1111/j.1530-0277.2008.00858.x

    View details for Web of Science ID 000263518400011

    View details for PubMedID 19120053

  • Neuroimaging of the Wernicke-Korsakoff Syndrome ALCOHOL AND ALCOHOLISM Sullivan, E. V., Pfefferbaum, A. 2009; 44 (2): 155-165


    Presented is the neuroradiological signature of acute Wernicke's encephalopathy (WE), derived from different types of magnetic resonance imaging (MRI) sequences. WE results from thiamine depletion, and its most typical antecedent is chronic alcohol dependence. Brain regions observed with in vivo MRI affected in acute WE include the mammillary bodies, periaqueductal and periventricular gray matter, collicular bodies and thalamus. These affected areas are usually edematous and are best visualized and quantified with MRI sequences that highlight such tissue. Following the acute WE phase and resolution of edema and inflammation of affected brain tissue, WE, if not adequately treated with thiamine repletion, can herald Korsakoff's syndrome (KS), with its symptomatic hallmark of global amnesia, that is, the inability to commit newly encountered (episodic) information to memory for later recall or recognition.Neuropathology of KS detectable with MRI has a different neuroradiological signature from the acute stage and can be observed as tissue shrinkage or atrophy of selective brain structures, including the mammillary bodies and thalamus and ventricular expansion, probably indicative of atrophy of surrounding gray matter nuclei. Quantification of these and additional gray matter structures known to underlie global amnesia reveal substantial bilateral volume deficits in the hippocampus, in addition to the mammillary bodies and thalamus, and modest deficits in the medial septum/diagonal band of Broca. The infratentorium is also affected, exhibiting volume deficits in cerebellar hemispheres, anterior superior vermis and pons, contributing to ataxia of gait and stance.Consideration of WKS structural brain changes in the context of the neuropathology of non-WKS alcoholism revealed a graded pattern of volume deficits, from mild in non-WKS alcoholics to moderate or severe in WKS, in the mammillary bodies, hippocampus, thalamus, cerebellum and pons. The development and resolution of brain structures affected in acute, chronic and treated WE was verified in longitudinal MRI study of rats that modeled of the interaction of extensive alcohol consumption and thiamine depletion and repletion.Thus, neuroradiological examination with MRI is valuable in the diagnosis of acute WE and enables in vivo tracking of the progression of the brain pathology of WE from the acute pathological phase to resolution with thiamine treatment or to progression to KS without treatment. Further, in vivo MRI facilitates translational studies to model antecedent conditions contributing to the development, sequelae and treatment of WE.

    View details for DOI 10.1093/alcalc/agn103

    View details for Web of Science ID 000263603100009

    View details for PubMedID 19066199

  • Problem solving, working memory, and motor correlates of association and commissural fiber bundles in normal aging: A quantitative fiber tracking study NEUROIMAGE Zahr, N. M., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2009; 44 (3): 1050-1062


    Normal aging is accompanied by decline in selective cognitive and motor functions. A concurrent decline in regional white matter integrity, detectable with diffusion tensor imaging (DTI), potentially contributes to waning function. DTI analysis of white matter loci indicates an anterior-to-posterior gradient distribution of declining fractional anisotropy (FA) and increasing diffusivity with age. Quantitative fiber tracking can be used to determine regional patterns of normal aging of fiber systems and test the functional ramifications of the DTI metrics. Here, we used quantitative fiber tracking to examine age effects on commissural (genu and splenium), bilateral association (cingulate, inferior longitudinal fasciculus and uncinate), and fornix fibers in 12 young and 12 elderly healthy men and women and tested functional correlates with concurrent assessment of a wide range of neuropsychological abilities. Principal component analysis of cognitive and motor tests on which the elderly achieved significantly lower scores than the young group was used for data reduction and yielded three factors: Problem Solving, Working Memory, and Motor. Age effects--lower FA or higher diffusivity--in the elderly were prominent in anterior tracts, specifically, genu, fornix, and uncinate fibers. Differential correlations between FA or diffusivity in fiber tracts and scores on Problem Solving, Working Memory, or Motor factors provide convergent validity to the biological meaningfulness of the integrity of the fibers tracked. The observed pattern of relations supports the possibility that regional degradation of white matter fiber integrity is a biological source of age-related functional compromise and may have the potential to limit accessibility to alternative neural systems to compensate for compromised function.

    View details for DOI 10.1016/j.neuroimage.2008.09.046

    View details for Web of Science ID 000262301500044

    View details for PubMedID 18977450

  • Relevance of Iron Deposition in Deep Gray Matter Brain Structures to Cognitive and Motor Performance in Healthy Elderly Men and Women: Exploratory Findings. Brain imaging and behavior Sullivan, E. V., Adalsteinsson, E., Rohlfing, T., Pfefferbaum, A. 2009; 3 (2): 167-175


    Iron deposition increases in normal aging, has its greatest presence in structures of the extrapyramidal system, and may contribute to functional decline. MR imaging provides a method for indexing iron deposition in brain structures because of iron's ferromagnetic properties, which interact with the MRI environment to cause signal intensity attenuation that is quantifiable by comparing images collected at 1.5 and 3.0 T. We tested functional correlates of an MR-based iron index in 10 healthy, elderly individuals previously reported to have a higher iron burden in the putamen and lower in the thalamus than young individuals. Lower scores on the Dementia Rating Scale and longer reaction times on a two-choice attention test correlated with higher iron estimates in the caudate nucleus and putamen; poorer Mini-Mental State Examination and Digit Symbol scores correlated with lower iron estimates in the thalamus. Further analyses based on multiple regression, which considered regional FDRI estimates and volume measures as predictors of performance, identified iron but not the sampled volume as the unique predictor in each case. These exploratory correlations suggest a substrate of performance degradation in aging and have implications for regional signal darkening in an array of MR-based imaging protocols.

    View details for PubMedID 20161183

  • Contribution of Regional White Matter Integrity to Visuospatial Construction Accuracy, Organizational Strategy, and Memory for a Complex Figure in Abstinent Alcoholics. Brain imaging and behavior Rosenbloom, M. J., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2009; 3 (4): 379-390


    Visuospatial construction ability as used in drawing complex figures is commonly impaired in chronic alcoholics, but memory for such information can be enhanced by use of a holistic drawing strategy during encoding. We administered the Rey-Osterrieth Complex Figure Test (ROCFT) to 41 alcoholic and 38 control men and women and assessed the contribution of diffusion tensor imaging (DTI) measures of integrity of selected white matter tracts to ROCFT copy accuracy, copy strategy, and recall accuracy. Although alcoholics copied the figure less accurately than controls, a more holistic strategy at copy was associated with better recall in both groups. Greater radial diffusivity, reflecting compromised myelin integrity, in occipital forceps and external capsule was associated with poorer copy accuracy in both groups. Lower FA, reflecting compromised fiber microstructure in the inferior cingulate bundle, which links frontal and medial temporal episodic memory systems, was associated with piecemeal copy strategy and poorer immediate recall in the alcoholics. The correlations were generally modest and should be considered exploratory. To the extent that the inferior cingulate was relatively spared in alcoholics, it may have provided an alternative pathway to the compromised frontal system for successful copy strategy and, by extension, aided recall.

    View details for PubMedID 20161607

  • Low striatal glutamate levels underlie cognitive decline in the elderly: Evidence from in vivo molecular spectroscopy CEREBRAL CORTEX Zahr, N. M., Mayer, D., Pfefferbaum, A., Sullivan, E. V. 2008; 18 (10): 2241-2250


    Glutamate (Glu), the principal excitatory neurotransmitter of prefrontal cortical efferents, potentially mediates higher order cognitive processes, and its altered availability may underlie mechanisms of age-related decline in frontally based functions. Although animal studies support a role for Glu in age-related cognitive deterioration, human studies, which require magnetic resonance spectroscopy for in vivo measurement of this neurotransmitter, have been impeded because of the similarity of Glu's spectroscopic signature to those of neighboring spectral brain metabolites. Here, we used a spectroscopic protocol, optimized for Glu detection, to examine the effect of age in 3 brain regions targeted by cortical efferents--the striatum, cerebellum, and pons--and to test whether performance on frontally based cognitive tests would be predicted by regional Glu levels. Healthy elderly men and women had lower Glu in the striatum but not pons or cerebellum than young adults. In the combined age groups, levels of striatal Glu (but no other proton metabolite also measured) correlated selectively with performance on cognitive tests showing age-related decline. The selective relations between performance and striatal Glu provide initial and novel, human in vivo support for age-related modification of Glu levels as contributing to cognitive decline in normal aging.

    View details for DOI 10.1093/cercor/bhm250

    View details for Web of Science ID 000259326700002

    View details for PubMedID 18234683

  • Reproducibility study of whole-brain H-1 spectroscopic imaging with automated quantification MAGNETIC RESONANCE IN MEDICINE Gu, M., Kim, D., Mayer, D., Sullivan, E. V., Pfefferbaum, A., Spielman, D. M. 2008; 60 (3): 542-547


    A reproducibility study of proton MR spectroscopic imaging ((1)H-MRSI) of the human brain was conducted to evaluate the reliability of an automated 3D in vivo spectroscopic imaging acquisition and associated quantification algorithm. A PRESS-based pulse sequence was implemented using dualband spectral-spatial RF pulses designed to fully excite the singlet resonances of choline (Cho), creatine (Cre), and N-acetyl aspartate (NAA) while simultaneously suppressing water and lipids; 1% of the water signal was left to be used as a reference signal for robust data processing, and additional lipid suppression was obtained using adiabatic inversion recovery. Spiral k-space trajectories were used for fast spectral and spatial encoding yielding high-quality spectra from 1 cc voxels throughout the brain with a 13-min acquisition time. Data were acquired with an 8-channel phased-array coil and optimal signal-to-noise ratio (SNR) for the combined signals was achieved using a weighting based on the residual water signal. Automated quantification of the spectrum of each voxel was performed using LCModel. The complete study consisted of eight healthy adult subjects to assess intersubject variations and two subjects scanned six times each to assess intrasubject variations. The results demonstrate that reproducible whole-brain (1)H-MRSI data can be robustly obtained with the proposed methods.

    View details for DOI 10.1002/mrm.21713

    View details for Web of Science ID 000259053900006

    View details for PubMedID 18727040

  • Improvement in memory and static balance with abstinence in alcoholic men and women: Selective relations with change in brain structure PSYCHIATRY RESEARCH-NEUROIMAGING Rosenbloom, M. J., Rohlfing, T., O'Reilly, A. W., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2007; 155 (2): 91-102


    We investigated whether changes in memory or static balance in chronic alcoholics, occurring with abstinence or relapse, are associated with changes in lateral and fourth ventricular volume. Alcoholics meeting DSM-IV criteria for Alcohol Dependence (n=15) and non-alcoholic controls (n=26) were examined twice at a mean interval of 2 years with standard Wechsler Abbreviated Scale of Intelligence (WASI), Wechsler Memory Scale-Revised (WMS-R) tests, an ataxia battery, and structural MRI. At study entry, alcoholics had been abstinent on average for over 4 months and achieved lower scores than controls on WASI General IQ Index, WMS-R General Memory Index, and the ataxia battery. The 10 alcoholics who maintained sobriety at retest did not differ at study entry in socio-demographic measures, alcohol use, or WASI and WMS-R summary scores from the five relapsers. At follow-up, abstainers improved more than controls on the WMS-R General Memory Index. Ataxia tended to improve in abstainers relative to controls. Associations were observed between memory and lateral ventricular volume change and between ataxia and fourth ventricular volume change in alcoholics but not in the controls. Both memory and ataxia can improve with sustained sobriety, and brain-behavior associations suggest selective brain structural substrates for the changes observed.

    View details for DOI 10.1016/j.pscychresns.2006.12.019

    View details for Web of Science ID 000248061000002

    View details for PubMedID 17407808

  • Development and resolution of brain lesions caused by pyrithiamine- and dietary-induced thiamine deficiency and alcohol exposure in the alcohol-preferring rat: A longitudinal magnetic resonance imaging and spectroscopy study NEUROPSYCHOPHARMACOLOGY Pfefferbaum, A., Adalsteinsson, E., Bell, R. L., Sullivan, E. V. 2007; 32 (5): 1159-1177


    Wernicke's encephalopathy (WE) is characterized by lesions in thalamus, hypothalamus (including mammillary nuclei), and inferior colliculi, results in serious disabilities, has an etiology of thiamine deficiency, is treatable with thiamine, and occurs most commonly with alcoholism. Despite decades of study, whether alcohol exposure exacerbates the neuropathology or retards its resolution remains controversial. To examine patterns of brain damage and recovery resulting from thiamine deprivation with and without alcohol exposure, we conducted in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3 T in alcohol-preferring (P) rats, which had voluntarily consumed large amounts of alcohol before thiamine manipulation. A total of 18 adult male P rats (nine alcohol-exposed) received a thiamine-deficient diet for 2 weeks: 10 (five alcohol-exposed) received intraperitoneal (i.p.) pyrithiamine (PT) and eight (four alcohol-exposed) received i.p. thiamine supplementation. Neurological signs developed by day 14. Rats were scanned before thiamine depletion and 18 and 35 days after thiamine repletion. Two-dimensional J-resolved MRS single-voxel spectra with water reference were collected in a voxel subtending the thalamus; metabolite quantification was corrected for voxel tissue content. MRI identified significant enlargement of dorsal ventricles and increase in signal intensities in thalamus, inferior colliculi, and mammillary nuclei of PT compared with thiamine-treated (TT) groups from MRI 1-2, followed by significant normalization from MRI 2-3 in thalamus and colliculi, but not mammillary nuclei and lateral ventricles. Voxel-by-voxel analysis revealed additional hyperintense signal clusters in the dorsal and ventral hippocampus and enlargement of the fourth ventricle. MRS showed a significant decline and then partial recovery in thalamic N-acetylaspartate, a marker of neuronal integrity, in PT compared with TT rats, with no change detected in creatine, choline, or glutamate. PT rats with prior alcohol exposure exhibited attenuated recovery in the thalamus and arrested growth of the corpus callosum; further, two of the five alcohol-exposed PT rats died prematurely. Parenchymal and ventricular changes with thiamine manipulation concur with human radiological signs of WE. The enduring macrostructural and neurochemical abnormalities involving critical nodes of Papez circuit carry liabilities for development of amnesia and incomplete recovery from other cognitive and motor functions subserved by the affected neural systems.

    View details for DOI 10.1038/sj.npp.1301107

    View details for Web of Science ID 000245758800016

    View details for PubMedID 16723995

  • Local-global interference is modulated by age, sex and anterior corpus callosum size BRAIN RESEARCH Mueller-Oehring, E. M., Schulte, T., Raassi, C., Pfefferbaum, A., Sullivan, E. V. 2007; 1142: 189-205


    To identify attentional and neural mechanisms affecting global and local feature extraction, we devised a global-local hierarchical letter paradigm to test the hypothesis that aging reduces functional cerebral lateralization through corpus callosum (CC) degradation. Participants (37 men and women, 26-79 years) performed a task requiring global, local, or global+local attention and underwent structural MRI for CC measurement. Although reaction time (RT) slowed with age, all participants had faster RTs to local than global targets. This local precedence effect together with greater interference from incongruent local information and greater response conflict from local targets each correlated with older age and smaller callosal genu (anterior) areas. These findings support the hypothesis that the CC mediates lateralized local-global processes by inhibition of task-irrelevant information under selective attention conditions. Further, with advancing age smaller genu size leads to less robust inhibition, thereby reducing cerebral lateralization and permitting interference to influence processing. Sex was an additional modifier of interference, in that callosum-interference relationships were evident in women but not in men. Regardless of age, smaller splenium (posterior) areas correlated with less response facilitation from repetition priming of global targets in men, but with greater response facilitation from repetition priming of local targets in women. Our data indicate the following dissociation: anterior callosal structure was associated with inhibitory processes (i.e., interference from incongruency and response conflict), which are vulnerable to the effects of age and sex, whereas posterior callosal structure was associated with facilitation processes from repetition priming dependent on sex and independent of age.

    View details for DOI 10.1016/j.brainres.2007.01.062

    View details for Web of Science ID 000245785000021

    View details for PubMedID 17335783

  • In vivo metabolite differences between the basal ganglia and cerebellum of the rat brain detected with proton MRS at 3T PSYCHIATRY RESEARCH-NEUROIMAGING Mayer, D., Zahr, N. M., Sullivan, E. V., Pfefferbaum, A. 2007; 154 (3): 267-273


    In vivo magnetic resonance spectroscopy (MRS) enables non-invasive longitudinal tracking of brain chemistry changes that can accompany aging, neurodegenerative disease, drug addiction and experimental manipulations in animals modeling such conditions. J-coupled resonances, such as glutamate, which are highly relevant to neuropsychiatric conditions are difficult to resolve on a clinical 3T MR scanner using conventional one-dimensional MRS sequences. We, therefore, implemented Constant Time PRESS (CT-PRESS) to quantify major metabolite and neurotransmitter biochemical signals, including glutamate, in two brain regions of the rat, basal ganglia and cerebellum. We acquired spectra at two distinct time points in two independent groups of six rats and analyzed metabolite levels using either creatine or water as a reference. Our results provide evidence that CT-PRESS at 3T is adequate and reliable for in vivo detection and quantification of glutamate in the rat brain and that regional differences occur in the signal intensities of the major metabolites. That the directionality of the differences depends on whether creatine or water is used as a reference for metabolite levels emphasizes the benefit to in vivo MRS of incorporating methods to establish absolute baseline metabolite concentrations.

    View details for DOI 10.1016/j.pscychresns.2006.11.005

    View details for Web of Science ID 000246132000008

    View details for PubMedID 17346948

  • In vivo riber tracking in the rat brain on a clinical 3T MRI system using a high strength insert gradient coil NEUROIMAGE Mayer, D., Zahr, N. M., Adalsteinsson, E., Rutt, B., Sullivan, E. V., Pfefferbaum, A. 2007; 35 (3): 1077-1085


    In vivo neuroimaging methods permit longitudinal quantitative examination of the dynamic course of neurodegenerative conditions in humans and animal models and enable assessment of therapeutic efforts in mitigating disease effects on brain systems. The study of conditions affecting white matter, such as multiple sclerosis, demyelinating conditions, and drug and alcohol dependence, can be accomplished with diffusion tensor imaging (DTI), a technique uniquely capable of probing the microstructural integrity of white matter fibers in the living brain. We used a 3T clinical MR scanner equipped with an insert gradient coil that yields an order of magnitude increase in performance over the whole-body hardware to acquire in vivo DTI images of rat brain. The resolution allowed for fiber tracking evaluation of fractional anisotropy (FA) and apparent diffusion coefficients in the genu and splenium of the corpus callosum. A comparison of short (46 min) and long (92 min) acquisition time DTI protocols indicated low but adequate signal-to-noise ratio (SNR=6.2) of the shorter protocol to conduct quantitative fiber tracking enhanced by multiple acquisitions. As observed in human studies, FA in the rat splenium was higher than in the genu. Advantages of this technology include the use of similar user interface, pulse sequences, and field strength for preclinical animal and clinical human research, enhancing translational capabilities. An additional benefit of scanning at lower field strength, such as 3 T, is the reduction of artifacts due to main field inhomogeneity relative to higher field animal systems.

    View details for DOI 10.1016/j.neuroimage.2007.01.006

    View details for Web of Science ID 000245956100009

    View details for PubMedID 17331742

  • Diffusion tensor imaging with quantitative fibre tracking in HIV infection and alcoholism comorbidity: synergistic white matter damage BRAIN Pfefferbaum, A., Rosenbloom, M. J., Adalsteinsson, E., Sullivan, E. V. 2007; 130: 48-64


    A substantial proportion of individuals infected with human immunodeficiency virus (HIV) also abuse alcohol. Given that each condition can disrupt brain structural integrity, with a predilection for white matter, we used MR diffusion tensor imaging (DTI) and quantitative fibre tracking to examine the separate and combined effects on the microstructure of the corpus callosum. Subjects were men and women with alcoholism alone (n = 87), HIV infection alone (n = 42), alcoholism and HIV infection comorbidity (n = 52) and non-affected controls (n = 88). The two alcoholism groups had similar lifetime alcohol consumption histories; the two HIV-infected groups had similar CD4+ counts and viral loads; all groups were matched in body mass index, and no participant was demented. Compared with controls, all patient groups had lower fractional anisotropy (FA) and higher mean diffusivity (MD) in callosal regions and fibre bundles coursing through the genu and splenium, but these effects were only significant in the two groups with alcoholism, which exhibited 0.65-1.2 SD abnormalities in FA and MD. The callosal regions were differentially affected by alcoholism, with the genu more affected than the splenium, a pattern even more pronounced in the fibre tracks. When the HIV-infected groups were divided by disease severity defined as an acquired immunodeficiency syndrome (AIDS)-defining event or low CD4+ counts (<200) and alcoholism comorbidity, the HIV-infected subgroup with AIDS and alcoholism exhibited approximately 2 SD FA and MD abnormalities in the callosal sectors and fibres, abnormalities that were more than twice the effect sizes observed in the other three HIV-infected subgroups. Degradation of the callosal microstructure was consistently associated with alcoholism, with evidence for compounded alcoholism-HIV effects. Functional relevance of the microstructural abnormalities was supported by associations between motor deficits and low FA or high MD within the diagnostic groups. The high prevalence of alcoholism in HIV-infected individuals and the interfering effect of alcohol on HIV pharmacological response and therapy compliance underscore the need to recognize the independent and synergistic contributions of each condition to brain structure and function.

    View details for DOI 10.1093/brain/awl242

    View details for Web of Science ID 000243061500005

    View details for PubMedID 16959813

  • Neuroradiological characterization of normal adult ageing BRITISH JOURNAL OF RADIOLOGY Sullivan, E. V., Pfefferbaum, A. 2007; 80: S99-S108


    This paper provides a review of MRI and diffusion tensor imaging (DTI) findings in normal ageing as an essential context for evaluating imaging in dementia, and adding to the ever-growing number of such overviews. An additional extensive literature details the physics, MR acquisition, image reconstruction and mathematical computation approaches to both imaging modalities. The aim of this review is to illustrate how MR imaging modalities, spanning structural and diffusion tensor imaging, are suitable for visualizing and quantifying the macrostructural and microstructural disruptions sustained by the brain in normal ageing and to recognize the importance of normative data for identifying abnormalities characterizing neurodegenerative diseases and other conditions affecting brain tissue integrity.

    View details for DOI 10.1259/bjr/22893432

    View details for Web of Science ID 000256312300005

    View details for PubMedID 18445750

  • In vivo quantification of ethanol kinetics in rat brain NEUROPSYCHOPHARMACOLOGY Adalsteinsson, E., Sullivan, E. V., Mayer, D., Pfefferbaum, A. 2006; 31 (12): 2683-2691


    Proton magnetic resonance spectroscopy was used at 3T to measure the uptake and clearance of brain ethanol in rats after bolus intraperitoneal (i.p.) or intragastric (i.g.) alcohol injection, and to estimate the effects of acute alcohol on brain metabolites. The observation duration was 1-1.5 h with temporal resolution of alcohol sampling ranging from 4 s-4 min. The observed time course of alcohol brain concentration followed a consistent pattern characterized by a rapid absorption, an intermediate distribution, and a slower clearance that approached a linear decay. In a sample of eight healthy Wistar rats, the intercept of the linear clearance term, extrapolated back to the time of injection, correlated well with the administered dose per unit of lean body mass. Alcohol concentration estimation based on spectroscopically measured clearance was compared with blood alcohol levels from blood samples at the end of observation, and were in good agreement with the administered dose. Serial proton spectroscopy measurements provide a valid in vivo method for quantifying brain alcohol uptake and elimination kinetics in real time.

    View details for DOI 10.1038/sj.npp.1301023

    View details for Web of Science ID 000242046800013

    View details for PubMedID 16407891

  • Contribution of alcoholism to brain dysmorphology in HIV infection: Effects on the ventricles and corpus callosum NEUROIMAGE Pfefferbaum, A., Rosenbloom, M. J., Rohlfing, T., Adalsteinsson, E., Kemper, C. A., Deresinski, S., Sullivan, E. V. 2006; 33 (1): 239-251


    Nonrigid registration and atlas-based parcellation methods were used to compare the volume of the ventricular system and the cross-sectional area of the midsagittal corpus callosum on brain MRIs from 272 subjects in four groups: patients with HIV infection, with and without alcoholism comorbidity, alcoholics, and controls. Prior to testing group differences in regional brain metrics, each measure was corrected by regression analysis for significant correlations with supratentorial cranial volume and age, observed in 121 normal control men and women, whose age spanned six decades. Disregarding HIV disease severity, we observed a graded pattern of modest enlargement of the total ventricular system (0.28 SD for uncomplicated HIV, 0.65 SD for HIV comorbid with alcoholism, and 0.72 SD for the alcoholism group). The pattern of callosal thinning showed a similar but small ( approximately 0.5 SD) graded effect. A different pattern emerged, however, when HIV severity in the context of alcoholism comorbidity was factored into the analysis. Substantially greater volume abnormalities were present in individuals with a history of an AIDS-defining event or low CD4+ T cell counts (

    View details for DOI 10.1016/j.neuroimage.2006.05.052

    View details for Web of Science ID 000241209800025

    View details for PubMedID 16877010

  • From rats to monkeys to man - The neurophysiology of alcoholism: A tribute to Henri Begleiter ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A. 2006; 30 (10): 1641-1642
  • Effect of vision, touch and stance on cerebellar vermian-related sway and tremor: A quantitative physiological and MRI study CEREBRAL CORTEX Sullivan, E. V., Rose, J., Pfefferbaum, A. 2006; 16 (8): 1077-1086


    Postural balance is impaired in individuals with pathology of the anterior superior vermis of the cerebellum. Chronic alcoholism, with its known vermian pathology, provides a viable model for studying the relationship between cerebellar pathology and postural stability. Decades of separate study of recovering alcoholics and post-mortem neuroanatomical analysis have demonstrated vermian pathology but few studies have used quantitative posturography, acquired concurrently with quantitative neuroimaging, to establish whether this brain structure-function relationship is selective in vivo. Here, 30 healthy men and 39 chronic alcoholic men, abstinent from alcohol for several months, underwent MRI for volumetric quantitation of the cerebellar vermis and three comparison brain regions, the cerebellar hemispheres, supratentorial cortex and corpus callosum. All subjects also participated in an experiment involving a force platform that measured sway path length and tremor during static standing balance under four sensory conditions and two stance conditions. Three novel findings emerged: (i) sway path length, a physiological index of postural control, was selectively related to volume of the cerebellar vermis and not to any comparison brain region in the alcoholics; (ii) spectral analysis revealed sway prominence in the 2-5 Hz band, another physiological sign of vermian lesions and also selectively related to vermian volume in the alcoholics; and (iii) despite substantial postural sway in the patients, they successfully used vision, touch and stance to normalize sway and reduce tremor. The selective relationship of sway path to vermian but not lateral cerebellar volume provides correlational evidence for functional differentiation of these cerebellar regions. Improvement to virtual normal levels in balance and reduction in sway and tremor with changes in vision, touch and stance provide evidence that adaptive mechanisms recruiting sensorimotor integration can be invoked to compensate for underlying cerebellar vermian-related dysfunction.

    View details for DOI 10.1093/cercor/bhj048

    View details for Web of Science ID 000238906300003

    View details for PubMedID 16221930

  • Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part II: Effects of voluntary chronic alcohol consumption ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Adalsteinsson, E., Sood, R., Mayer, D., Bell, R., McBride, W., Li, T., Sullivan, E. V. 2006; 30 (7): 1248-1261


    Tracking the dynamic course of human alcoholism brain pathology can be accomplished only through naturalistic study and without opportunity for experimental manipulation. Development of an animal model of alcohol-induced brain damage, in which animals consume large amounts of alcohol following cycles of alcohol access and deprivation and are examined regularly with neuroimaging methods, would enable hypothesis testing focused on the degree, nature, and factors resulting in alcohol-induced brain damage and the prospects for recovery or relapse.We report the results of longitudinal magnetic resonance imaging (MRI) studies of the effects of free-choice chronic alcohol intake on the brains of 2 cohorts of selectively bred alcohol-preferring (P) rats. In the companion paper, we described the MRI acquisition and analysis methods, delineation of brain regions, and growth patterns in total brain and selective structures of the control rats in the present study. Both cohorts were studied as adults for about 1 year and consumed high doses of alcohol for most of the study duration. The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark.Brain structures of the adult P rats in both the alcohol-exposed and the water control conditions showed significant growth, which was attenuated in a few measures in the alcohol-exposed groups. The region with the greatest demonstrable effect was the corpus callosum, measured on midsagittal images.The P rats showed an age-alcohol interaction different from humans, in that normal growth in selective brain regions that continues in adult rats was retarded.

    View details for DOI 10.1111/j.1530-0277.2006.00146.x

    View details for Web of Science ID 000238253100019

    View details for PubMedID 16792573

  • Selective age-related degradation of anterior callosal fiber bundles quantified in vivo with fiber tracking CEREBRAL CORTEX Sullivan, E. V., Adalsteinsson, E., Pfefferbaum, A. 2006; 16 (7): 1030-1039


    The corpus callosum, the principal white matter structure enabling interhemispheric information transfer, is heterogeneous in its microstructural composition, heterotopic in its anteroposterior cortical connectivity, and differentially susceptible to aging. In vivo characterization of callosal features is possible with diffusion tensor imaging (DTI), a magnetic resonance imaging method sensitive to the detection of white matter's linear structure. We implemented a quantitative fiber tracking approach to examine age-related variation in regional microstructural characteristics [fractional anisotropy (FA) and apparent diffusion coefficient (ADC)] of callosal fibers in 10 younger (29 +/- 5 years) and 10 older (72 +/- 5 years) healthy adults. Fiber tracking was performed on 2.5 mm isotropic voxels collected at 3 T. Fiber targets comprised the midsagittal corpus callosum, divided into six regions based on known callosal anatomical projections. FA and ADC for each voxel of each fiber identified were determined; lower FA and higher ADC reflect degraded microstructural tissue integrity. Older subjects had lower FA (P < 0.002), higher ADC (P < 0.006), and fewer (P < 0.005) fibers than younger subjects. Group x region interactions indicated disproportionately lower FA (P = 0.0001) and higher ADC (P < 0.006) in the older than younger group in frontal fiber bundles relative to posterior bundles. As a test of the functional significance of the fiber bundle metrics, the older subjects were administered the Stroop Task, which showed significant correlations between regional fiber bundle integrity and performance. These results validate this quantitative fiber tracking approach and confirm the selective vulnerability of frontal white matter systems to normal aging, likely substrates of age-related declines in cognitive processes dependent on prefrontal circuitry integrity.

    View details for DOI 10.1093/cercor/bhj045

    View details for Web of Science ID 000238391200012

    View details for PubMedID 16207932

  • Dysmorphology and microstruotural degradation of the corpus callosum: Interaction of age and alcoholism NEUROBIOLOGY OF AGING Pfefferbaum, A., Adalsteinsson, E., Sullivan, E. V. 2006; 27 (7): 994-1009


    Chronic alcohol abuse is a ubiquitous health and societal problem, with a growing prevalence in the older population. Alcoholism is a source of substantial deterioration in brain tissue and has been consistently observed in vivo and postmortem in white matter. To quantify the potential compounded effect of age and alcoholism, we used conventional structural MRI and diffusion tensor imaging (DTI) to examine the macrostructural and microstructural integrity of the corpus callosum, one of the most prominent white matter structures of the brain, in 131 adults, age 27-75 years. Compared with the 74 controls, the 40 alcoholic men and 17 alcoholic women, who were abstinent from alcohol for an average of 3 months, showed similar patterns and extents of callosal shrinkage, which was greatest in the genu and body and less prominent in the splenium. Microstructural integrity was measured with DTI as fractional anisotropy, an index of intravoxel orientational coherence of white matter fibers, and bulk mean diffusivity, an index of the amount of intravoxel water motility. The macrostructural shrinkage was accompanied by abnormalities in anisotropy and diffusivity of the microstructural environment of these callosal regions, indicative of disruption of structural constituents of local brain white matter. Correlational analyses revealed an age-alcohol interaction, where older alcoholics had smaller genu and splenium and higher diffusivity in these regions than younger alcoholics. Significant correlations between regional MRI and DTI measures and performance on working memory, visuospatial ability, and gait and balance provided evidence for the functional ramifications of the callosal abnormalities in the alcoholics. Thus, despite abstinence from alcohol, the interaction of age and recent alcoholism history exerted a compounded untoward effect on callosal macrostructure and microstructure.

    View details for DOI 10.1016/j.neurobiolaging.2005.05.007

    View details for Web of Science ID 000238012700011

    View details for PubMedID 15964101

  • Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part I: Adult brain growth ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Adalsteinsson, E., Sood, R., Mayer, D., Bell, R., McBride, W., Li, T., Pfefferbaum, A. 2006; 30 (7): 1234-1247


    The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat.We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions.Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain structures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error.Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter-dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease.

    View details for DOI 10.1111/j.1530-0277.2006.00145.x

    View details for Web of Science ID 000238253100018

    View details for PubMedID 16792572

  • FMRI evidence for individual differences in premotor modulation of extrastriatal visual-perceptual processing of redundant targets NEUROIMAGE Schulte, T., CHEN, S. H., Muller-Oehring, E. M., Adalsteinsson, E., Pfefferbaum, A., Sullivan, E. V. 2006; 30 (3): 973-982


    To perceive the vast array of stimuli in the world around us, the visual system employs parallel processing mechanisms that ensure efficiency in perceiving multiple objects in a scene. A way to test this efficiency is to measure reaction time (RT) to pairs of identical stimuli, presented singly or as doublets; typically, the resulting phenomenon is the redundant targets effect (RTE), which manifests as faster RTs to paired than singly presented stimuli. It is controversial, however, whether the neural locus of the parallel processing mechanisms invoked to produce the RTE is perceptual or motor and why some studies observe a substantial RTE and others do not. To resolve these two issues, we measured the RTE in young adults while undergoing functional MRI. Regarding the question of a perceptual or motor basis for the RTE, we observed that bilateral activation of extrastriate cortex was prominent in paired vs. the sum of the two single stimulus conditions, indicating that the RTE invoked perceptual mechanisms; by contrast, the motor cortex was not disproportionately activated in this comparison. Regarding the magnitude of the RTE, we compared activation patterns in individuals with small vs. large RTEs and observed that frontal and premotor areas were activated with small RTEs. These data indicate that the primary processing level of response facilitation, observed as the RTE, is perceptual, but the modulation of the RTE magnitude is premotor and associated with basic aspects of response selection and preparation.

    View details for DOI 10.1016/j.neuroimage.2005.10.023

    View details for Web of Science ID 000236894800030

    View details for PubMedID 16356737

  • Visuoperceptual learning in alcoholic Korsakoff syndrome ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Pfefferbaum, A., Sullivan, E. V. 2006; 30 (4): 680-687


    Relative to the characteristically profound deficits of explicit memory, components of implicit memory remain largely intact in patients with alcohol-induced Korsakoff syndrome (KS). Perceptual priming occurs in KS and transfer of learning has been consistently observed on mirror reading, a perceptual reversal task. Although priming also occurs with fragmented pictures, a perceptual closure task, it is unclear whether transfer of learning can occur. This study examined visuoperceptual learning in 4 men with alcoholic KS, 9 recently detoxified alcoholic men (ALC), 21 healthy age-matched normal control men (NC), and 6 young normal control men (YNC). Subjects were tested with the Gollin Incomplete Pictures Test at initial and 1-hour and 1-day retest sessions. Both alcoholic groups (KS, ALC) were impaired in visuoperceptual ability. All subject groups showed visuoperceptual learning. The KS group showed additional learning after continued exposure to the stimuli, despite their nonmnemonic visuospatial deficits and profound explicit memory impairment for the test stimuli. Transfer of learning to similar but new stimuli was not evident in either the KS or young healthy control subjects; learning occurred only for the specific items presented. The persistence of learning beyond the life of the percept, which was independent of declarative features (such as item recall), suggests that perceptual learning and memory reflects an intact cognitive memory process in KS. This process is likely mediated by posterior cortical networks relatively unaffected in KS and that are independent of the hippocampal-diencephalic declarative memory system.

    View details for DOI 10.1111/j.1530-0277.2006.00085.x

    View details for Web of Science ID 000236756300013

    View details for PubMedID 16573587

  • Deformation-based brain morphometry to track the course of alcoholism: Differences between intra-subject and inter-subject analysis PSYCHIATRY RESEARCH-NEUROIMAGING Rohlfing, T., SULLIVAN, E. V., Pfefferbaum, A. 2006; 146 (2): 157-170


    Substantial changes in brain morphology mark the course of alcoholism from development through dependence, recovery, and relapse. These changes can be characterized with deformation-based morphometry, which quantifies shape differences between anatomical structures, either in different subjects (cross-sectional) or in the same subject over time (longitudinal). Here we present analyses of data from a longitudinal magnetic resonance imaging (MRI) study on the effects of alcoholism on brain structure. Images were acquired from alcoholic women (n=7, mean age 47.8+/-8.3 years) and age-matched control women (n=16, mean age 51.2+/-7.5 years). From each subject, we acquired two structural MR brain images, separated by approximately 2 years (mean 21.6+/-7 months). We performed two types of morphometry using log-Jacobian maps of inter-subject and intra-subject nonrigid coordinate transformations, justified by the invariance of relevant statistics (mean, standard deviation, z-score, and t-test) under changes of the spatial and temporal reference coordinate system. With all images from one time point, a cross-sectional inter-subject morphometry determined group differences between alcoholics and normal controls. We compared these results with longitudinal intra-subject morphometry based on two images per subject acquired at different times (approximately 2 years apart). Inter- and intra-subject analysis produced partially conflicting results. Whereas the intra-subject analysis indicated faster ventricular volume increases in the alcoholics (+11% per year) than in the controls (+2% per year), the inter-subject analysis showed, on average, smaller absolute ventricle volumes in the alcoholics than in the controls (-33% relative volume). These differences were confirmed by manual planimetry and were statistically significant whether tested based on difference or change, integrated over the volume of the ventricles. Other changes and group differences were consistent between the two analyses, e.g., reduction of white matter (including corpus callosum) and increase in CSF volume, and these are in agreement with established effects of alcoholism on brain structure. We conclude that intra-subject morphometry of longitudinal data is preferable to inter-subject morphometry for detecting dynamic changes due to a disease, especially when only small samples are available. Our analysis demonstrates that the distinction between group differences observed at a point in time vs. over time is not merely academic but can substantially reduce the validity of the outcomes of actual morphometric studies. This discrepancy in results underscores the importance of distinguishing between volume differences and volume changes in morphometric analyses.

    View details for DOI 10.1016/j.pscychresns.2005.12.002

    View details for Web of Science ID 000237123700006

    View details for PubMedID 16500088

  • Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2006; 59 (4): 364-372


    Postmortem and in vivo studies consistently report degeneration of brain white matter in alcohol-dependent men and women. The full extent of the white matter involvement in uncomplicated alcoholism, however, is unknown, yet knowledge of the distribution of white matter degradation might provide clues to mechanisms underlying the pathology.To examine whether the white matter involvement is widespread or, alternatively, is regionally restricted in uncomplicated alcoholism, we used in vivo magnetic resonance diffusion tensor imaging (DTI) to quantify the microstructure of brain tissue. Accordingly, we acquired DTI data in 57 alcoholics (40 men, 17 women) who had been sober, on average, for 3 months and 74 demographically-matched control subjects (32 men, 42 women). Alcoholic men had consumed about twice as much alcohol in their lifetimes as the alcoholic women. Supratentorial white matter fractional anisotropy (FA), a DTI measure of intravoxel orientational coherence of tissue, was calculated across the full anterior-posterior extent of the brain in coronal sections, and a slice profile of the mean white matter FA was created for each subject. Group differences between alcoholics and control subjects were tested for each slice in three regions: the left and right hemispheres and a midsagittal sample; men and women were tested separately.Alcoholic men and women each showed widespread FA deficits in all three regions relative to their gender-matched control subjects that were evident on a slice-by-slice basis. Furthermore, the number of slices showing FA deficits was significantly greater in the alcoholic men than women.The widespread distribution of white matter deficits is in contrast to the highly regional-specific deficits seen in nutritional deficiency syndromes that can accompany alcoholism.

    View details for DOI 10.1016/j.biopsych.2005.06.025

    View details for Web of Science ID 000235670800010

    View details for PubMedID 16125148

  • Diffusion tensor imaging and aging NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Sullivan, E. V., Pfefferbaum, A. 2006; 30 (6): 749-761


    Magnetic resonance diffusion tensor imaging (DTI) is a non-invasive in vivo method for characterizing the integrity of anatomical connections and white matter circuitry and provides a quantitative assessment of the brain's white matter microstructure. DTI studies reveal age-related declines in white matter fractional ansiotropy (FA) in normal healthy adults in whom volume declines are not necessarily detectable. The decline is equivalent in men and women, is linear from about age 20 years onwards, and has a frontal distribution. Studies combining regional DTI metrics and tests of specific cognitive and motor functions have shown that age-related declines in white matter integrity are associated with similar declines in interhemispheric transfer, especially dependent on frontal systems. Emerging from recent DTI findings and conceptualizations of neural causes of cognitive decline in aging, we propose three white matter-mediated neural system hypotheses of aging brain structure and function: (1) the anteroposterior gradient, (2) bilateral recruitment of brain systems via the corpus callosum for frontally based task execution, and (3) frontocerebellar synergism. These hypotheses are not mutually exclusive but establish a basis for posing testable questions about brain systems recruited when those used in youth are altered by aging.

    View details for DOI 10.1016/j.neubiorev.2006.06.002

    View details for Web of Science ID 000241208800004

    View details for PubMedID 16887187

  • Regional striatal volume abnormalities in schizophrenia: Effects of comorbidity for alcoholism, recency of alcoholic drinking, and antipsychotic medication type SCHIZOPHRENIA RESEARCH Deshmukh, A., Rosenbloom, M. J., De Rosa, E., Sullivan, E. V., Pfefferbaum, A. 2005; 79 (2-3): 189-200


    Striatal structures form critical nodes of multiple circuits that are implicated in the pathophysiology of schizophrenia and alcoholism. Here, we examined the separate and combined effects of schizophrenia and alcoholism and effects of medication type and drinking recency on striatal volumes. Accordingly, we measured caudate nucleus, putamen, and nucleus accumbens in 27 schizophrenic, 25 alcohol-dependent, 19 comorbid (schizophrenia and alcohol dependence or abuse), and 51 age-matched control men. Schizophrenics were classified by antipsychotic medication (typical or atypical), and alcoholics were classified by recency of sobriety. All measured structures were smaller in the patient groups than the control group. The caudate deficit was comparable across groups, whereas putamen and nucleus accumbens deficits were greater in schizophrenia than alcoholism; comorbids fell between these groups. Schizophrenic patients treated with atypical medication showed greater volume deficits in the putamen than those treated with typical medication. Recently sober (<3 weeks) alcoholics had greater deficits in nucleus accumbens than longer sober drinkers. In conclusion, caudate, putamen, and nucleus accumbens exhibited different patterns of volume deficit in patients with alcoholism and schizophrenia alone, with no evidence for compounded deficits in comorbid patients. Further, these cross-sectional data provide indirect support for at least partial recovery of nucleus accumbens volume with sobriety in alcoholics, regardless of schizophrenia comorbidity.

    View details for DOI 10.1016/j.schres.2005.04.025

    View details for Web of Science ID 000233074600005

    View details for PubMedID 15963693

  • Corpus callosal microstructural integrity influences interhemispheric processing: A diffusion tensor imaging study CEREBRAL CORTEX Schulte, T., Sullivan, E. V., Muller-Oehring, E. M., Adalsteinsson, E., Pfefferbaum, A. 2005; 15 (9): 1384-1392


    Normal aging and chronic alcoholism result in disruption of brain white matter microstructure that does not typically cause complete lesions but may underlie degradation of functions requiring interhemispheric information transfer. We examined whether the microstructural integrity of the corpus callosum assessed with diffusion tensor imaging (DTI) would relate to interhemispheric processing speed. DTI yields estimates of fractional anisotropy (FA), a measure of orientation and intravoxel coherence of water diffusion usually in white matter fibers, and diffusivity (), a measure of the amount of intracellular and extracellular fluid diffusion. We tested the hypothesis that FA and would be correlated with (i) the crossed-uncrossed difference (CUD), testing visuomotor interhemispheric transfer; and (ii) the redundant targets effect (RTE), testing parallel processing of visual information presented to each cerebral hemisphere. FA was lower and higher in alcoholics than in controls. In controls but not alcoholics, large CUDs correlated with low FA and high in total corpus callosum and regionally in the genu and splenium. In alcoholics but not controls, small RTEs, elicited with equiluminant stimuli, correlated with low FA in genu and splenium and high in the callosal body. The results provide in vivo evidence for disruption of corpus callosum microstructure in normal aging and alcoholism that has functional ramifications for efficiency in interhemispheric processing.

    View details for DOI 10.1093/cercor/bhi020

    View details for Web of Science ID 000231296900010

    View details for PubMedID 15635059

  • Neurocircuitry in alcoholism: a substrate of disruption and repair PSYCHOPHARMACOLOGY Sullivan, E. V., Pfefferbaum, A. 2005; 180 (4): 583-594


    The chronic, excessive consumption of alcohol results in significant modification of selective neural systems of the brain structure, physiology, and function. Quantitative MR structural imaging, diffusion tensor imaging (DTI), and functional MRI (fMRI), together with neuropsychological challenges, have enabled rigorous in vivo characterization of the results of alcoholism on the brain in the human condition. Neuroimaging has also enabled longitudinal study for the examination of alcoholism's dynamic course through periods of drinking and sobriety. Controlled studies have revealed compelling evidence for alcohol-related brain structural and functional modification--some longstanding, some transient, and some compensatory. Patterns of circuitry disruption identified through structural and functional MRI studies suggest a central role for degradation of frontocerebellar neuronal nodes and connecting circuitry affecting widespread brain regions and contributing to alcoholism's salient, enduring, and debilitating cognitive and motor deficits--executive dysfunction, visuospatial impairment, and ataxia.

    View details for DOI 10.1007/s00213-005-2267-6

    View details for Web of Science ID 000231731800002

    View details for PubMedID 15834536

  • Alcoholic neurobiology: Changes in dependence and recovery ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Crews, F. T., Buckley, T., Dodd, P. R., Ende, G., Foley, N., Harper, C., He, J., Innes, D., Loh, E. W., Pfefferbaum, A., Zou, J., SULLIVAN, E. V. 2005; 29 (8): 1504-1513


    This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October, 2004. Chronic alcoholism follows a fluctuating course, which provides a naturalistic experiment in vulnerability, resilience, and recovery of human neural systems in response to presence, absence, and history of the neurotoxic effects of alcoholism. Alcohol dependence is a progressive chronic disease that is associated with changes in neuroanatomy, neurophysiology, neural gene expression, psychology, and behavior. Specifically, alcohol dependence is characterized by a neuropsychological profile of mild to moderate impairment in executive functions, visuospatial abilities, and postural stability, together with relative sparing of declarative memory, language skills, and primary motor and perceptual abilities. Recovery from alcoholism is associated with a partial reversal of CNS deficits that occur in alcoholism. The reversal of deficits during recovery from alcoholism indicates that brain structure is capable of repair and restructuring in response to insult in adulthood. Indirect support of this repair model derives from studies of selective neuropsychological processes, structural and functional neuroimaging studies, and preclinical studies on degeneration and regeneration during the development of alcohol dependence and recovery form dependence. Genetics and brain regional specificity contribute to unique changes in neuropsychology and neuroanatomy in alcoholism and recovery. This symposium includes state-of-the-art presentations on changes that occur during active alcoholism as well as those that may occur during recovery-abstinence from alcohol dependence. Included are human neuroimaging and neuropsychological assessments, changes in human brain gene expression, allelic combinations of genes associated with alcohol dependence and preclinical studies investigating mechanisms of alcohol induced neurotoxicity, and neuroprogenetor cell expansion during recovery from alcohol dependence.

    View details for DOI 10.1097/01.alc.0000175013.50644.61

    View details for Web of Science ID 000231767900018

    View details for PubMedID 16156047

  • Cortical NAA deficits in HIV infection without dementia: Influence of alcoholism comorbidity NEUROPSYCHOPHARMACOLOGY Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2005; 30 (7): 1392-1399


    Alcoholism comorbidity is highly prevalent in individuals infected with human immunodeficiency virus (HIV). Each condition is known to affect brain structure, function, and metabolism, but the combined effects on the brain have only recently been considered. Single-voxel, proton MR spectroscopy (MRS) has yielded sensitive measures of early brain deterioration in the progression of HIV, but has limited coverage of neocortex, whereas MRS imaging (MRSI) can simultaneously interrogate large regions of cortex. Included were 15 men with HIV+alcoholism, nine men with HIV alone, eight men with alcoholism alone (abstinent for 3-17 months), and 23 controls. The two HIV groups were matched in T-cell count and were not demented; the two alcoholism groups were relatively matched in lifetime alcohol consumption. We used MRSI with a variable-density spiral sequence to quantify major proton metabolites--N-acetylaspartate (NAA), creatine (Cr), and choline (Cho)-in the superior parietal-occipital cortex. Metabolites were expressed in absolute units and as the NAA/Cr ratio. Significant group effects were present for NAA and Cr. Only the HIV+alcoholism group was significantly affected, exhibiting a 0.8 SD deficit in NAA and a 1.0 SD deficit in Cr. The deficits were not related to highly active antiretroviral therapy (HAART) status. Neither HIV infection nor alcoholism independently resulted in parietal-occipital cortical metabolite abnormalities, yet each disease carried a liability that put affected individuals at a heightened risk of neuronal compromise when the diseases were compounded. Further, the use of absolute measures revealed deficits in NAA and Cr that would have gone undetected if these metabolites were expressed as a ratio.

    View details for DOI 10.1038/sj.npp.1300723

    View details for Web of Science ID 000229881800017

    View details for PubMedID 15812566

  • Differentiating pathologic delta from healthy physiologic delta in patients with Alzheimer disease SLEEP Crowley, K., SULLIVAN, E. V., Adalsteinsson, E., Pfefferbaum, A., Colrain, I. M. 2005; 28 (7): 865-870


    In patients with Alzheimer disease, the electroencephalogram during wakefulness shows pathologic signs of abundant, diffuse, large-amplitude delta activity. The carryover of this abnormal delta activity into non-rapid eye movement sleep raises the question of whether the observed delta electroencephalographic activity during sleep in Alzheimer disease in any way reflects normal physiologic delta activity slow-wave sleep. The objective of the study was to compare patients with Alzheimer disease with age-matched controls using an experimentally controlled procedure that can test the capacity of the nervous system to generate physiologic delta-frequency responses during sleep.Research sleep laboratory.Seven ambulatory patients with Alzheimer disease (mean age = 70.0 +/- 5.77 years) meeting the National Institute of Neurological and Communicative Diseases and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease and 8 controls (mean age = 69.25 +/- 4.95 years), underwent at least 1 night of evoked-potential recordings.Data were collected during stage 2 sleep. Responses to stimuli were classified based on whether they produced a K-complex. Averages of K-complex responses were calculated, latencies and amplitudes of components evaluated, and K-complex incidence was determined. Relative to controls, subjects with Alzheimer disease produced significantly fewer evoked K-complexes (P < .001) and had substantially smaller N550 amplitudes than controls (P < .05). A lower probability of eliciting a K-complex correlated with greater dementia severity, as measured by the Mini Mental State Examination and Dementia Rating Scale.Despite observed increases in pathologic delta-frequency electroencephalographic activity, patients with Alzheimer disease have an impaired capacity to generate normal physiologic delta responses during non-rapid eye movement sleep.

    View details for Web of Science ID 000230501700016

    View details for PubMedID 16124667

  • Preservation of hippocampal volume throughout adulthood in healthy men and women NEUROBIOLOGY OF AGING Sullivan, E. V., Marsh, L., Pfefferbaum, A. 2005; 26 (7): 1093-1098


    To address controversies regarding the effect of age on the hippocampus, volumes of hippocampus and a comparison structure, temporal cortex, were measured on magnetic resonance imaging (MRI) in 84 healthy men and 44 healthy women (20-85 years). Neither men nor women showed significant correlations between hippocampal volumes and age, despite significant age-related decline in temporal volumes. Absence of hippocampus age relationships endured when restricting analyses to older individuals (> or =50 years) and considering menopause and hormone replacement therapy.

    View details for DOI 10.1016/j.neurobiolaging.2004.09.015

    View details for Web of Science ID 000227821000014

    View details for PubMedID 15748789

  • Frontal circuitry degradation marks healthy adult aging: Evidence from diffusion tensor imaging NEUROIMAGE Pfefferbaum, A., Adalsteinsson, E., Sullivan, E. V. 2005; 26 (3): 891-899


    In vivo study of white matter microstructural integrity through magnetic resonance diffusion tensor imaging (DTI) permits examination of degradation of axonal circuitry that may underlie functional decline of frontally-based processes in normal adult aging. Determination of the pattern of age-related degradation of white matter microstructure requires quantitative comparison of the rostral-caudal and superior-inferior extents of the brain's white matter. To date, this has not been accomplished, probably because of significant artifacts from spatial distortion and poor signal resolution that precludes accurate analysis in prefrontal and inferior brain regions. Here, we report a profile analysis of the integrity of white matter microstructure across the supratentorium and in selected focal regions using DTI data collected at high-field strength (3 T), with isotropic voxel acquisition, and an analysis based on a concurrently-acquired field map to permit accurate quantification of artifact-prone, anterior and inferior brain regions. The groups comprised 10 younger and 10 older individuals; all were high functioning, highly educated, and in excellent health. The DTI profile analysis revealed a robust frontal distribution of low white matter anisotropy and high bulk mean diffusivity in healthy older compared with younger adults. In contrast to frontal fiber systems, posterior systems were largely preserved with age. A second analysis, based on focal samples of FA, confirmed that the age-related FA decline was restricted to frontal regions, leaving posterior and inferior brain regions relatively intact. The selective decline of anterior anisotropy with advancing age provides evidence for the potential of a microstructural white matter mechanism for the commonly observed decline in frontally-based functions.

    View details for DOI 10.1016/j.neuroimage.2005.02.034

    View details for Web of Science ID 000230211100025

    View details for PubMedID 15955499

  • Striatal and forebrain nuclei volumes: Contribution to motor function and working memory deficits in alcoholism BIOLOGICAL PSYCHIATRY Sullivan, E. V., Deshmukh, A., De Rosa, E., Rosenbloom, M. J., Pfefferbaum, A. 2005; 57 (7): 768-776


    Striatal structures are involved in dopaminergic alcohol reward mechanisms and aspects of motor control. Basal forebrain structures hold cholinergic mechanisms influencing memory formation, vulnerable to chronic alcoholism; however, alcoholism's effect on volumes of these structures has seldom been considered with in vivo measurement.We measured bilateral volumes of caudate nucleus, putamen, nucleus accumbens, and medial septal/diagonal band (MS/DB) in 25 men with alcohol dependence and 51 age-matched control men. Six alcoholic subjects had been drinking recently, and 19 had been sober.Volumes of caudate and putamen were smaller in the alcoholics than in the control subjects, regardless of length of sobriety. Recent drinkers showed greater deficits in nucleus accumbens than sober alcoholics. Putamen volume was positively correlated with grip strength; MS/DB volume was positively correlated with verbal working memory independently of the negative association between age-standardized MS/DB and age in alcoholics.Caudate and putamen volume deficits occur and endure in chronic alcoholism. Nucleus accumbens might be especially sensitive to recent alcohol exposure. Striatal volumes should be considered in functional imaging studies of alcohol craving that target striatal brain regions. The age-alcohol interaction for MS/DB volumes is consistent with a cholinergic mechanism for the working memory impairment observed in the alcoholics.

    View details for DOI 10.1016/j.biopsych.2004.12.012

    View details for Web of Science ID 000228125000011

    View details for PubMedID 15820234

  • Persistent cognitive deficits in community-treated alcoholic men and women volunteering for research: Limited contribution from psychiatric comorbidity JOURNAL OF STUDIES ON ALCOHOL Rosenbloom, M. J., O'Reilly, A., Sassoon, S. A., SULLIVAN, E. V., Pfefferbaum, A. 2005; 66 (2): 254-265


    The contribution of psychiatric comorbidity to cognitive status was assessed in a sample of treatment-seeking alcoholics who met criteria to participate in studies of effects of chronic alcohol misuse on brain structure and cognition.Alcoholic men (n = 43) and women (n = 21) who responded to notices about a research study were screened, clinically assessed and administered Wechsler Memory and Intelligence tests after 3 months of sobriety, on average. Cognitive performance was compared with that of an age-matched sample of healthy controls (n = 51).As a group, the alcoholics achieved significantly lower scores than controls on summary indices of the Wechsler Memory and Adult Intelligence Scales and showed greater decline from estimated premorbid intelligence levels than controls. Almost 60% of the alcoholics had at least one additional psychiatric (mood or anxiety) or past substance-dependence comorbidity. There were no marked sex differences in patterns of comorbidity. Comorbid alcoholics were younger, had consumed less alcohol over their lifetime and performed between noncomorbid alcoholics and controls on all tests.Mood and anxiety comorbidity did not necessarily compound poor cognitive test performance associated with chronic alcohol misuse. While unexpected, this finding suggests that, in this sample, poorer cognitive performance was more a function of alcoholism per se than nonalcoholic comorbidity.

    View details for Web of Science ID 000229028100012

    View details for PubMedID 15957677

  • Neuroimaging of rodent and primate models of alcoholism: Initial reports from the integrative neuroscience initiative on alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Sable, H. J., Strother, W. N., Friedman, D. P., Davenport, A., Tillman-Smith, H., Kraft, R. A., Wyatt, C., Szeliga, K. T., Buchheimer, N. C., Daunais, J. B., Adalsteinsson, E., Pfefferbaum, A., Grant, K. A. 2005; 29 (2): 287-294


    Neuroimaging of animal models of alcoholism offers a unique path for translational research to the human condition. Animal models permit manipulation of variables that are uncontrollable in clinical, human investigation. This symposium, which took place at the annual meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, on June 29th, 2004, presented initial findings based on neuroimaging studies from the two centers of the Integrative Neuroscience Initiative on Alcoholism funded by the National Institute on Alcohol Abuse and Alcoholism. Effects of alcohol exposure were assessed with in vitro glucose metabolic imaging of rat brain, in vitro receptor imaging of monkey brain, in vivo magnetic resonance imaging of monkey brain, and in vivo magnetic resonance spectroscopic quantification of alcohol metabolism kinetics in rat brain.

    View details for DOI 10.1097/01.ALC.0000153546.39946.EC

    View details for Web of Science ID 000227221700013

    View details for PubMedID 15714052

  • Disruption of brain white matter microstructure by excessive intracellular and extracellular fluid in alcoholism: Evidence from diffusion tensor imaging NEUROPSYCHOPHARMACOLOGY Pfefferbaum, A., SULLIVAN, E. V. 2005; 30 (2): 423-432


    Magnetic resonance diffusion tensor imaging (DTI) has revealed the disruption of brain white matter microstructure in normal aging and alcoholism undetectable with conventional structural MR imaging. The metrics of DTI can be useful in establishing the nature of the observed microstructural aberrations. Abnormally low fractional anisotropy (FA), a measure of diffusion orientation and coherence, may result from increased intracellular or extracellular fluid, which would be reflected in complementary high apparent diffusion coefficients (bulk mean diffusivity) and low FA, or from disorganization of fiber structure, which would be reflected in low FA but with a lack of the inverse FA and diffusivity relationship. To test these competing possibilities, we examined 15 alcoholic men and 31 control men with DTI to quantify diffusivity in the genu and splenium of the corpus callosum and centrum semiovale. In addition to the previously observed FA deficits in all the three brain regions, the alcoholics had abnormally high white matter diffusivity values in the genu and centrum. Further, inverse correlations between FA and diffusivity were significant in the genu (r=-0.52, p<0.05) and centrum (r=-0.92, p=0.0001). Multiple regression analyses examining diffusivity and age as predictors of FA identified diffusivity as a significant unique contributor to FA in both regions. These results suggest that decreased orientational coherence of brain white matter in alcoholism is attributable, at least in part, to the accumulation of intracellular and extracellular fluid in excess of that occurring in aging, and that the differential influence of these fluid compartments can vary across brain regions.

    View details for DOI 10.1038/sj.npp.1300623

    View details for Web of Science ID 000226569900022

    View details for PubMedID 15562292

  • Differential effect of HIV infection and alcoholism on conflict processing, attentional allocation, and perceptual load: Evidence from a Stroop Match-to-Sample task BIOLOGICAL PSYCHIATRY Schulte, T., Mueller-Oehring, E. M., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2005; 57 (1): 67-75


    Alcoholism and human immunodeficiency virus (HIV) infection each can impair components of selective attention, probably through disruption of the integrity of the frontoparietal neural systems that underlie conflict processing, attentional allocation, and perceptual load.We studied 18 patients with alcoholism (ALC) alone, 19 with HIV infection alone (HIV), 20 with both disorders (H+A), and 19 healthy control subjects (CTL). We used a novel paradigm (Stroop Match-to-Sample tasks), in which subjects saw either a valid or invalid color cue before a target word, printed in a color that was either congruent or incongruent with the word's meaning.All groups showed a significant Stroop effect, cue-target color Match effect, and interaction between Match and Stroop, with an exaggerated Stroop effect for the Match condition. The HIV patients were comparable to CTL, whereas ALC showed mild delays, with further delays associated with comorbidity with HIV. Although H+A profited from a valid match to Stroop stimuli, they were compromised in disengaging attention from the invalidly cued color.Impairment in conflict processing and attentional allocation in alcoholism suggests disruption of frontal-parietal attentional systems. Although HIV alone did not demonstrate detectable impairment in performance, HIV conferred liability on attentional processes when combined with alcohol abuse.

    View details for DOI 10.1016/j.biopsych.2004.09.025

    View details for Web of Science ID 000226421800010

    View details for PubMedID 15607302

  • In vivo structural imaging of the rat brain with a 3-T clinical human scanner JOURNAL OF MAGNETIC RESONANCE IMAGING Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2004; 20 (5): 779-785


    To examine the feasibility of using product acquisition software on a 3-T human MRI system to acquire high-resolution structural brain images in the rat.Three sets of dual spin-echo, high-resolution (0.234 x 0.234 mm in-plane, 0.5 mm thick) images covering the entire rat brain were collected and averaged in 66 min. The images had sufficient signal-to-noise ratio (SNR) and resolution for visual identification and manual outlining of exemplary structures, including the lateral ventricles and dorsal and ventral portions of the hippocampus. Further, the data were adequate for unsupervised, automated segmentation, permitting quantification of the dorsolateral ventricles. The images compared favorably with those collected on a 7-T system.Interrater reliabilities (intraclass correlations) of manual ventricular scoring were greater than 0.97, and manual vs. automated correlations were 0.97. The variability of lateral ventricular size across animals was substantially higher than that of the hippocampus.The large variability of some brain structures that can exist across even a highly selected strain of rats can readily be detected with the use of human 3-T systems for the study of small animals.

    View details for DOI 10.1002/jmri.20181

    View details for Web of Science ID 000224762700006

    View details for PubMedID 15503335

  • Perceptual learning in detoxified alcoholic men: Contributions from explicit memory, executive function, and age ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Pfefferbaum, A., Sullivan, E. V. 2004; 28 (11): 1657-1665


    Visuospatial and visuoperceptual deficits have consistently been observed in detoxified alcoholics; however, the severity of impairment varies with test and task type. Identifying the component processes and factors that underlie a particular deficit may reveal why some visuospatial and visuoperceptual tasks are more compromised than others and may lead to the specification of neural systems that are particularly vulnerable in alcoholism.We examined visuoperception and perceptual learning with a picture fragment identification task in 51 recently detoxified nonamnesic alcoholic men (aged 29-66 years) compared with 63 normal control men (aged 21-70 years). Executive function and explicit declarative memory were also assessed.Despite deficits in the primary components of visuoperception and explicit memory for visuospatial stimuli, the alcoholics showed normal perceptual learning. Although the alcoholics and controls performed at comparable levels on the perceptual learning task, multiple regression analyses indicated that the factors accounting for perceptual learning variance differed between and within groups. Visuoperceptual abilities consistently predicted perceptual learning in the control subjects but not the alcoholic subjects. Explicit memory contributed to perceptual learning performance in both the alcoholic and control groups. Frontal executive ability consistently predicted perceptual learning in the alcoholic subjects, but it had predictive ability only in the control subjects as time elapsed. Age was significantly correlated with perceptual learning performance in both groups. Lifetime alcohol consumption, but not alcoholism duration, was an independent predictor of 1-hr perceptual learning.These correlational analyses suggest that controls invoke basic visuospatial processes to perform a perceptual learning task, whereas alcoholics invoke higher-order cognitive processes (i.e., frontal executive systems) to perform the same task at normal levels. Use of more demanding cognitive systems by the alcoholics may be less efficient and more costly to processing capacity than those invoked by controls.

    View details for DOI 10.1097/01.ALC.0000145690.48510.DA

    View details for Web of Science ID 000225201900009

    View details for PubMedID 15547452

  • Brain volumes, RBC status, and hepatic function in alcoholics after 1 and 4 weeks of sobriety: Predictors of outcome AMERICAN JOURNAL OF PSYCHIATRY Pfefferbaum, A., Rosenbloom, M. J., Serventi, K. L., SULLIVAN, E. V. 2004; 161 (7): 1190-1196


    The authors asked if hematological indices of RBC status and hepatic function in newly sober alcoholic men are related to abnormalities in brain morphology, change with normalization of brain function during short-term sobriety, and predict prolonged sobriety.Alcoholic men received brain magnetic resonance imaging and laboratory assessments on admission and before discharge from an inpatient treatment program. Healthy comparison men were similarly tested.On admission, RBC count, hemoglobin level, and hematocrit were significantly lower in alcoholic subjects than comparison subjects; mean corpuscular volume, SGOT, SGPT, and gamma-glutamyl transpeptidase were significantly higher. By discharge, all measures had improved, although RBC count, mean corpuscular volume, and gamma-glutamyl transpeptidase levels remained significantly different from those of comparison subjects. Upon admission, alcoholic men had smaller cortical white and gray matter and larger lateral and third ventricle volumes, with reduced lateral ventricle and increased anterior cortical gray matter volumes by discharge. Lower RBC count, hemoglobin level, and hematocrit were associated with lower white matter and higher ventricular volumes at admission. Change in these measures was related to reduction in ventricular volume with treatment. By discharge, associations among RBC count, hemoglobin level, and hematocrit and white matter and ventricular volumes were less marked than at admission. Discharge hemoglobin value and hematocrit discriminated patients who maintained sobriety from those who relapsed. Hepatic function showed limited association with brain measures at admission and discharge.Hemograms reflect alcohol-related abnormalities in brain morphology, improvement over short-term sobriety, and liability to relapse after treatment.

    View details for Web of Science ID 000222462700008

    View details for PubMedID 15229050

  • Recovery of short-term memory and psychomotor speed but not postural stability with long-term sobriety in alcoholic women NEUROPSYCHOLOGY Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2004; 18 (3): 589-597


    The authors assessed effects of extended abstinence on cognitive and motor function deficits previously observed in a group of alcoholic women (n = 43) initially tested after 15 weeks of sobriety. Alcoholic women were retested 1 and 4 years later, and control women were retested 3 years later. At Year 1, 14 of 23 returners had maintained sobriety, but they did not perform significantly better than relapsers; the group as a whole continued to show deficits relative to age norms. By Year 4, 13 of 14 returners had maintained sobriety for more than 30 months; as a group, these women had returned to normal levels on tests of memory and psychomotor speed but remained impaired in standing balance.

    View details for DOI 10.1037/0894-4105.18.3.589

    View details for Web of Science ID 000222706700020

    View details for PubMedID 15291737

  • In vivo 2D J-resolved magnetic resonance spectroscopy of rat brain with a 3-T clinical human scanner NEUROIMAGE Adalsteinsson, E., Hurd, R. E., Mayer, D., Sailasuta, N., SULLIVAN, E. V., Pfefferbaum, A. 2004; 22 (1): 381-386


    A clinical 3-T scanner equipped with a custom-made transmit/receive birdcage coil was used to collect 2D J-resolved single-voxel spectroscopy in vivo of rat brain. Four adult Wistar rats were scanned twice each, with a 2-week interval. Voxel size was approximately 5 x 10 x 5 mm(3). Total spectroscopic acquisition time was 14 min for collection of two 4:20 min water-suppressed acquisitions and one 4:20 min acquisition acquired in the absence of water suppression. The unsuppressed water data were used in post-processing to reduce residual water side bands, as well as for metabolite signal normalization to account for variations in coil loading and voxel size. Peak areas were estimated for resonances from N-acetyl aspartate (NAA), creatine, choline, taurine, glutamate, and combined glutamate and glutamine. T(2)-relaxation times were estimated for NAA and creatine. The average deviation from the mean of repeated measures for glutamate, combined glutamate and glutamine, and taurine ranged from 7.6% to 18.3%, while for NAA, creatine, and choline, the deviation was less than 3%. The estimated T(2) values for NAA (mean +/- SD = 330 +/- 57 ms) and creatine (174 +/- 27 ms) were similar to those reported previously for rat brain and for human gray and white matter. These results indicate that reliable, small animal brain MR spectroscopy can be performed on a human clinical 3-T scanner.

    View details for DOI 10.1016/j.neuroimage.2003.12.046

    View details for Web of Science ID 000221190200039

    View details for PubMedID 15110030

  • Postmortem MR imaging of formalin-fixed human brain NEUROIMAGE Pfefferbaum, A., SULLIVAN, E. V., Adalsteinsson, E., Garrick, T., Harper, C. 2004; 21 (4): 1585-1595


    High-resolution postmortem neuroimaging of the brain can play a role in research programs by providing archival and reslicable images of brain specimens before permanent sectioning. These images can supplement evidence attained from both traditional neuropathological observations and in vivo neuroimaging. Differential brain tissue conspicuity, detectable with MRI, is determined by the density and mobility of water protons. Water content is about 70% in white matter, 80% in gray matter, and 99% in cerebrospinal fluid (CSF). To the extent that brain tissue contrast is determined by the number and microenvironment of water protons, timing parameters of MR image acquisition can interrogate this environment. Because the chemical environment of protons is different in living from dead tissue, optimal temporal imaging parameters, for example, for spin-echo imaging, commonly used for in vivo clinical and research study are different from those best for postmortem imaging. Here, we present a series of observations to identify relaxation times and optimal parameters for high-resolution structural imaging of formalin-fixed postmortem brain tissue using commercially available clinical scanners and protocols. Examples of high-resolution images and results from attempts at diffusion imaging are presented.

    View details for DOI 10.1016/j.neuroimage.2003.11.024

    View details for Web of Science ID 000220723900036

    View details for PubMedID 15050582

  • Balance and gait deficits in schizophrenia compounded by the comorbidity of alcoholism AMERICAN JOURNAL OF PSYCHIATRY Sullivan, E. V., Rosenbloom, M. J., Pfefferbaum, A. 2004; 161 (4): 751-755


    Alcoholism carries a liability of balance and gait instability that persists with sobriety. Such deficits are less well documented in schizophrenia and may be compounded by comorbidity with alcoholism, which is prevalent in schizophrenia.The authors administered quantitative ataxia tests to 10 patients comorbid for schizophrenia and alcohol dependence/abuse, 10 nonalcoholic patients with schizophrenia, 24 nonschizophrenic patients with alcohol dependence, and 27 age-matched comparison men.All three patient groups were impaired relative to the comparison subjects. The comorbid group was significantly more impaired than the alcoholic group on most tests and was more impaired than the schizophrenia patients, especially when tested with eyes open.Rigorous quantitative testing revealed gait and balance deficits in schizophrenia, even without alcohol dependence, and exacerbated deficits in schizophrenia comorbid with alcoholism. The enhancement of postural stability expected with visual information was dampened in comorbid patients, implicating compromised sensorimotor integrative abilities.

    View details for Web of Science ID 000221276200026

    View details for PubMedID 15056526

  • The human basal forebrain integrates the old and the new NEURON De Rosa, E., Desmond, J. E., Anderson, A. K., Pfefferbaum, A., SULLIVAN, E. V. 2004; 41 (5): 825-837


    Acquisition of new learning is challenged by the phenomenon of proactive interference (PI), which occurs when previous learning disrupts later learning. Whereas human neuroimaging studies have focused on the cortical contributions to interference resolution, animal studies demonstrate that efficient resolution of PI depends on cholinergic modulation from basal forebrain (BF). Whether the BF promotes PI resolution in humans is unknown. Here, we adapted a PI paradigm from animal studies for use in a functional MRI experiment. During PI resolution, neurologically intact subjects recruited a BF network that included afferent anterior and posterior cortical sites associated with efficient memory acquisition and perceptual processing. Despite normal performance, nonamnesic patients with alcoholism, which is known to disrupt BF function, did not activate a BF network but instead invoked anterior cortical sites traditionally associated with executive function. These results provide evidence for parallel neural systems, each with the potential to resolve interference in the face of competing information.

    View details for Web of Science ID 000221458200016

    View details for PubMedID 15003180

  • Alcoholism damages the brain, but does moderate alcohol use? LANCET NEUROLOGY Pfefferbaum, A. 2004; 3 (3): 143-144

    View details for Web of Science ID 000220167400014

    View details for PubMedID 14980527

  • Morphological changes in aging brain structures are differentially affected by time-linked environmental influences despite strong genetic stability NEUROBIOLOGY OF AGING Pfefferbaum, A., SULLIVAN, E. V., Carmelli, D. 2004; 25 (2): 175-183


    This longitudinal study used the full twin model to estimate change and stability of genetic contributions to morphology of two brain structures, the corpus callosum and lateral ventricles. The 142 subjects were 34 monozygotic (MZ) and 37 dizygotic (DZ) elderly male twin pairs from the National Heart, Lung, and Blood Institute (NHLBI) Twin Study who underwent brain magnetic resonance imaging twice, separated by a 4-year interval. Genetic factors accounted for a substantial portion of individual differences in the size of the corpus callosum and its substructures and of lateral ventricular size. Longitudinal genetic analyses revealed no significant change in the heritability of these structures and no evidence for new genetic variance at Time 2 not present at Time 1. However, both the callosal and ventricular measures showed evidence for new environmental variance at Time 2 not present at Time 1. Confirming a previously posed hypothesis, the phenotypic correlation between absolute change in height of the corpus callosum and absolute change in ventricular volume was significant. Bivariate genetic analysis estimated a significant genetic correlation between the changes in these two structures and the genetic variance in the change of callosal height was entirely due to genes involved in the expansion of ventricles. Genetic stability was present even in old age when brain and other morphological changes can be rapid and highly variable across individuals, inconsistent with an hypothesis that random DNA damage is the cause of aging.

    View details for DOI 10.1016/S0197-4580(03)00045-9

    View details for Web of Science ID 000188844200005

    View details for PubMedID 14749135

  • Effects of age and sex on volumes of the thalamus, pons, and cortex NEUROBIOLOGY OF AGING Sullivan, E. V., Rosenbloom, M., Serventi, K. L., Pfefferbaum, A. 2004; 25 (2): 185-192


    Volumes of thalamus, pons, cortical gray matter, and white matter were derived from MR brain images of healthy men and women spanning the adult age range in order to delineate patterns of aging and to compare age and sex effects in thalamus and pons with such effects in cortical gray and white matter volumes. Men had larger intracranial volume (ICV) than women, but ICV did not correlate with age in either sex. Thalamic, pontine, and cortical white matter volumes did not differ between men and women once ICV differences were taken into account, but men had more cortical gray matter than women even after accounting for ICV. Volumes of pons and thalamus were associated, independent of ICV, in women but not in men. Thalamic volume declined linearly with age at a similar rate in both men and women, whereas cortical gray matter volume declined more steeply with age in men than women. Both pontine and cortical white matter volumes remained stable across the age span in both men and women.

    View details for DOI 10.1016/S0197-4580(03)00044-7

    View details for Web of Science ID 000188844200006

    View details for PubMedID 14749136

  • Parallel interhemispheric processing in aging and alcoholism: relation to corpus callosum size NEUROPSYCHOLOGIA Schulte, T., Pfefferbaum, A., Sullivan, E. V. 2004; 42 (2): 257-271


    We tested parallel processing of visual information using the redundant targets effect (RTE) in 12 alcoholics and 13 matched controls. The paradigm was a simple reaction time (RT) task with targets presented in the same (uncrossed), opposite (crossed), or both (redundant) visual-fields. In older alcoholics (>50 years) the RT gain invoked by redundant targets did not exceed probability measures, suggesting compromised interhemispheric processing of parallel information in this subgroup compared with controls or younger alcoholics. The difference between crossed and uncrossed reaction times (CUD), an index of interhemispheric transfer time (ITT), was greater in older than younger subjects. Moreover, the CUD was negatively correlated with the corpus callosum (CC) total area and body in controls, supporting the concept of a structure-function relationship of interhemispheric transfer. This relationship was not found in alcoholics, although the midsagittal area of the CC, genu, and body but not intracranial volume (ICV), was significantly smaller in alcoholics than controls. These results suggest that chronic alcohol abuse together with advancing age exert subtle disruption on parallel interhemispheric processing reliant on callosal connections.

    View details for DOI 10.1016/S0028-3932(03)00155-6

    View details for Web of Science ID 000187220600012

    View details for PubMedID 14644111

  • In vivo 2D J-resolved magentic resonance spectroscopy of rat brain with a 3T clinical human scanner. NeuroImage in press. Pfefferbaum A, Adalsteinsson E, Hurd RE, Mayer D, Sailasuta N, Sullivan EV 2004
  • Brain volumes, blood chemistry, and liver function in alcoholics after one and four weeks of sobriety: Predictors of outcome. American Journal of Psychiatry in press. Pfefferbaum A, Rosenbloom MJ, Serventi KL, Sullivan EV 2004
  • Alcoholic drinking damages the brain; does moderate alcohol use? Lancet Neurology (March) in press. Pfefferbaum A 2004
  • Gray matter-N-acetyl aspartate deficits in secondary progressive but not relapsing-remitting multiple sclerosis AMERICAN JOURNAL OF NEURORADIOLOGY Adalsteinsson, E., Langer-Gould, A., Homer, R. J., Rao, A., SULLIVAN, E. V., Lima, C. A., Pfefferbaum, A., Atlas, S. W. 2003; 24 (10): 1941-1945


    Spectroscopic examination of multiple sclerosis (MS) patients has revealed abnormally low N-acetyl-aspartate (NAA) signal intensity, even in brain tissue that appears normal on high-resolution structural MR images but has yielded inconclusive evidence to distinguish the well-documented clinical differences between MS subtypes. This study used proton MR spectroscopic imaging (MRSI) and high-resolution MR imaging to characterize metabolite profiles in normal-appearing brain tissue of relapsing-remitting multiple sclerosis (RRMS) and secondary progressive (SP) MS.Volumetric spiral MRSI was used together with high-resolution MR imaging to derive absolute measures of metabolite concentrations separately in normal-appearing supratentorial cerebral gray matter and white matter in five RRMS patients, five SPMS patients, and nine age-matched controls. Structural MR images were segmented into compartments of gray matter, white matter, CSF, and lesions, and metabolite signals per unit of tissue volume were calculated for gray matter and white matter separately.Only the SPMS group had significantly lower NAA concentrations in normal-appearing gray matter compared with concentrations in controls. NAA in normal-appearing white matter was equally reduced in RRMS and SPMS patients. The functional relevance of this brain metabolite measure was suggested by the observed but statistically nonsignificant correlation between higher disability scores on the Expanded Disability Status Scale and lower gray matter NAA concentrations.The otherwise occult abnormality in supratentorial gray matter in SPMS but not RRMS may explain the more severe physical and cognitive impairments afflicting patients with SPMS that do not correlate well with visible lesion burden.

    View details for Web of Science ID 000186744800006

    View details for PubMedID 14625214

  • Replicability of diffusion tensor imaging measurements of fractional anisotropy and trace in brain JOURNAL OF MAGNETIC RESONANCE IMAGING Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2003; 18 (4): 427-433


    To evaluate within-scanner and between-scanner reliability of fractional anisotropy (FA) and trace (sum of the diagonal elements of the diffusion tensor) as measured by diffusion tensor imaging (DTI).Ten young healthy adults were scanned on three separate days, on two different systems made by the same manufacturer. One scan was acquired at one site, and two scans were acquired on two different occasions on another scanner at another site. Three levels of analysis were used to compare the DTI metrics: 1) a voxel-by-voxel analysis of all supratentorial brain (gray matter + white matter + cerebrospinal fluid) and of supratentorial white matter; 2) a slice-by-slice analysis of supratentorial white matter; and 3) a single-region analysis of the corpus callosum.The voxel-by-voxel analysis of all supratentorial brain found that FA and trace measures and correlations were equivalently and significantly higher within than across scanners. For supratentorial white matter, FA was similar within and across scanners, whereas trace demonstrated across-scanner bias. A similar pattern was observed for the slice-by-slice comparison. For the single-region analysis of the corpus callosum, within-scanner FA and trace measures were highly reproducible for FA (CV = 1.9%) and trace (CV = 2.6%), but both DTI measures showed a systematic mean bias across scanners (CV = 4.5% for FA and CV = 7.5% for trace).These estimates of measurement variation and scanner bias can be used to predict effect sizes for longitudinal and multisite studies using diffusion tensor imaging.

    View details for DOI 10.1002/jmri.10377

    View details for Web of Science ID 000185630100005

    View details for PubMedID 14508779

  • Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study NEUROIMAGE Desmond, J. E., CHEN, S. H., DeRosa, E., Pryor, M. R., Pfefferbaum, A., SULLIVAN, E. V. 2003; 19 (4): 1510-1520


    Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.

    View details for DOI 10.1016/S1053-8119(03)00102-2

    View details for Web of Science ID 000185079000022

    View details for PubMedID 12948707

  • Effects of alcohol dependence comorbidity and antipsychotic medication on volumes of the thalamus and pons in schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Sullivan, E. V., Rosenbloom, M. J., Serventi, K. L., Deshmukh, A., Pfefferbaum, A. 2003; 160 (6): 1110-1116


    Postmortem and in vivo brain imaging studies have identified abnormalities in the thalamus and the pons in both schizophrenia and alcoholism. The authors sought to determine whether patients with both schizophrenia and alcohol dependence would manifest exaggerated volume deficits in either structure.Volumetric measures of the left and right thalamus and the pons were derived from magnetic resonance imaging scans obtained from 27 patients with schizophrenia, 19 patients with schizophrenia and comorbid alcohol dependence, 25 patients with alcohol dependence without comorbid axis I disorders, and 51 healthy comparison subjects.The alcohol-dependent patients had significant volume deficits in both the thalamus and the pons. Among patients with schizophrenia, there were no differences in thalamus volumes between those with and without comorbid alcohol dependence. However, patients with schizophrenia who were taking atypical antipsychotic medications had bilateral thalamic deficits, whereas those taking typical neuroleptics did not. Patients with schizophrenia and comorbid alcohol dependence had deficits in the pons.Patients with schizophrenia and comorbid alcohol dependence are at risk for alcohol-related reduction of pontine structures that are not necessarily affected by schizophrenia per se. The effect of alcohol dependence on the thalamus in schizophrenic patients may be mitigated by the type of neuroleptic medication they receive.

    View details for Web of Science ID 000183240800014

    View details for PubMedID 12777269

  • Alcoholic men endorse more DSM-IV withdrawal symptoms than alcoholic women matched in drinking history JOURNAL OF STUDIES ON ALCOHOL Deshmukh, A., Rosenbloom, M. J., Sassoon, S., O'Reilly, A., Pfefferbaum, A., SULLIVAN, E. V. 2003; 64 (3): 375-379


    Given gender differences in alcohol metabolism, drinking patterns and alcohol-related problems, we asked whether men and women recruited for research protocols from treatment programs would meet different subsets of alcohol dependence or withdrawal criteria or differ in current level of functioning.The subjects were 66 men and 62 women meeting DSM-III-R or DSM-IV criteria for alcohol dependence. Gender differences were tested infrequency counts of criteria endorsed and Global Assessment of Functioning (GAF) scores.All seven alcohol dependence criteria were endorsed by 50% of the sample. There were no significant gender differences in frequency of individual criteria endorsed. However, more men than women tended to endorse the withdrawal criterion for alcohol dependence and the tremor criterion for alcohol withdrawal, whereas women had higher GAF scores. When subgroups of men and women were matched on alcohol consumption variables, significantly more men than women endorsed the withdrawal criterion for alcohol dependence and the anxiety criterion for alcohol withdrawal, and women still had significantly higher GAF scores than men.DSM criteria provide a similar characterization of alcohol dependence in male and female research volunteers. Despite this similarity, the DSM criteria were sensitive to gender differences, which can now be challenged with rigorous testing.

    View details for Web of Science ID 000183221500009

    View details for PubMedID 12817826

  • Increased brain white matter diffusivity in normal adult aging: Relationship to anisotropy and partial voluming MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., SULLIVAN, E. V. 2003; 49 (5): 953-961


    Diffusion tensor imaging (DTI) was used to examine 1) age-related changes in genu, splenium, and centrum semiovale white matter diffusivity in 64 healthy men and women (age 23-85 years); 2) the relationship between diffusivity (trace) and fractional anisotropy (FA) across and within individuals; and 3) the role of macrostructural and microstructural partial voluming effects on the DTI metrics. Regional differences were greater in FA (approximately 43%) than in trace (approximately 16%). Depending on the region of interest, trace increased with age (r = 0.24 to 0.58) and FA decreased with age (r = -0.29 to -0.79). FA was inversely correlated with trace, even when controlling for age. Histogram analysis of trace and FA following systematic expansion and dilation of the white matter regions demonstrated greater susceptibility of FA than trace to error arising from macrostructural partial voluming, i.e., erroneous inclusion of primarily nonwhite-matter voxels. Three-phase ellipsoid shape analysis revealed that after morphometric erosion the spherical component remained greater in older than younger subjects in the splenium and centrum, suggesting that age-related reduction in FA arises from intravoxel increased interstitial fluid. Reducing the size of the white matter samples to control for macrostructural partial voluming attenuated but did not negate effects, indicating that observed changes in white matter with aging can reflect real microstructural alterations rather than sampling artifact. Morphological dilation of white matter regions of interest resulting in purposeful inclusion of non-white matter pixels significantly reduced mean FA, suggesting that reports of FA values below 0.25 in healthy adults may reflect partial voluming rather than actual changes in white matter coherence.

    View details for DOI 10.1002/mrm.10452

    View details for Web of Science ID 000182642400022

    View details for PubMedID 12704779

  • Compounded brain volume deficits in schizophrenia-alcoholism comorbidity ARCHIVES OF GENERAL PSYCHIATRY Mathalon, D. H., Pfefferbaum, A., Lim, K. O., Rosenbloom, M. J., SULLIVAN, E. V. 2003; 60 (3): 245-252


    Schizophrenia and alcoholism are characterized by brain volume abnormalities. Despite the frequent comorbidity of these conditions, the potentially compounded effects of comorbidity on brain structure have seldom been rigorously assessed.To determine the compounding effect of schizophrenia and alcoholism on regional brain volumes, we performed retrospective quantitative analysis of magnetic resonance images from men who participated in research protocols at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif. Participants were selected on the basis of diagnostic criteria, yielding 4 comparison groups: 35 men comorbid for DSM-III-R schizophrenia or schizoaffective disorder and lifetime alcohol abuse or dependence; 64 men with DSM-III-R schizophrenia or schizoaffective disorder; 62 men with Research Diagnostic Criteria alcoholism; and 62 healthy men screened to exclude any Axis I diagnosis or heavy alcohol use. The comorbid group matched the schizophrenia group on age and illness severity but was younger and drank 5 times less alcohol in their lifetimes than the alcoholism group. Gray and white matter volumes from 6 cortical regions were expressed as age- and head size-corrected z scores and were subjected to multivariate profile analyses.Gray matter volume deficits were present in all 3 patient groups but were greatest in the comorbid group. In the comorbid group, the most prominent volume deficits were in the prefrontal and anterior superior temporal regions.Despite lower alcohol exposure than in pure alcoholism, the comorbidity of schizophrenia with alcoholism has a particularly profound effect on prefrontal gray matter volume, compounding the prominent prefrontal deficits present independently in schizophrenia and alcoholism.

    View details for Web of Science ID 000181572200004

    View details for PubMedID 12622657

  • Diffusion tensor imaging in normal aging and neuropsychiatric disorders EUROPEAN JOURNAL OF RADIOLOGY SULLIVAN, E. V., Pfefferbaum, A. 2003; 45 (3): 244-255


    The application of diffusion imaging to the quantitative study of the effects of normal aging and neuropsychiatric diseases on brain tissue microstructure has witnessed its greatest development just over the last few years. Measures derived from diffusion imaging have already been shown to have great utility in identifying age- and disease-related degradation of regional microstructure, particularly of white matter. Investigations comparing diagnoses hold promise for contribution to differential diagnosis. Correlations with cognitive and motor performance provide evidence for functional ramifications of these diffusion measures.

    View details for Web of Science ID 000181482500010

    View details for PubMedID 12595109

  • How important are brain banks for alcohol research? ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Harper, C., Garrick, T., Matsumoto, I., Pfefferbaum, A., Adalsteinsson, E., Sullivan, E., Dodd, P., Lewohl, J., Butterworth, R. 2003; 27 (2): 310-323


    This article contains the proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, organized and chaired by Clive Harper and co-chaired by Izuru Matsumoto. The presentations were (1) Introduction, by Clive Harper; (2) The quality of tissue-a critical issue, by Therese Garrick; (3) The first systematic brain tissue donor program in Japan, by Izuru Matsumoto; (4) Brain scans after death-really! by Adolf Pfefferbaum, Elfar Adalsteinsson, and Edith Sullivan; (5) Capture that (genial) expression, by Joanne Lewohl and Peter Dodd; and (6) Neurochemical/pharmacological studies: experimental design and limitations, by Roger Butterworth.

    View details for DOI 10.1097/01.ALC.0000052585.81056.CA

    View details for Web of Science ID 000181172400018

    View details for PubMedID 12605081

  • Disruption of frontocerebellar circuitry and function in alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V., Harding, A. J., Pentney, R., Dlugos, C., Martin, P. R., Parks, M. H., Desmond, J. E., CHEN, S. H., Pryor, M. R., De Rosa, E., Pfefferbaum, A. 2003; 27 (2): 301-309


    This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol-related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and Functional reorganization of the brain in alcoholism: neuroimaging evidence, by John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf Pfefferbaum, and Edith V. Sullivan.

    View details for DOI 10.1097/01.ALC.0000052584.05305.98

    View details for Web of Science ID 000181172400017

    View details for PubMedID 12605080

  • Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics ALCOHOL RESEARCH & HEALTH Rosenbloom, M., SULLIVAN, E. V., Pfefferbaum, A. 2003; 27 (2): 146-152


    Brain imaging using conventional magnetic resonance imaging (MRI) has revealed that several brain structures in people with a history of chronic alcohol dependence are smaller in volume than the same brain structures in nonalcoholic control subjects. Areas that are particularly affected are the frontal lobes, which are involved in reasoning, judgment, and problem solving. Older people are especially vulnerable to the damaging effects of alcohol. It is unclear whether women show consistently more vulnerability to these changes in the brain than men do. In general, alcoholics evaluated before and after a period of abstinence show some recovery of tissue volume, whereas alcoholics evaluated again after continued drinking show further reductions in brain tissue volume. A new MR technique called diffusion tensor imaging (DTI) can aid in detecting the degradation of fibers (i.e., white matter) that carry information between brain cells (i.e., gray matter). With DTI, researchers studying alcoholics have been able to detect abnormalities in white matter not visible with conventional MRI. Ultimately DTI may be useful in elucidating the mechanisms that underlie macrostructural and functional brain changes seen with abstinence and relapse.

    View details for Web of Science ID 000223800500004

    View details for PubMedID 15303625

  • Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study. Magnetic resonance spectroscopy. Psychiatry research Nordahl, T. E., Salo, R., Possin, K., Gibson, D. R., Flynn, N., Leamon, M., Galloway, G. P., Pfefferbaum, A., Spielman, D. M., Adalsteinsson, E., Sullivan, E. V. 2002; 116 (1-2): 43-52


    Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/-6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03; MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.: control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.

    View details for PubMedID 12426033

  • Clinical signs of cerebellar dysfunction in schizophrenia, alcoholism, and their comorbidity SCHIZOPHRENIA RESEARCH Deshmukh, A., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2002; 57 (2-3): 281-291


    Abnormalities of cerebellar structure and function, long recognized as a hallmark of chronic alcohol abuse, have also occasionally been noted in patients with schizophrenia. We used a four-point rating scale to assess clinical signs of cerebellar dysfunction in men meeting DSM-IV criteria for schizophrenia (N=34) and alcohol dependence (N=15) as well as normal control subjects (N=28). Compared to controls, alcoholics had impaired ratings of gait ataxia and instability of stance with eyes closed, and schizophrenics had impaired ratings of stance with eyes closed. The incidence of dysdiadochokinesia was greater in schizophrenics, but not alcoholics, than controls. The incidence of gait and stance abnormalities was higher in both patient groups relative to controls: within the schizophrenic group, 50-70% of those with positive signs for gait or stance impairment were comorbid for alcoholism, while only 25% of those with positive signs for dysdiadochokinesia were comorbid for alcoholism. The presence of dysdiadochokinesia in the schizophrenic group suggests cerebellar dysfunction that is independent of the effects of alcohol. By contrast, clinical signs of cerebellar dysfunction of gait and stance in patients with schizophrenia may be secondary to the effects of alcohol on the cerebellum.

    View details for Web of Science ID 000178358100018

    View details for PubMedID 12223260

  • The effects of alcoholism on auditory evoked potentials during sleep JOURNAL OF SLEEP RESEARCH Nicholas, C. L., SULLIVAN, E. V., Pfefferbaum, A., Trinder, J., Colrain, I. M. 2002; 11 (3): 247-253


    Normal aging is associated with a reduction in the probability that an auditory stimulus will evoke a K-complex during sleep. Additional concomitants of aging are a reduction in the amplitude of the K-complex-related N550, an augmentation of the P2 component and the appearance of a long-lasting positivity (LLP) in the auditory evoked potential. Normal aging is also associated with a dramatic reduction in slow wave sleep (SWS) and a reduction in the volume of cortical gray matter, particularly in the frontal and prefrontal regions of the brain. As in aging, alcoholism is associated with reductions in both cortical gray matter and SWS. It can, therefore, be hypothesized that alcoholics would show similar evoked potential changes to those seen in aging. To test this hypothesis, we studied seven middle-aged abstinent long-term alcoholics and eight age-matched normal controls. Each subject spent one night in the laboratory. Electroencephalogram (EEG) was recorded from six midline scalp sites and auditory stimuli were presented during stage 2 non-rapid eye movement sleep. N550 amplitude in the K-complex average was lower in the alcoholics as compared with controls as was the likelihood of K-complex production. No differences were noted in either amplitude or latency of the P2 or N350 components, and both groups displayed a prominent LLP potential. The pattern of reduced K-complex production and N550 amplitude in alcoholics as compared with age-matched controls is consistent with an hypothesized association between atrophy of the frontal lobes and reductions in SWS and K-complexes. The finding also suggests that the evoked K-complex may be a relatively simple measure of the effect of alcoholism on EEG during sleep.

    View details for Web of Science ID 000177852300009

    View details for PubMedID 12220321

  • Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals PSYCHIATRY RESEARCH Salo, R., Nordahl, T. E., Possin, K., Leamon, M., Gibson, D. R., Galloway, G. P., Flynn, N. M., Henik, A., Pfefferbaum, A., SULLIVAN, E. V. 2002; 111 (1): 65-74


    Chronic methamphetamine abuse is associated with disruption of frontostriatal function involving serotonin and dopamine circuitry. Clinically, methamphetamine-dependent (MD) individuals are highly distractible and have difficulty focussing. Here, we used a computerized single-trial version of the Stroop Test to examine selective attention and priming in MD. Subject groups comprised eight MD men (31.7+/-7.2 years of age), who had used methamphetamine for 15.75+/-8.4 years but were currently abstinent for 2-4 months, and 12 controls (35.7+9.7 years of age). Compared with the control group, the MD group exhibited significantly greater interference (P<0.05) despite intact priming. Error rates did not differ between the groups. This preliminary finding of reduced cognitive inhibition in MD individuals is consistent with the distractibility they show clinically. Furthermore, the dissociation between explicit attentional performance and priming effects suggests that some attentional functions are not as affected by long-term methamphetamine use as others.

    View details for Web of Science ID 000177511200008

    View details for PubMedID 12140121

  • Alcoholism and AIDS: Magnetic resonance imaging approaches for detecting interactive neuropathology ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Rosenbloom, M., SULLIVAN, E. V. 2002; 26 (7): 1031-1046


    Both alcohol abuse and human immunodeficiency virus (HIV) infection have deleterious effects on brain structure, metabolism and function. In individuals with both afflictions these effects are doubtless additive and may interact to produce synergistic adverse effects. Further, the normal processes of aging produce brain degeneration that leaves older people especially vulnerable to the untoward effects of alcohol abuse and HIV infection. Advances in in vivo brain imaging now make practical the clinical study of the interaction of alcoholism and HIV infection and the potential of increased vulnerability produced by advancing age. In addition to structural magnetic resonance imaging (MRI), which provides quantitative assessments of brain macrostructure, are diffusion tensor imaging (DTI), which assesses microstructural integrity, magnetic resonance spectroscopy (MRS), which provides assessment of brain chemical moieties related to neuronal viability, and functional magnetic resonance imaging (fMRI), which provides assessment of localized blood oxygenation state association with performance of specific cognitive or motor tasks. Here, we first review postmortem observations on patients with HIV infection and with alcoholism to identify the cell types and brain regions most affected by the end stage of the disease. We then review in vivo neuroimaging studies of brain changes associated with HIV infection, chronic alcohol use, their interaction, and the potentiating effects of age. While there are many studies of people with either HIV infection or chronic alcohol use alone currently little has been published on the interactive effects of these variables, despite the high prevalence of overlap. We conclude with a consideration of the methodological issues such studies must address.

    View details for DOI 10.1097/01.ALC.0000021146.01778.55

    View details for Web of Science ID 000176989100013

    View details for PubMedID 12170114

  • Influences of chorion type on measurements of the corpus callosum in adult monozygotic male twins? AMERICAN JOURNAL OF HUMAN BIOLOGY Reed, T., Pfefferbaum, A., SULLIVAN, E. V., Carmelli, D. 2002; 14 (3): 338-346


    MRI imaging was used to estimate volumes of corpus callosum structure in 45 pairs of identical (monozygotic, MZ) twins from the National Heart, Lung, and Blood Institute (NHLBI) twin study. Age range of the study subjects was from 68-78 years. Finger, palm, and footprint data (dermatoglyphics) collected at previous examinations of the NHLBI twin study were available for 39 pairs. The dermatoglyphics were scored for an index to retrospectively assess chorion type in MZ twin-pairs. The results indicated an association between variability in various structures of the corpus callosum with some of these dermatoglyphic traits, suggesting greater structural variation within pairs with dichorionic placentas. In contrast, total intracranial volume, which has similar heritability estimates as a result of shared genetic effects with the corpus callosum, was unrelated to the dermatoglyphic traits. The results provide indirect evidence that the intrauterine environment may influence twin-pair similarity of corpus callosum measures in adults.

    View details for DOI 10.1002/ajhb.10027

    View details for Web of Science ID 000175224400006

    View details for PubMedID 12001090

  • Speed and efficiency but not accuracy or timing deficits of limb movements in alcoholic men and women ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Desmond, J. E., Lim, K. O., Pfefferbaum, A. 2002; 26 (5): 705-713


    Lesions of the cerebellum, a concomitant of alcoholism, can disrupt quality and regularity of movement. Whether evidence for such dysfunction lingers in patients with uncomplicated alcoholism, which is known to affect cerebellar structural integrity, is controversial.We used quantitative measures to examine component processes of five classes of movement associated with regional cerebellar function: limb ataxia (alternated finger tapping and variants of the finger-to-nose and heel-to-shin tests), paced tapping, eye-hand coordinated tracing, timed response reflecting preparation and execution time, and postural stability. The subjects examined were 39 abstinent alcoholics (13 men and 26 women) and 21 age-matched controls (9 men and 12 women). For limb ataxia, the dependent measures were the trajectory deviation from the subject's own average movement path and the speed of travel from beginning points to endpoints.Repeated-measures analysis of variance comparing movement speed of finger to nose and heel to shin yielded significant interactions in all conditions (p < 0.007); this indicated that the alcoholics were relatively slower in the upper- than lower-limb tasks. Movements by the alcoholic men were significantly slower but less deviant from an ideal trajectory in all upper-limb conditions than those of the control men (p < 0.002). Although measures of lower-limb movement trajectory did not distinguish the groups, tests of ataxia of stance and gait did. The groups did not differ, however, on tests of timed tapping or sinusoid tracing.Alcohol-related postural instability in abstinent alcoholics is functional evidence supporting the postulated damage to the anterior superior vermis. Altered speed or accuracy trade-offs, with alcoholics moving slower to attain equivalent or even smaller trajectory deviations, are symptomatic of cerebellar hemisphere dysfunction that is characterized by deliberation of otherwise automatic movements.

    View details for Web of Science ID 000175643900016

    View details for PubMedID 12045480

  • Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men CEREBRAL CORTEX Sullivan, E. V., Pfefferbaum, A., Adalsteinsson, E., Swan, G. E., Carmelli, D. 2002; 12 (4): 438-445


    Brain structure changes in size with normal aging, but the rate at which different structures change is controversial. We used magnetic resonance imaging (MRI) performed twice, 4 years apart, to compare rates of age-related size change of the corpus callosum, which has been inconsistently observed to thin with age, with change in the lateral ventricles, which are well established to enlarge. Subjects were 215 community dwelling, elderly men (70-82 years old at initial MRI), who were participants in a longitudinal study of cardiovascular risk factors. Percent change in size was significant for both the callosal and ventricular measures, but annual rate of ventricular expansion (2.9%) was significantly greater than annual rate of callosal thinning (-0.9%). Callosal regions showed statistically equivalent rates of shrinkage; ventricular dilatation was symmetrical. Neither callosal and ventricular rates of change correlated with each other (r = 0.01), nor did genu and splenium rates of change correlate with each other (r = 0.05). Tests of speeded processing were administered contemporaneously with both MRIs to examine functional ramifications of observed brain changes. Decline in the Mini-Mental State Examination was related to thinning of the splenium, and decline in Stroop test word reading was selectively related to thinning of the callosal body. These longitudinal data support the contentions that differential rates of change occur in different brain regions in normal aging, age-related callosal thinning contributes to functional declines, and rate of change in one region can be independent of rate of change in another region, even within a brain structure.

    View details for Web of Science ID 000174370200010

    View details for PubMedID 11884358

  • Microstructural but not macrostructural disruption of white matter in women with chronic alcoholism NEUROIMAGE Pfefferbaum, A., SULLIVAN, E. V. 2002; 15 (3): 708-718


    The results of in vivo neuroimaging studies assessing whether and where brain white matter damage occurs in alcoholic women is controversial. To address this controversy, we examined regional white matter macrostructure and microstructure, the latter of which may be more sensitive to the detection of subtle fiber disruption than gross measures of size. Accordingly, we used conventional magnetic resonance imaging (MRI) to quantify regional callosal size and diffusion tensor imaging (DTI) to examine intravoxel coherence (fractional anisotropy, FA) and intervoxel coherence (C) of white matter of the genu and splenium of the corpus callosum and of the centrum semiovale in 12 detoxified alcoholic women and 18 control women. Additional analyses examined sex differences in FA and C in alcoholic women compared with alcoholic men. Despite absence of group differences in regional areas of callosal macrostructure, the alcoholic women had lower FA and C in genu and centrum semiovale than the control group of women. These measures also correlated with total lifetime consumption of alcohol and performance on a test of visual search in the alcoholic women. Sex comparisons revealed similar extents of FA abnormality in the genu and centrum semiovale in alcoholic men and women and differential effects in other DTI measures, with abnormalities present in splenium FA and C in the men and abnormalities present in centrum C in the women. These results provide in vivo evidence for disruption of white matter microstructure in alcoholic women not necessarily detectable with coarser measures of white matter mass and perhaps antedating its appearance.

    View details for DOI 10.1006/nimg.2001.1018

    View details for Web of Science ID 000174163900025

    View details for PubMedID 11848714

  • Corpus callosum, pons, and cortical white matter in alcoholic women ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Rosenbloom, M., Serventi, K. L., SULLIVAN, E. V. 2002; 26 (3): 400-406


    To measure the effect of alcohol abuse on white matter brain macrostructure in women with alcoholism and to determine whether observed abnormalities interact with age.Quantitative measures of corpus callosum area, cortical white matter volume, and pons volume were derived from magnetic resonance imaging scans obtained from 34 women with DSM-III-R alcoholism (aged 28-64, mean 41 years) and 35 healthy women (aged 22-65, mean 42 years). Transverse relaxation time of the pons was also obtained.No significant group differences in any brain measures were observed. However, in alcoholics greater length of sobriety was associated with more cortical white matter, and higher lifetime levels of alcohol consumption were associated with smaller volumes and prolonged transverse relaxation time in the pons.Despite a lack of overall deficits in white matter macrostructural size in alcoholic women, certain white matter structures showed alcohol exposure vulnerability whereas others showed evidence of recovery with abstinence.

    View details for Web of Science ID 000174612800015

    View details for PubMedID 11923595

  • N-acetylaspartate - A marker of neuronal integrity ANNALS OF NEUROLOGY SULLIVAN, E. V., Adalsteinsson, E., Spielman, D. M., Hurd, R. E., Pfefferbaum, A. 2001; 50 (6): 823-823

    View details for Web of Science ID 000172410900022

    View details for PubMedID 11761485

  • Structural brain abnormalities in patients with schizophrenia, epilepsy, and epilepsy with chronic interictal psychosis PSYCHIATRY RESEARCH-NEUROIMAGING Marsh, L., SULLIVAN, E. V., Morrell, M., Lim, K. O., Pfefferbaum, A. 2001; 108 (1): 1-15


    Chronic interictal psychotic syndromes, often resembling schizophrenia, develop in some patients with epilepsy. Although widespread brain abnormalities are recognized as characteristic of schizophrenia, prevailing but controversial hypotheses on the co-occurrence of epilepsy and psychosis implicate left temporal lobe pathology. In this study, quantitative MRI methods were used to address the regional specificity of structural brain abnormalities in patients with epilepsy plus chronic interictal psychosis (E+PSY, n=9) relative to three comparison groups: unilateral temporal lobe epilepsy without chronic psychosis (TLE, n=18), schizophrenia (SCZ, n=46), and healthy control subjects (HC, n=57). Brain measures, derived from a coronal spin-echo MRI sequence, were adjusted for age and cerebral volume. Relative to HC, all patient groups had ventricular enlargement and smaller temporal lobe, frontoparietal, and superior temporal gyrus gray matter volumes, with the extent of these abnormalities greatest in E+PSY. Only TLE had temporal lobe white matter deficits, as well as smaller hippocampi, which were ipsilateral to the seizure focus. Structural brain abnormalities in E+PSY are not restricted to the left temporal lobe. The confluence of cortical gray matter deficits in E+PSY and SCZ suggests salience to chronic psychosis.

    View details for Web of Science ID 000172053800001

    View details for PubMedID 11677063

  • Reorganization of frontal systems used by alcoholics for spatial working memory: An fMRI study NEUROIMAGE Pfefferbaum, A., Desmond, J. E., Galloway, C., Menon, V., Glover, G. H., SULLIVAN, E. V. 2001; 14 (1): 7-20


    Chronic alcoholism is associated with impairment in sustained attention and visual working memory. Thus, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks, assumed to be subserved by regions of prefrontal cortex. To identify neural substrates associated with this impairment, we used functional MRI (fMRI) to determine whether alcoholics invoke the same or different brain systems as controls when engaged in working memory tasks that the two groups were able to perform at equivalent levels. The fMRI spatial working memory paradigm instructed subjects to respond with a button press when a target position was either in the center of the field (match to center) or matched the spatial position of one presented two items previously (match 2-back) or to rest. Using whole-brain fMRI, alcoholics showed diminished activation frontal cortical systems compared to controls (bilateral dorsolateral prefrontal cortex) when responding 2-back vs rest. In the center vs rest contrast, the control group compared with the alcoholic group activated a large expanse of prefrontal cortex (including Brodmann areas 9, 10, and 45), whereas there was significantly greater activation by the alcoholic group relative to the control group localized more posteriorly and inferiorly in the frontal cortex (area 47). Examination of within group activation patterns revealed two different patterns of activation: the control group exhibited activation of the dorsal ("Where?") stream for visual spatial working memory processing, whereas the alcoholic group exhibited activation of the ventral ("What?") stream and declarative memory systems to accomplish the spatial working memory task. The differences in the pattern of brain activations exhibited by the alcoholic and control groups, despite equivalence in behavioral performance, is consistent with a functional reorganization of the brain systems invoked by alcoholic individuals or invocation of an inappropriate brain system when engaged in a visual spatial task requiring working memory.

    View details for Web of Science ID 000169498000002

    View details for PubMedID 11525339

  • Genetic regulation of regional microstructure of the corpus callosum in late life NEUROREPORT Pfefferbaum, A., SULLIVAN, E. V., Carmelli, D. 2001; 12 (8): 1677-1681


    In order to identify brain structural phenotypes that remain under significant genetic control in late adulthood, we examined the heritability of corpus callosum macrostructure (i.e. size) using MRI and microstructure (e.g. myelin) using diffusion tensor imaging in 15 monozygotic and 18 dizygotic twin pairs of elderly men. The relative proportion of genetic to environmental influences varied considerably by region and structural type and was 5:1 for callosal macrostructure, 3:1 for splenium microstructure, and 1:1 for genu microstructure. This is the first in vivo identification of quantifiable phenotypes of brain white matter microstructure and demonstrates significant and differential genetic regulation in old age, with anterior interhemispheric connecting pathways more susceptible than posterior pathways to environmental influences.

    View details for Web of Science ID 000169185400028

    View details for PubMedID 11409738

  • Functional magnetic resonance imaging evidence for disrupted basal ganglia function in schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Menon, V., Anagnoson, R. T., Glover, G. H., Pfefferbaum, A. 2001; 158 (4): 646-649


    This study was an examination of basal ganglia dysfunction in schizophrenia using functional magnetic resonance imaging (fMRI).The authors used a motor sequencing task to investigate activation of the caudate, anterior putamen plus globus pallidus, and posterior putamen plus globus pallidus in eight subjects with schizophrenia and 12 group-matched comparison subjects. Differences in activation of the thalamus, the target of direct output from the globus pallidus, were also examined.The schizophrenia subjects showed significant bilateral deficits in the posterior putamen, globus pallidus, and thalamus but not the anterior putamen plus globus pallidus or caudate. Functional connectivity analysis revealed that the deficits in thalamic activation were related to deficits in posterior putamen and globus pallidus activation.These results provide fMRI evidence for basal ganglia dysfunction in subjects with schizophrenia and suggest that this deficit results in disrupted outflow to the thalamus. These deficits may underlie the behavioral impairments in goal-directed action observed in schizophrenia.

    View details for Web of Science ID 000167931900023

    View details for PubMedID 11282705

  • Remote memory for public figures in Alzheimer's disease: Relationships to regional cortical and limbic brain volumes JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Fama, R., Shear, P. K., Marsh, L., Yesavage, J. A., Tinklenberg, J. R., Lim, K. O., Pfefferbaum, A., Sullivan, E. V. 2001; 7 (3): 384-390


    This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal-occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory.

    View details for Web of Science ID 000168425100012

    View details for PubMedID 11311039

  • Functional neuroanatomy of auditory working memory in schizophrenia: Relation to positive and negative symptoms NEUROIMAGE Menon, V., Anagnoson, R. T., Mathalon, D. H., Glover, G. H., Pfefferbaum, A. 2001; 13 (3): 433-446


    Functional brain imaging studies of working memory (WM) in schizophrenia have yielded inconsistent results regarding deficits in the dorsolateral prefrontal (DLPFC) and parietal cortices. In spite of its potential importance in schizophrenia, there have been few investigations of WM deficits using auditory stimuli and no functional imaging studies have attempted to relate brain activation during auditory WM to positive and negative symptoms of schizophrenia. We used a two-back auditory WM paradigm in a functional MRI study of men with schizophrenia (N = 11) and controls (N = 13). Region of interest analysis was used to investigate group differences in activation as well as correlations with symptom scores from the Brief Psychiatric Rating Scale. Patients with schizophrenia performed significantly worse and were slower than control subjects in the WM task. Patients also showed decreased lateralization of activation and significant WM related activation deficits in the left and right DLPFC, frontal operculum, inferior parietal, and superior parietal cortex but not in the anterior cingulate or superior temporal gyrus. These results indicate that in addition to the prefrontal cortex, parietal cortex function is also disrupted during WM in schizophrenia. Withdrawal-retardation symptom scores were inversely correlated with frontal operculum activation. Thinking disturbance symptom scores were inversely correlated with right DLPFC activation. Our findings suggest an association between thinking disturbance symptoms, particularly unusual thought content, and disrupted WM processing in schizophrenia.

    View details for DOI 10.1006/nimg.2000.0699

    View details for Web of Science ID 000167154300005

    View details for PubMedID 11170809

  • Equivalent disruption of regional white matter microstructure in ageing healthy men and women NEUROREPORT SULLIVAN, E. V., Adalsteinsson, E., Hedehus, M., Ju, C., Moseley, M., Lim, K. O., Pfefferbaum, A. 2001; 12 (1): 99-104


    Diffusion tensor imaging was used to measure regional differences in brain white matter microstructure (intravoxel coherence) and macrostructure (intervoxel coherence) and age-related differences between men and women. Neuropsychiatrically healthy men and women, spanning the adult age range, showed the same pattern of variation in regional white matter coherence. The greatest coherence measured was in corpus callosum, where commissural fibers have one primary orientation, lower in the centrum semiovale, where fibers cross from multiple axes, and lowest in pericallosal areas, where fibers weave and interstitial fluid commonly pools. Age-related declines in intravoxel coherence was equally strong and strikingly similar in men and women, with evidence for greater age-dependent deterioration in frontal than parietal regions. Degree of regional white matter coherence correlated with gait, balance, and interhemispheric transfer test scores.

    View details for Web of Science ID 000166411900022

    View details for PubMedID 11201100

  • Heritability of hippocampal size in elderly twin men: Equivalent influence from genes and environment HIPPOCAMPUS Sullivan, E. V., Pfefferbaum, A., Swan, G. E., Carmelli, D. 2001; 11 (6): 754-762


    Recent studies have established that environmental factors can modify hippocampal structure and enhance function in adult rodents, but the extent to which genes and the environment exert differential contributions to hippocampal structural integrity in humans is unknown. Here, we applied the twin model in a large sample of elderly twin men to examine in late life the balance of environmental and genetic effects on the size of the hippocampus in comparison with other brain structures. This study provides novel evidence that the volume of the hippocampus, as measured on MRI, is subject to substantially less genetic control than are comparison brain regions also measured: temporal horn volume, midsagittal area of the corpus callosum, and intracranial volume (ICV). In particular, about 60% of the temporal horn variance and 80% of the callosal and ICV variance was attributable to genetic influences, whereas only 40% of the hippocampal variance was attributable to genetic influences. These results suggest that environment, whether by itself or in interaction with genes, has the potential of exerting greater and possibly longer control in modifying hippocampal size than other brain regions that are under greater genetic control. Considering the potential of environmental modification of this structure suggested by lower heritability, the hippocampus appears well-suited to support the dynamic processes of encoding and consolidation of new, declarataive memories.

    View details for Web of Science ID 000172988800016

    View details for PubMedID 11811670

  • Basal ganglia involvement in memory-guided movement sequencing NEUROREPORT Menon, V., Anagnoson, R. T., Glover, G. H., Pfefferbaum, A. 2000; 11 (16): 3641-3645


    The basal ganglia (BG) are thought to play a critical role in motor planning and movement sequencing. While electrophysiological and imaging studies have shown that the dorso-lateral prefrontal cortex (DLPFC) is involved in working memory (WM), the involvement of the BG in this process is not well understood. We used a motor sequencing task to investigate the differential role of BG nuclei in memory-guided movement. Significant activation was observed in the DLPFC and posterior putamen and globus pallidus (GP), with a trend in the caudate and no differences in the anterior putamen. We then investigated the effect of BG outflow on thalamic activation using functional connectivity analysis. Activation in the posterior putamen + GP was found to be correlated with thalamic activation only in the hemisphere contralateral to movement. These results provide the first fMRI evidence that the BG may modulate activity in the thalamus during working memory-guided movement sequencing. Our findings suggest that the BG activation may reflect increased motor sequencing demands during the memory-guided movement condition and, specifically, that the posterior putamen and GP may play a role in maintenance of representations in WM in a manner that contributes to planning and temporal organization of motor sequencing.

    View details for Web of Science ID 000165301600048

    View details for PubMedID 11095535

  • Left temporal deficit of P300 in patients with schizophrenia: effects of task INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY Ford, J. M., Mathalon, D. H., White, P. M., Pfefferbaum, A. 2000; 38 (1): 71-79


    P300 is often, but not always, observed to be more reduced over left than right temporal lobes in patients with schizophrenia. The possibility that task differences contribute to the inconsistency in the literature was explored in this study. ERPs were collected from 17 right-handed men with schizophrenia (DSM-IIIR) and 11 right-handed healthy male community controls, performing three auditory oddball tasks - respond to a target tone by: (1) counting; (2) pressing a response button with the right index finger; or (3) pressing a response button with the left index finger. Although patients with schizophrenia had smaller and later P300 amplitudes than controls, they did not have smaller P300s over the left temporal scalp (T3) than over the right (T4). P300 recorded over the left (C3) and right (C4) motor cortices indicated sensitivity to responding hand, with greater negativity being associated with contralateral button pressing. Failure to find P300 asymmetry is not related to the presence or absence of a button pressing task, or the hand used for button pressing. Rather, P300 asymmetry may be related to structural neuroanatomical asymmetries.

    View details for Web of Science ID 000090143800006

    View details for PubMedID 11027795

  • Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia ARCHIVES OF GENERAL PSYCHIATRY Sullivan, E. V., Deshmukh, A., Desmond, J. E., Mathalon, D. H., Rosenbloom, M. J., Lim, K. O., Pfefferbaum, A. 2000; 57 (9): 894-902


    It is controversial whether cerebellar tissue volume deficits occur in schizophrenia and, if so, what regions and tissue types are affected. Complicating such investigations is the high incidence of alcoholism comorbidity in patients with schizophrenia that itself can contribute to cerebellar abnormalities.We studied 61 healthy men (control subjects), 25 men with alcoholism, 27 men with schizophrenia, and 19 men comorbid for schizophrenia and alcoholism with the use of magnetic resonance imaging. Cerebellar structures were outlined manually, tissue classification was determined statistically, and regional volumes were corrected for normal variation in head size and age.Patients with schizophrenia alone had enlarged fourth ventricles (1.5 SD relative to controls) but showed no cerebellar tissue volume deficits. The alcoholic group had gray and white matter vermian deficits (-0.5 SD), most prominent in anterior superior lobules, and gray matter hemisphere deficits (-0.8 SD), but not fourth ventricle enlargement. The comorbid group had cerebellar hemisphere (-1.3 SD) and vermian gray matter volume deficits (-0.7 SD) and fourth ventricular enlargement (1.6 SD); these abnormalities were greater than in either single-diagnosis group, despite significantly lower levels of alcohol consumption compared with the alcoholic group. Gray matter volume in the anterior superior vermis correlated with lifetime alcohol consumption in the schizophrenic and comorbid groups when combined.Cerebellar tissue volume deficits were detected in schizophrenia only when accompanied by alcoholism. By contrast, fourth ventricular enlargement occurred in schizophrenia even without alcoholism, although it was exacerbated by alcoholism. These findings support a model of cerebellar supersensitivity to alcohol-related tissue volume deficits in schizophrenia.

    View details for Web of Science ID 000089179500011

    View details for PubMedID 10986553

  • In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., SULLIVAN, E. V., Hedehus, M., Adalsteinsson, E., Lim, K. O., Moseley, M. 2000; 24 (8): 1214-1221


    Postmortem studies report degradation of brain white matter microstructure in chronic alcoholism, but until recently, in vivo neuroimaging could provide measurement only at a macrostructural level. The development of magnetic resonance diffusion tensor imaging (DTI) for clinical use offers a method for depicting and quantifying the diffusion properties of white matter expressed as intravoxel and intervoxel coherence of tracts and fibers.This study used DTI to examine the intravoxel coherence measured as fractional anisotropy (FA) and intervoxel coherence (C) of white matter tracts of the genu and splenium of the corpus callosum and of the centrum semiovale in 15 detoxified alcoholic men and 31 nonalcoholic control subjects. Exploratory correlational analyses examined the relationships between regional DTI measures and tests of attention and working memory in the alcoholic patients.The alcoholic group had lower regional FA than the control group. C was lower in the alcoholics than controls in the splenium only. Working memory correlated positively with splenium FA, whereas attention correlated positively with genu C.These results provide in vivo evidence for disruption of white matter microstructure in alcoholism and suggest that interruption of white matter fiber coherence contributes to disturbance in attention and working memory in chronic alcoholism.

    View details for Web of Science ID 000088831600012

    View details for PubMedID 10968660

  • Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., SULLIVAN, E. V., Hedehus, M., Lim, K. O., Adalsteinsson, E., Moseley, M. 2000; 44 (2): 259-268


    Echo planar (EP) diffusion tensor imaging (DTI) permits in vivo identification of the orientation and coherence of brain white matter tracts but suffers from field inhomogeneity-induced geometric distortion. To reduce spatial distortion, polynomial warping corrections were applied and the effects tested on measures of fractional anisotropy (FA) in the genu and splenium of corpus callosum. Implementation entailed spatially warping EP images obtained without diffusion weighting (b = 0) to long-echo T(2)-weighted fast spin echo images, collected for anatomical delineation, tissue segmentation, and coregistration with the diffusion images. Using the optimal warping procedure (third-order polynomial), the effects of age on FA and a quantitative measure of intervoxel coherence (C) in the genu, splenium, centrum semiovale, and frontal and parietal pericallosal white matter were examined in 31 healthy men (23-76 years). FA declined significantly with age in all regions except the splenium, whereas intervoxel coherence positively correlated with age in the genu. Magn Reson Med 44:259-268, 2000.

    View details for Web of Science ID 000088545600013

    View details for PubMedID 10918325

  • Optimal voxel size for measuring global gray and white matter proton metabolite concentrations using chemical shift imaging MAGNETIC RESONANCE IN MEDICINE Hanson, L. G., Adalsteinsson, E., Pfefferbaum, A., Spielman, D. M. 2000; 44 (1): 10-18


    Quantification of gray and white matter levels of spectroscopically visible metabolites can provide important insights into brain development and pathological conditions. Chemical shift imaging offers a gain in efficiency for estimation of global gray and white matter metabolite concentrations compared to single voxel methods. In the present study, the optimal voxel size is calculated from segmented human brain data and accompanying field maps. The optimal voxel size is found to be approximately 8 cc, but a wide range of values, 4-64 cc, can be chosen with little increase in estimated concentration error (<15%). Magn Reson Med 44:10-18, 2000.

    View details for Web of Science ID 000087917000003

    View details for PubMedID 10893515

  • Segregation analysis of drinking problem in elderly men and their first-degree relatives from the Western Collaborative Group Study ANNALS OF EPIDEMIOLOGY Cheng, L. S., Carmelli, D., Swan, G. E., Pfefferbaum, A. 2000; 10 (5): 309-315


    The purpose of this study is to determine the mode of inheritance of alcohol-related drinking problems.Family history was collected by interview from 493 elderly male participants (probands) in a follow-up cardiovascular exam of healthy white men living in the San Francisco Bay Area and Los Angeles. Segregation analysis was used to test for the presence of a major gene effect underlying the liability to develop an alcohol-related drinking problem.The results showed that the liability to drinking problem is due, in part, to a single major gene with no residual effects from shared familial influences.These results suggest that at least one major gene is involved in the genetic predisposition to develop drinking problem in late adulthood.

    View details for Web of Science ID 000088620900007

    View details for PubMedID 10942879

  • Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer's disease LANCET Adalsteinsson, E., SULLIVAN, E. V., Kleinhans, N., Spielman, D. M., Pfefferbaum, A. 2000; 355 (9216): 1696-1697


    In patients with Alzheimer's disease, but not in health controls, longitudinal magnetic resonance spectroscopy shows a striking decline in the neuronal marker, N-acetyl aspartate, despite little decline in underlying grey-matter volume.

    View details for Web of Science ID 000086983800017

    View details for PubMedID 10905250

  • Pattern of motor and cognitive deficits in detoxified alcoholic men ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Rosenbloom, M. J., Pfefferbaum, A. 2000; 24 (5): 611-621


    Chronic excessive consumption of alcohol produces marked deficits in cognitive and motor abilities, although not all functions are affected to the same extent. Furthermore, although the occurrence of neuropsychological deficits in recently detoxified alcoholics is firmly established, the relative severity of these deficits, the specific neural systems that underlie the deficits, and their relationship to age and alcohol consumption variables either are less established or have proven elusive altogether.We administered an extensive battery of neuropsychological tests, chosen for their known sensitivity to brain lesions in specific locations, to 71 recently (1 month) detoxified alcoholic men and 74 healthy controls who spanned the adult age range. Test scores were standardized to the controls for age and grouped a priori into composites that reflected performance in six functional domains: executive functions, short-term memory, upper limb motor ability, declarative memory, visuospatial abilities, and gait and balance. Analogous verbal and nonverbal materials and left- and right-hand upper limb motor tasks were used to test whether alcohol-related deficits were greater for left or right hemisphere.Compared with controls, the alcoholics were impaired on executive functions, visuospatial abilities, and gait and balance even after we accounted for group differences in estimated premorbid IQ and education. Within the alcoholic group, the most salient deficits were in gait and balance and visuospatial abilities. No consistent lateralized deficit was observed across the four domains tested. Unlike the cognitive composites, the upper limb motor ability and gait and balance composites both showed increasing vulnerability to age, with an independent contribution to the gait and balance dysfunction from the amount of alcohol consumed over a lifetime.The pattern of functional deficits implicates at least two principal neural systems: the cerebellar-frontal system and the corticocortical system between the prefrontal and parietal cortices. In addition, age and amount of alcohol consumption were better predictors of motor than cognitive impairments.

    View details for Web of Science ID 000087216000005

    View details for PubMedID 10832902

  • Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: Relationships to changes in brain structure NEUROPSYCHOLOGY Sullivan, E. V., Rosenbloom, M. J., Lim, K. O., Pfefferbaum, A. 2000; 14 (2): 178-188


    Chronic alcoholism is associated with cognitive and motor deficits, and there is evidence for reversibility with sobriety. Alcoholic men were examined after 1 month of sobriety and 2 to 12 months later with cognitive and motor tests and magnetic resonance imaging. In this naturalistic study, 20 alcoholic participants had abstained and 22 had resumed drinking at retesting. Abstainers sustained greater improvement than relapsers on tests of delayed recall of drawings, visuospatial function, attention, gait, and balance. Shrinkage in 3rd ventricle volume across all participants significantly correlated with improvement in nonverbal short-term memory. Additional brain structure-function relationships, most involving short-term memory, were observed when analyses were restricted to alcoholic men who had maintained complete abstinence, were light relapsers for at least 3 months, or had consumed no more than 10 drinks prior to follow-up testing. Thus, alcoholic men who maintain abstinence can show substantial functional improvement that is related to improvement in brain structure condition.

    View details for DOI 10.1037//0894-4105.14.2.178

    View details for Web of Science ID 000087480700002

    View details for PubMedID 10791858

  • Trait and state aspects of P300 amplitude reduction in schizophrenia: A retrospective longitudinal study BIOLOGICAL PSYCHIATRY Mathalon, D. H., Ford, J. M., Pfefferbaum, A. 2000; 47 (5): 434-449


    The P300 component of the auditory event-related brain potential (ERP) is consistently reduced in schizophrenia. Longitudinal data are examined to determine whether P300 amplitude is a trait marker of schizophrenia or a state marker tracking clinical fluctuations over time.Schizophrenic men (DSM-III-R) (n = 36) received ERP and the Brief Psychiatric Rating Scale (BPRS) assessments on multiple occasions, at varying intervals, under varying medication states. Automatically elicited auditory P3a and effortfully elicited auditory and visual P3b amplitudes were assessed. Brief Psychiatric Rating Scale scores were regressed on P300 amplitude within patients using both multiple regression models and nonparametric analyses of individual patient slopes. Event related brain potentials in patients were compared to ERPs from 34 age-matched control men, and stability of P300 over time was estimated with intraclass correlations.P300 amplitude, regardless of elicitation method or sensory modality, tracked BPRS Total and positive symptom scores over time, decreasing with symptom exacerbations and increasing with improvements. In addition, effortful auditory and visual P3b amplitudes tracked negative symptoms, and automatic auditory P3a tracked depression-anxiety symptoms. When analyses were limited to unmedicated occasions, auditory P3a and P3b persisted in tracking BPRS Total scores, with additional tracking of positive symptoms by P3b and mood symptoms by P3a. Mean auditory and visual P3bs, averaged over all measurement occasions for each individual, were inversely related to mean negative symptoms. Auditory P3a and P3b, but not visual P3b, amplitudes were smaller in patients than control subjects, even when patients were least symptomatic. P300 amplitudes showed high test-retest reliability in control subjects and patients and moderate stability over time in patients.Auditory, and possibly visual, P300 amplitudes track fluctuations in clinical state, but only auditory P300 amplitude is a trait marker of schizophrenia.

    View details for Web of Science ID 000085721400008

    View details for PubMedID 10704955

  • P300 reduction and prolongation with illness duration in schizophrenia BIOLOGICAL PSYCHIATRY Mathalon, D. H., Ford, J. M., Rosenbloom, M., Pfefferbaum, A. 2000; 47 (5): 413-427


    The P300 component of the auditory event-related potential (ERP) is both reduced in amplitude and delayed in schizophrenia. P300 is prolonged and, less consistently, reduced with normal aging. Additional latency delays are observed in neurodegenerative disorders. We asked whether P300 is reduced and delayed with longer illness duration in schizophrenia, consistent with a neurodegenerative process.P300 amplitude and latency were recorded to infrequent auditory target stimuli from 35 men with schizophrenia (DSM-III-R) and 26 control men. Effects of current age, age of onset, and duration of illness on P300 were assessed using regression analysis.P300 amplitude showed no age-related decrease in either group; however, among schizophrenic participants, P300 amplitude correlated positively with onset age and negatively with illness duration. P300 latency correlated positively with age in schizophrenic participants and also tended to increase with age in controls. Slopes of the latency-age relationships were significantly greater in schizophrenic participants than in control participants. Latency also correlated positively with illness duration but showed no relationship to onset age.P300 amplitude and latency are reduced and delayed with longer illness duration in schizophrenia, consistent with a progressive pathophysiological process. Reduced P300 amplitude may also be a marker of an early onset variant of schizophrenia.

    View details for Web of Science ID 000085721400006

    View details for PubMedID 10704953

  • alpha 2 macroglobulin and the risk of Alzheimer's disease NEUROLOGY Dodel, R. C., Du, Y., Bales, K. R., Gao, F., Eastwood, B., Glazier, B., Zimmer, R., Cordell, B., Hake, A., Evans, R., Gallagher-Thompson, D., Thompson, L. W., Tinklenberg, J. R., Pfefferbaum, A., SULLIVAN, E. V., Yesavage, J., Altstiel, L., Gasser, T., Farlow, M. R., Murphy, G. M., Paul, S. M. 2000; 54 (2): 438-442


    alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56).We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism.We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors.Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

    View details for Web of Science ID 000085043800030

    View details for PubMedID 10668709

  • Brain structure in men remains highly heritable in the seventh and eighth decades of life NEUROBIOLOGY OF AGING Pfefferbaum, A., SULLIVAN, E. V., Swan, G. E., Carmelli, D. 2000; 21 (1): 63-74


    The midsagittal cross-sectional dimensions of the corpus callosum, the coronal cross-sectional area of the lateral ventricles at the level of the pons, and a three-dimensional estimate of intracranial volume were derived from magnetic resonance brain images obtained from 45 monozygotic and 40 dizygotic male twin pairs aged 68 to 78. Univariate genetic analyses indicated strong genetic influences contributing significantly to the variability of each brain structure. The estimated proportion of genetic variance (i.e. heritability) was 81% for intracranial volume, 79% for the midline cross-sectional area of the corpus callosum, and 79% for lateral ventricle size. There was no evidence that shared environmental influences contributed significantly to twin-pair similarities. We further used bivariate genetic modeling to estimate the genetic and environmental correlation between correlated brain structures. Intracranial volume and corpus callosum area was highly correlated, and this relationship was entirely due to shared genetic effects between these two brain structures. By contrast, the relationship between the height of the corpus callosum and the size of the lateral ventricles was due to both genetic and environmental influences in common. Corresponding genetic and environmental correlations were 0.68 and 0.58, respectively, indicating that more than half of the genetic and environmental influences on these two brain structures were shared. The manner in which the brain responds to the environment with advancing age is highly genetically determined, both for the lateral ventricles, which dilate with aging and disease, and for the corpus callosum, which is deformed in shape by age-related ventricular enlargement, whereas its midline cross-sectional area remains unchanged.

    View details for Web of Science ID 000086931500009

    View details for PubMedID 10794850

  • Cortical gray matter deficit in patients with bipolar disorder SCHIZOPHRENIA RESEARCH Lim, K. O., Rosenbloom, M. J., Faustman, W. O., SULLIVAN, E. V., Pfefferbaum, A. 1999; 40 (3): 219-227


    cortical gray matter volume deficit and ventricular enlargement are well documented in schizophrenia, but their presence in bipolar disorder is less well cortical gray matter, white matter and sulcal CSF, as well as lateral and third ventricular volume measures, were derived from axial MRI brain images obtained on age-matched bipolar (n=9), schizophrenic (n=9), and control (n=16) subjects. All subjects were free of history of alcohol or other substance dependence.relative to controls, bipolar patients had widespread volume deficits of cortical gray matter but not of cortical white matter. Schizophrenic patients had an even more severe cortical gray matter deficit and greater sulcal and lateral ventricular enlargement than the bipolar patients.this group of patients with bipolar disorder had a widespread deficit of cortical gray matter similar to, but less pronounced than, that observed in patients with schizophrenia.

    View details for Web of Science ID 000084023000006

    View details for PubMedID 10638860

  • In vivo mammillary body volume deficits in amnesic and nonamnesic alcoholics ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V., Lane, B., Deshmukh, A., Rosenbloom, M. J., Desmond, J. E., Lim, K. O., Pfeferbaum, A. 1999; 23 (10): 1629-1636


    Neuropathological studies use the presence of mammillary body (MB) pathology as a cardinal, diagnostic feature of Wernicke's encephalopathy (WE) in neuropsychiatric diseases, most notably alcoholism. Although Korsakoffs Syndrome (KS), which is marked behaviorally by dense global amnesia, is a typical sequela of WE, it remains controversial whether these two conditions necessarily co-occur and whether MB pathology is therefore a diagnostic requisite for KS.We investigated these issues by examining, in vivo, 24 nonamnesic alcoholics (ALC), 5 amnesic alcoholics (KS), and 51 normal controls with three-dimensional MRI and memory testing. MB volume was determined from successive, 1 mm thick slices.The ALC group had significantly smaller MB volumes bilaterally (mean = 54.5 +/- 22.0 mm3) than controls (mean = 66.3 +/- 17.1 mm3), and the KS group had even smaller MB volumes than the ALC group (mean = 20.7 +/- 14.8 mm3). Only 2 ALC patients met historical clinical criteria for past WE, and their MB volumes were well within range of the remaining 22 ALC patients. Although all five KS patients met historical clinical criteria for WE, three KS did not have accompanying dementia and had the same degree of MB volume loss as the ALC; the remaining two KS had accompanying dementia and MB volumes half the volume of the ALC group and of KS patients without dementia.These findings provide volumetric in vivo evidence that: (1) MB volume deficits do occur in alcoholics without amnesia, although these deficits are not present in ail such alcoholics; (2) greater MB volume deficits are present in alcoholics with clinically detectable amnesia or dementia; (3) MB shrinkage is related to severity of cognitive and memory dysfunction, which suggests a continuum of MB pathology in chronic alcoholism to KS; and (4) the presence of WE in all of the KS patients and in the two ALC patients with the greatest long-term declarative memory deficit supports the possibility of an additional and unique pathology distinguishing nonamnesic and amnesic alcoholism.

    View details for Web of Science ID 000083279500011

    View details for PubMedID 10549995

  • N-acetyl aspartic acid (NAA) and N-acetyl aspartylglutamic acid (NAAG) in human ventricular, subarachnoid, and lumbar cerebrospinal fluid NEUROCHEMICAL RESEARCH Faull, K. F., Rafie, R., Pascoe, N., Marsh, L., Pfefferbaum, A. 1999; 24 (10): 1249-1261


    N-Acetylaspartic and N-acetylaspartylglutamic acid concentrations in human ventricular, subarachnoid and lumbar cerebrospinal fluid were measured by combined gas chromatography-mass spectrometry using selected ion monitoring with deuterated internal standards. N-Acetylaspartate concentrations were in the range 55, 9, and 1 microM, respectively; N-acetylaspartylglutamate concentrations in the same fluids were in the range 8, 3 and 4 microM, respectively. There did not appear to be any difference in lumbar fluid concentrations of either compound between control subjects, schizophrenic patients, Alzheimer's disease patients and a pooled group of patients with neurological degeneration. Ventricular concentrations of both compounds were greatly increased in deceased patients suggesting that maintenance of their intracellular concentrations is probably energy dependent. The concentrations of these compounds in lumbar cerebrospinal fluid from living, and ventricular cerebrospinal fluid from deceased subjects were weakly correlated with one another. In lumbar fluid neither compound appeared to be correlated with age. Analysis of serially collected lumbar samples from two subjects showed a weak concentration gradient for both compounds. Neither antipsychotic medication nor the acid transport inhibitor probenecid had any effect on lumbar concentrations of either compound. Attempts to use anion exchange high pressure liquid chromatography with UV detection for measurement of the low concentrations of N-acetylaspartate found in cerebrospinal fluid from living subjects were unsuccessful.

    View details for Web of Science ID 000082409500007

    View details for PubMedID 10492520

  • Failures of automatic and strategic processing in schizophrenia: comparisons of event-related brain potential and startle blink modification SCHIZOPHRENIA RESEARCH Ford, J. M., Roth, W. T., Menon, V., Pfefferbaum, A. 1999; 37 (2): 149-163


    Noises elicit startle blinks that are inhibited when immediately (approximately 100 ms) preceded by non-startling prepulses, perhaps reflecting automatic sensory gating. Startle blinks are facilitated when preceded by prepulses at longer lead intervals, perhaps reflecting strategic processes. Event-related brain potentials (ERPs) and startle blinks were used to investigate the well-documented prepulse inhibition failure in schizophrenia. Blinks and ERPs were recorded from 15 schizophrenic men and 20 age-matched controls to noises alone and to noises preceded by prepulses at 120 (PP120), 500 (PP500) and 4000 ms (PP4000) lead intervals. Neither blinks nor any of the ERP components elicited by the noise alone differentiated schizophrenics from controls, although responses to noises were modified by prepulses differently in the two groups. With the N1 component of the ERP, patients showed normal inhibition but lacked facilitation, and with P2, patients lacked inhibition, but showed normal facilitation. With reflex blinks and P300, inhibition was seen in both groups, but no facilitation. These results suggest that different neural circuits are involved in blink and cortical reflections of startle modification in schizophrenics and controls, with both automatic and strategic processes being impaired in schizophrenia.

    View details for Web of Science ID 000080583700003

    View details for PubMedID 10374650

  • Compromised white matter tract integrity in schizophrenia inferred from diffusion tensor imaging ARCHIVES OF GENERAL PSYCHIATRY Lim, K. O., Hedehus, M., Moseley, M., de Crespigny, A., SULLIVAN, E. V., Pfefferbaum, A. 1999; 56 (4): 367-374


    Current investigations suggest that brain white matter may be qualitatively altered in schizophrenia even in the face of normal white matter volume. Diffusion tensor imaging provides a new approach for quantifying the directional coherence and possibly connectivity of white matter fibers in vivo.Ten men who were veterans of the US Armed Forces and met the DSM-IV criteria for schizophrenia and 10 healthy, age-matched control men were scanned using magnetic resonance diffusion tensor imaging and magnetic resonance structural imaging.Relative to controls, the patients with schizophrenia exhibited lower anisotropy in white matter, despite absence of a white matter volume deficit. In contrast to the white matter pattern, gray matter anisotropy did not distinguish the groups, even though the patients with schizophrenia had a significant gray matter volume deficit. The abnormal white matter anisotropy in patients with schizophrenia was present in both hemispheres and was widespread, extending from the frontal to occipital brain regions.Despite the small sample size, diffusion tensor imaging was powerful enough to yield significant group differences, indicating widespread alteration in brain white matter integrity but not necessarily white matter volume in schizophrenia.

    View details for Web of Science ID 000079504400011

    View details for PubMedID 10197834

  • In vivo brain concentrations of N-acetyl compounds, creatine, and choline in Alzheimer disease ARCHIVES OF GENERAL PSYCHIATRY Pfefferbaum, A., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Lim, K. O. 1999; 56 (2): 185-192


    Alzheimer disease (AD) and normal aging result in cortical gray matter volume deficits. The extent to which the remaining cortex is functionally compromised can be estimated in vivo with magnetic resonance spectroscopic imaging.To assess the effects of age and dementia on gray matter and white matter concentrations of 3 metabolites visible in the proton spectrum: N-acetyl compounds, present only in living neurons; creatine plus phosphocreatine, reflecting high-energy phosphate metabolism; and choline, increasing with membrane synthesis and degradation.Fifteen healthy young individuals, 19 healthy elderly individuals, and 16 patients with AD underwent 3-dimensional magnetic resonance spectroscopic imaging and memory and language testing.Gray matter N-acetyl compound concentrations (signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal) was significantly reduced only in patients with AD, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young control group. Both the healthy elderly and AD groups had abnormally high gray matter creatine plus phosphocreatine concentrations. Gray matter choline concentrations were higher in the elderly than the younger controls, and even higher in the AD group than in the elderly control group. Functional significance of these findings was supported by correlations between poorer performance on recognition memory tests and lower gray matter N-acetyl compounds in elderly controls and higher gray matter creatine plus phosphocreatine and choline concentrations in patients with AD.Cortical gray matter volume deficits in patients with AD are accompanied by disease-related increases in gray matter choline concentrations suggestive of cellular degeneration and reduced N-acetyl compound concentrations, with possible effects on behavioral function.

    View details for Web of Science ID 000078553600010

    View details for PubMedID 10025444

  • In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: Effects of normal aging MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Lim, K. O. 1999; 41 (2): 276-284


    Volumetric proton magnetic resonance spectroscopic imaging (MRSI) was used to generate brain metabolite maps in 15 young and 19 elderly adult volunteers. All subjects also had structural MR scans, and a model, which took into account the underlying structural composition of the brain contributing to each metabolite voxel, was developed and used to estimate the concentration of the N-acetyl-moiety (NAc), creatine (Cr), and choline (Cho) in gray matter and white matter. NAc concentration (signal intensity per unit volume of brain) was higher in gray than white matter and did not differ between young and old subjects despite significant gray matter volume deficits in the older subjects. To the extent that NAc is an index of neuronal integrity, the available gray matter appears to be intact in these older healthy adults. Cr concentrations were much higher in gray than white matter and significantly higher in the old than young subjects. Cho concentration in gray matter was also significantly higher in old than young subjects. Independent determination of metabolite values rather than use of ratios is essential for characterizing age-related changes in brain MRS metabolites.

    View details for Web of Science ID 000078804500010

    View details for PubMedID 10080274

  • Severity of schizophrenia and magnetic resonance imaging abnormalities: A comparison of state and veterans hospital patients BIOLOGICAL PSYCHIATRY Marsh, L., Lim, K. O., Hoff, A. L., Harris, D., Beal, M., Minn, K., Faustman, W. O., Csernansky, J. G., SULLIVAN, E. V., Pfefferbaum, A. 1999; 45 (1): 49-61


    The relationship between illness severity and neuroanatomical abnormalities in schizophrenia remains unclear. The purpose of this study was to test whether the pattern and extent of brain volume abnormalities differed between two patient groups, distinguished by their overall severity and clinical course of schizophrenia.Subjects were 56 severely ill, chronically hospitalized schizophrenic men from Napa State Hospital (SH-SZ), 44 moderately ill, acutely hospitalized schizophrenic men from the Palo Alto Veterans Administration Health Care System (VA-SZ), and 52 healthy male control subjects. Temporolimbic, ventricular, and frontoparietal volumes, quantified from 3-mm coronal spin-echo magnetic resonance images and adjusted for cerebral volume and age, were compared using analysis of variance.Compared to control subjects, both SZ groups had smaller (p < .05) temporal lobe and frontoparietal gray matter volumes and larger ventricles and temporal sulci. Whereas SH-SZ had more pronounced cerebrospinal fluid and frontoparietal abnormalities relative to VA-SZ; VA-SZ had greater temporal lobe gray matter deficits. Neither patients group had hippocampal or cerebral volume deficits relative to control subjects. There were no differences between diagnostic subtypes.The magnitude of volume abnormalities in schizophrenia varies with respect to disease severity and to brain region, but disease severity is not associated with anatomically distinct subgroups.

    View details for Web of Science ID 000077967900006

    View details for PubMedID 9894575

  • Cerebrospinal fluid glutamate inversely correlates with positive symptom severity in unmedicated male schizophrenic/schizoaffective patients BIOLOGICAL PSYCHIATRY Faustman, W. O., Bardgett, M., Faull, K. F., Pfefferbaum, A., Csernansky, J. G. 1999; 45 (1): 68-75


    Recent hypotheses have suggested that diminished brain glutamate may be of importance in the neurochemical basis of schizophrenia.We assayed cerebrospinal fluid for glutamate and obtained clinical symptom ratings in 19 medication-free (except p.r.n. chloral hydrate) schizophrenic or schizoaffective (typically with significant schizophrenic qualities) male inpatients.Ratings of positive symptoms were significantly inversely correlated (rs = -.457, p < .05, one-tailed test) with glutamate concentrations. Hallucinatory behavior was strongly correlated (rs = -.621, p < .01, one-tailed test) with glutamate. A subset of 11 patients consented to a second lumbar puncture (LP) after treatment with haloperidol (typically 15 or 20 mg/day) for 2-4 weeks. Haloperidol treatment did not alter glutamate concentrations. No correlations were noted between glutamate and symptoms in the medicated subsample. Though approximately half the patients received chloral hydrate during the 72 hours prior to the unmedicated LP, the correlations between positive symptoms and glutamate in the patients who received no chloral hydrate prior to the LP were quite similar to those found in the overall sample.The results provide further support for the potential importance of glutamate in the neurochemical basis of schizophrenia.

    View details for Web of Science ID 000077967900008

    View details for PubMedID 9894577

  • A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval ARCHIVES OF GENERAL PSYCHIATRY Pfefferbaum, A., SULLIVAN, E. V., Rosenbloom, M. J., Mathalon, H., Lim, K. O. 1998; 55 (10): 905-912


    We report on structural brain changes during a 5-year period in healthy control and alcoholic men.Alcoholic patients (n = 16), from an initial group of 58 who underwent brain magnetic resonance imaging scanning while in treatment, were rescanned with the same acquisition sequence approximately 5 years later. Control subjects (n = 28) spanning the same age range also were scanned twice at a comparable interval. Changes in brain volume were corrected for error due to differences in head placement between scans and expressed as slopes (cubic centimeters per year), percentage of change over baseline for the control subjects, and standardized change for the alcoholic patients. The alcoholic patients varied considerably in the percentage of time that symptoms of alcohol dependence were present and in the amount of alcohol consumed during follow-up.The cortical gray matter diminished in volume over time in the control subjects, most prominently in the prefrontal cortex, while the lateral and third ventricles enlarged. The alcoholic patients showed similar age-related changes with a greater rate of gray matter volume loss than the control subjects in the anterior superior temporal lobe. The amount of alcohol consumed during follow-up predicted the rate of cortical gray matter volume loss, as well as sulcal expansion. The rate of ventricular enlargement in alcoholic patients who maintained virtual sobriety was comparable to that in the control subjects.During a 5-year period, brain volume shrinkage is exaggerated in the prefrontal cortex in normal aging with additional loss in the anterior superior temporal cortex in alcoholism. The association of cortical gray matter volume reduction with alcohol consumption over time suggests that continued alcohol abuse results in progressive brain tissue volume shrinkage.

    View details for Web of Science ID 000076415500008

    View details for PubMedID 9783561

  • Differential contributions of cognitive and motor component processes to physical and instrumental activities of daily living in Parkinson's disease ARCHIVES OF CLINICAL NEUROPSYCHOLOGY Cahn, D. A., SULLIVAN, E. V., Shear, P. K., Pfefferbaum, A., Heit, G., Silverberg, G. 1998; 13 (7): 575-583


    Patients with Parkinson's disease (PD) become dependent upon caregivers because motor and cognitive disabilities interfere with their ability to carry out activities of daily living (ADLs). However, PD patients display diverse motor and cognitive symptoms, and it is not yet known which are most responsible for ADL dysfunction. The purpose of this study was to identify the contributions that specific cognitive and motor functions make to ADLs. Executive functioning, in particular sequencing, was a significant independent predictor of instrumental ADLs whereas simple motor functioning was not. By contrast, simple motor functioning, but not executive functioning, was a significant independent predictor of physical ADLs. Dementia severity, as measured by the Dementia Rating Scale, was significantly correlated with instrumental but not physical ADLs. The identification of selective relationships between motor and cognitive functioning and ADLs may ultimately provide a model for evaluating the benefits and limitations of different treatments for PD.

    View details for Web of Science ID 000075851200001

    View details for PubMedID 14590618

  • Association between regional brain volumes and clozapine response in schizophrenia BIOLOGICAL PSYCHIATRY Lauriello, J., Mathalon, D. H., Rosenbloom, M., SULLIVAN, E. V., Faustman, W. O., Ringo, D. L., Lim, K. O., Pfefferbaum, A. 1998; 43 (12): 879-886


    Clozapine has shown considerable therapeutic promise in the treatment of schizophrenia; however, the clinical risks and initial high treatment costs associated with its administration motivate the search to identify patients who will best respond. Neuroimaging studies have suggested that prefrontal sulcal prominence may be a predictor of nonresponsiveness.We used magnetic resonance imaging (MRI) to test whether volumes in any cortical regions of the brain were associated with symptom improvement with clozapine treatment. The 21 schizophrenic men studied were clinically evaluated during treatment with typical neuroleptics (baseline) and after a mean of 6.2 months treatment with clozapine (final dose 300-900, median = 562 mg/day). At least a 20% improvement on total Brief Psychiatric Rating Scale (BPRS) was seen in 47.6% of the schizophrenics. Clinical improvement was regressed on baseline differences in clinical severity, and the residual scores were related to MRI values.Patients with larger anterior superior temporal lobe cerebrospinal fluid volumes (primarily sylvian fissure) showed greater improvement on total BPRS and withdrawal/retardation symptoms.Even schizophrenics with significant brain dysmorphology can have a positive clinical response to clozapine.

    View details for Web of Science ID 000074039800005

    View details for PubMedID 9627742

  • Differential activation of dorsal basal ganglia during externally and self paced sequences of arm movements NEUROREPORT Menon, V., Glover, G. H., Pfefferbaum, A. 1998; 9 (7): 1567-1573


    The basal ganglia are thought to be critically involved in motor control. However, the relative contributions of the various sub-components are not known. Although, in principle, functional magnetic resonance imaging (fMRI) provides adequate resolution to image the basal ganglia at the spatial scale of the individual nuclei, activating these nuclei with fMRI has proven to be difficult. Here we report two tasks, involving externally and self paced sequences of arm movements, which resulted in significant activation of contralateral posterior (post-commissural) putamen and globus pallidus. This activation did not significantly differ between the tasks. In contrast, significant activation of the contralateral and ipsilateral anterior caudate and anterior putamen was observed only during externally paced arm movements. These results suggest a dissociation in the roles of the anterior and posterior dorsal basal ganglia: the anterior caudate and putamen may be involved in sensory to motor mapping and the posterior putamen and globus pallidus may be involved in the motor response itself. The findings support the hypothesis that the basal ganglia may be involved in gating sensory influences onto motor areas.

    View details for Web of Science ID 000074000000061

    View details for PubMedID 9631468

  • Proton magnetic resonance spectroscopic imaging of cortical gray and white matter in schizophrenia ARCHIVES OF GENERAL PSYCHIATRY Lim, K. O., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Rosenbloom, M. J., Pfefferbaum, A. 1998; 55 (4): 346-352


    To apply in vivo proton magnetic resonance spectroscopy imaging estimates of N-acetylaspartate (NAA), a neuronal marker, to clarify the relative contribution of neuronal and glial changes to the widespread volume deficit of cortical gray matter seen in patients with schizophrenia with magnetic resonance images.Ten male veterans meeting criteria of the DSM-IV, for schizophrenia and 9 healthy age-matched men for comparison were scanned using spectroscopic, anatomical, and field-map sequences. Instrument and collection variables were standardized to allow an estimation of comparable values for NAA, choline, and creatine for all subjects. Metabolite values from each voxel on 3 upper cortical slices were regressed against the gray tissue proportion of that voxel to derive estimates of gray and white matter NAA, creatine, and choline concentrations.The volume of cortical gray matter was reduced in patients with schizophrenia, but NAA signal intensity from a comparable region was normal. In contrast, the volume of cortical white matter was normal in patients with schizophrenia, but NAA signal intensity from a comparable region was reduced.The lack of reduction in gray matter NAA signal intensity suggests that the cortical gray matter deficit in these patients involved both neuronal and glial compartments rather than a neurodegenerative process in which there is a decrease in the neuronal relative to the glial compartment. Reduced white matter NAA signal intensity without a white matter volume deficit may reflect abnormal axonal connections.

    View details for Web of Science ID 000072993300009

    View details for PubMedID 9554430

  • Profile of cortical gray matter volume deficits characteristic of schizophrenia CEREBRAL CORTEX SULLIVAN, E. V., Lim, K. O., Mathalon, D., Marsh, L., Beal, D. M., Harris, D., Hoff, A. L., Faustman, W. O., Pfefferbaum, A. 1998; 8 (2): 117-124


    Quantitative magnetic resonance imaging (MRI) studies from our laboratory have reported that patients with schizophrenia show a widespread cortical gray matter volume deficit, which is especially pronounced in the prefrontal and anterior superior temporal cortices. The present study compared two separate samples of schizophrenic patients -- 71 men from a Veterans Administration (VA) hospital and a sample of 57 severely ill men from a state hospital (SH) -- in an effort to test whether the pattern of brain volume abnormalities previously observed in VA schizophrenic patients can be generalized to other groups of schizophrenic patients. MRI-derived brain volumes of gray matter, white matter and sulcal cerebrospinal fluid (CSF) in six cortical regions, and CSF in the lateral and third ventricles were computed. All MRI volumes were adjusted for normal variation in head size and age and were expressed as standardized Z-scores, which also permitted structures of different sizes to be compared directly. The two schizophrenic groups displayed similar patterns of volume abnormalities: cortical gray matter but not white matter volume deficits that were widespread but especially notable in the prefrontal and temporal regions. The regional gray matter deficits in the SH group were generally greater than those in the VA group, particularly in the prefrontal and posterior superior temporal regions. Both schizophrenic groups had abnormally large volumes of the cortical sulci and lateral and third ventricles; however, the SH group showed greater enlargements, the most prominent occurring in the ventricles and temporal sulci. The overlapping patterns of cortical gray matter deficits in the two groups provide evidence for generality of this pattern of regional brain volume abnormalities in schizophrenia.

    View details for Web of Science ID 000072118300003

    View details for PubMedID 9542891

  • Structural MRI correlates of recognition memory in Alzheimer's disease JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Cahn, D. A., SULLIVAN, E. V., Shear, P. K., Marsh, L., Fama, R., Lim, K. O., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. 1998; 4 (2): 106-114


    Neuroimaging and lesion studies have demonstrated that hippocampal volume correlates with memory performance, but material-specific lateralization of this structure-function relationship has been inconsistent. This MRI study examined the relative contributions of left and right temporal lobe volumes to verbal and nonverbal recognition memory in a group of 20 Alzheimer's disease (AD) patients. There was a significant relationship between extent of right hippocampal and right temporal gray matter tissue volume deficit and performance on the face recognition subtest of the Warrington Recognition Memory Test. The face recognition test correlated with right hemisphere volume but not to left, indicating a material-specific relationship between brain structure and function in this patient group. Right temporal horn volume did not account for a significant proportion of variance in face recognition memory. Although word recognition was not significantly correlated with either left or right hippocampal volume in the total group, there was a strong correlation between left hippocampal volume and word recognition memory in the female AD patients. Thus, face recognition shows a material specific relationship with select lateralized hippocampal and temporal cortical volumes in AD patients, regardless of gender, whereas the verbal recognition-left-hippocampal volume relationship may be mediated by gender.

    View details for Web of Science ID 000075146200002

    View details for PubMedID 9529820

  • Patterns of regional cortical dysmorphology distinguishing schizophrenia and chronic alcoholism BIOLOGICAL PSYCHIATRY SULLIVAN, E. V., Mathalon, D. H., Lim, K. O., Marsh, L., Pfefferbaum, A. 1998; 43 (2): 118-131


    This study used magnetic resonance imaging (MRI) to compare the extent and pattern of tissue volume deficit and cerebrospinal fluid volume enlargement in chronic alcoholics and schizophrenics.The subjects included 62 detoxified chronic alcoholics (26-63 years), 71 schizophrenics (23-63 years), and 73 controls spanning the adult age range (21-70 years). MRI volumes were adjusted for normal variation in head size and age established from the control group.Both patient groups showed widespread cortical gray matter volume deficits compared with controls, but only the alcoholics had white matter volume deficits. The schizophrenics had significantly greater volume deficits in the prefrontal and anterior superior temporal gray matter than in the more posterior cortical regions. By contrast, the deficits in the alcoholics were relatively homogeneous across the cortex. For white matter, the deficits in the alcoholics were greatest in the prefrontal and temporal-parietal regions. Although both patient groups had abnormally larger cortical sulci and lateral and third ventricles than the controls, the alcoholics had significantly larger sulcal volumes in the frontal, anterior, and posterior parietal-occipital regions than the schizophrenics.This quantitative MRI study revealed different patterns of regional cortical volume abnormalities in schizophrenics and alcoholics. The schizophrenic group exhibited cortical gray matter volume deficits of modestly greater magnitude than that observed in the alcoholic group, and the alcoholics but not the schizophrenics exhibited cortical white matter volume deficits.

    View details for Web of Science ID 000072093000005

    View details for PubMedID 9474444

  • Structural magnetic resonance imaging abnormalities in men with severe chronic schizophrenia and an early age at clinical onset ARCHIVES OF GENERAL PSYCHIATRY Marsh, L., Harris, D., Lim, K. O., Beal, M., Hoff, A. L., Minn, K., Csernansky, J. G., DEMENT, S., Faustman, W. O., SULLIVAN, E. V., Pfefferbaum, A. 1997; 54 (12): 1104-1112


    Early age at onset of schizophrenia often signifies a more severe form of the illness. However, the relationship between age at onset and brain abnormalities has not been established. We assessed temporal-limbic morphometry in severely ill men with chronic schizophrenia who had a relatively early onset of illness and examined the relationships among regional brain volumes, clinical symptoms, and age at illness onset.Temporal lobe, superior temporal gyrus, hippocampus, temporal horn, lateral ventricles, third ventricle, and frontoparietal volumes were measured on magnetic resonance imaging data from 56 schizophrenic men (mean [SD] age at illness onset, 16.6 [4.2] years) recruited from a state hospital and 52 age- and range-matched healthy control men.Patients had significantly smaller gray matter volumes in the temporal lobe, superior temporal gyrus, and frontoparietal regions; smaller temporal lobe white matter volumes; and larger cerebrospinal fluid volumes for temporal lobe sulci and the 3 ventricular measures. There were no group differences in hippocampal volumes. Psychotic symptom subscores from the Brief Psychiatric Rating Scale were selectively correlated with smaller left posterior superior temporal gyrus gray matter volumes. None of the brain measurements were significantly correlated with age at illness onset.Data from this unique sample of severely ill schizophrenic men emphasize a pattern of structural abnormalities involving the cortex, but not the hippocampus, in schizophrenia. Furthermore, these data support theories suggesting that superior temporal gyrus abnormalities contribute selectively to psychotic symptoms and that the extent of structural abnormalities is unrelated to age of clinical symptom onset.

    View details for Web of Science ID A1997YJ96900006

    View details for PubMedID 9400346

  • Quantification of cerebellar structures with MRI PSYCHIATRY RESEARCH-NEUROIMAGING Deshmukh, A. R., Desmond, J. E., SULLIVAN, E. V., Lane, B. F., Lane, B., Matsumoto, B., Marsh, L., Lim, K. O., Pfefferbaum, A. 1997; 75 (3): 159-171


    Methodological issues have limited neuroimaging studies of cerebellar structures. In this article we describe a method that addresses some of these limitations and phantom studies that examine the validity of the image manipulations. We compared volumes derived from 3D Spoiled Gradient Recalled Acquisition MR images sliced with respect to three different alignment methods: one based on cerebellar landmarks, another on cerebral landmarks and a third on the plane of acquisition. Examination of coefficients of variation, coefficients of error and convergent validity suggests that although regional cerebellar volumes based on cerebellar landmarks provide the best estimates of the true volumes, observed differences between volume measurements from alignments based on cerebellar or cerebral landmarks were generally not significant and were inconsequential. In this case, the measure was improved with alignment along local, relevant cerebellar landmarks. A set of phantom experiments showed that realignment, reslicing and interpolation in 3-dimensional image processing exerted, at most, trivial distortion on the estimates of actual object volumes.

    View details for Web of Science ID 000071115400003

    View details for PubMedID 9437773

  • Deficits in multiple systems of working memory in schizophrenia SCHIZOPHRENIA RESEARCH Spindler, K. A., SULLIVAN, E. V., Menon, V., Lim, K. O., Pfefferbaum, A. 1997; 27 (1): 1-10


    Working memory, the ability to hold and manipulate information 'on-line' in a temporary memory store, is impaired in schizophrenia. This impairment may be characterized within the framework of two opposing theoretical models: (1) central executive as coordinator of component processes of working memory or (2) multiple independent systems of spatial and object memory. In order to test which of these models better explains the working memory deficit of schizophrenia, 14 schizophrenic patients and 12 age- and gender-matched control subjects performed tests of spatial memory (dot location), object memory (shapes, color dots) and a dual paradigm (dot location + shapes). If schizophrenia impairs the central executive, a group-by-task interaction would demonstrate excessively worse performance on the dual than single tasks in schizophrenics relative to controls; however, the absence of an interaction would be consistent with deficits in the multiple working memory systems. The schizophrenic group was significantly impaired on all measures, and both the schizophrenic and control performance was worse on the dual than the single tasks. Despite the schizophrenic group performance deficits on the single tasks, the extent of such deficit did not appear additive and contributive to the dual tasks. The lack of a group-by-task interaction provided no support for the central executive model of dysfunction. Rather, the results uphold the model of working memory deficits arising from compromise of multiple (here spatial and object), relatively independent systems, both of which are affected in schizophrenia.

    View details for Web of Science ID A1997YD36900001

    View details for PubMedID 9373889

  • Combined event-related fMRI and EEG evidence for temporal-parietal cortex activation during target detection NEUROREPORT Menon, V., Ford, J. M., Lim, K. O., Glover, G. H., Pfefferbaum, A. 1997; 8 (14): 3029-3037


    Target detection is the process of bringing a salient stimulus into conscious awareness. Target detection evokes a prominent event-related potential (ERP) component (P3) in the electroencephalogram (EEG). We combined the high spatial resolution of functional magnetic resonance imaging (fMRI) with the high temporal resolution of EEG to investigate the neural generators of the P3. Event-related brain activation (ERBA) and ERPs were computed by time-locked averaging of fMRI and EEG, respectively, recorded using the same paradigm in the same subjects. Target detection elicited significantly greater ERBAs bilaterally in the temporal-parietal cortex, thalamus and anterior cingulate. Spatio-temporal modelling of ERPs based on dipole locations derived from the ERBAs indicated that bilateral sources in the temporal-parietal cortex are the main generators of the P3. The findings provide convergent fMRI and EEG evidence for significant activation of the temporal-parietal cortex 285-610 ms after stimulus onset during target detection. The methods developed here provide a novel multimodal neuroimaging technique to investigate the spatio-temporal aspects of processes underlying brain function.

    View details for Web of Science ID A1997XX91000009

    View details for PubMedID 9331910

  • Cortical and hippocampal volume deficits in temporal lobe epilepsy EPILEPSIA Marsh, L., Morrell, M. J., Shear, P. K., SULLIVAN, E. V., Freeman, H., Marie, A., Lim, K. O., Pfefferbaum, A. 1997; 38 (5): 576-587


    To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE).Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA).As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe.Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.

    View details for Web of Science ID A1997WX71900011

    View details for PubMedID 9184604

  • Patterns of content, contextual, and working memory impairments in schizophrenia and nonamnesic alcoholism NEUROPSYCHOLOGY SULLIVAN, E. V., Shear, P. K., Zipursky, R. B., SAGAR, H. J., Pfefferbaum, A. 1997; 11 (2): 195-206


    This study used tests of content memory (item recognition of words and abstract designs), context memory (order recognition of verbal and nonverbal items), and working memory (recognition at a short retention interval) to examine patterns of performance in 27 schizophrenic patients, 52 chronic alcoholic patients, and 66 healthy control participants. When performance was age- and IQ-adjusted the schizophrenia group was significantly impaired in item and order recognition of verbal and nonverbal material; the alcoholic group was impaired only in order recognition for both material types. Item- and order-recognition deficits in the schizophrenia group were greatest at the shortest retention intervals, a pattern previously observed in patients with Parkinson's disease, suggesting a prominence of a working memory deficit in schizophrenia.

    View details for Web of Science ID A1997WT56900004

    View details for PubMedID 9110327

  • Automatic and effortful processing in aging and dementia: Event-related brain potentials NEUROBIOLOGY OF AGING Ford, J. M., Roth, W. T., Isaacks, B. G., Tinklenberg, J. R., Yesavage, J., Pfefferbaum, A. 1997; 18 (2): 169-180


    Automatic and effortful processes were investigated using event-related brain potentials (ERPs) recorded from moderately impaired subjects with probable Alzheimer's Disease (AD), normal elderly, and normal young controls. The effects of effortful attention on ERPs to loud noises and the effects of stimulus intrusiveness on effortfully elicited ERPs were studied. First, ERPs to task relevant and irrelevant startling noises were compared. Second, ERPs to startling noises and moderate tones were compared when both were targets. The effects of age (young vs. elderly controls) and effects of dementing disease (AD subjects vs. elderly controls) were also assessed. Effortful attention augmented noise-elicited P300 amplitude in elderly subjects, but not in young. Intrusiveness augmented task-relevant P300 amplitude in young subjects, but not in elderly. Neither variable affected P300 amplitude in AD subjects. Thus, effects of age and disease depended on how P300 was elicited: when effortfully elicited, P300 amplitude was affected by disease but not age; when automatically elicited, P300 amplitude was affected by age but not disease. N1 effects differed from P300 effects.

    View details for Web of Science ID A1997XP01300006

    View details for PubMedID 9258894

  • Effects of 'seroquel' (quetiapine) on platelet serotonin-2 binding in schizophrenia JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Faustman, W. O., Ringo, D. L., Lauriello, J., Lim, K. O., Pfefferbaum, A., Bardgett, M. E., Csernansky, J. G. 1996; 16 (6): 464-466

    View details for Web of Science ID A1996VW91400015

    View details for PubMedID 8959478

  • Mammillary body and cerebellar shrinkage in chronic alcoholics with and without amnesia ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Shear, P. K., SULLIVAN, E. V., Lane, B., Pfefferbaum, A. 1996; 20 (8): 1489-1495


    Mammillary body and cerebellar atrophy have been described as postmorten neuropathologic markers of Korsakoff's syndrome. This study examined whether shrinkage in the mammillary bodies and cerebellum is present consistently in amnesic chronic alcoholics during life and whether the degree of abnormality in these patients differs from that in nonamnesic alcoholic and healthy controls. The severity of shrinkage in the mammillary bodies, cerebellar hemispheres, and cerebellar vermis visualizable on MRI scans was rated on a three-point scale in 33 chronic nonamnesic alcoholics, 9 amnesic alcoholics, and 20 healthy controls. Although both alcoholic groups showed significant mammillary body and cerebellar shrinkage relative to controls, the two patient groups did not differ from each other. Furthermore, four of eight amnesic patients in our sample did not demonstrate clinically significant mammillary body atrophy. These results suggest that alcoholism is associated with mammillary body and cerebellar tissue volume loss but do not provide evidence that these markers distinguish accurately between amnesic and nonamnesic patients. In addition, they suggest that visualizable mammillary body atrophy is not necessary for the development of amnesia in alcoholic patients.

    View details for Web of Science ID A1996VU64400025

    View details for PubMedID 8947329

  • The effect of stimulus-response incompatibility on P3 latency depends on the task but not on age BIOLOGICAL PSYCHOLOGY Christensen, C. A., Ford, J. M., Pfefferbaum, A. 1996; 44 (2): 121-141


    To help identify the loci of age-related slowing of cognitive processing, the effects of stimulus-response (S-R) incompatibility and stimulus degradation on P3 latency and reaction time (RT) were assessed in ten young and ten elderly women. Subjects saw the words right, left, RIGHT, or LEFT in tasks which required responses to (1) the meaning of the word (WORD) (2) its case (CASE) and (3) both (CASE/WORD). Each task was tested with regular and degraded stimuli. On half the trials, the stimulus and response were incompatible. Although RTs and P3s of elderly subjects were slower, especially RTs in CASE/WORD, stimulus degradation and S-R incompatibility did not differentially affect the two groups, suggesting that cognitive processing of older subjects is not especially prolonged in perceptual and response-related stages. For both groups RTs and P3s were task dependent and were prolonged by degradation and S-R incompatibility. Incompatibility delayed RTs in WORD and CASE/WORD but P3s in WORD only. Thus, young and elderly subjects show qualitatively similar psychophysiological and behavioral indicators of processing speed.

    View details for Web of Science ID A1996VP86400004

    View details for PubMedID 8913525

  • Gray matter deficits in young onset schizophrenia are independent of age of onset BIOLOGICAL PSYCHIATRY Lim, K. O., Harris, D., Beal, M., Hoff, A. L., Minn, K., Csernansky, J. G., Faustman, W. O., Marsh, L., SULLIVAN, E. V., Pfefferbaum, A. 1996; 40 (1): 4-13


    This study examined whether the degree of brain dysmorphology observable in adulthood was related to onset age of schizophrenic symptoms. Brain magnetic resonance imaging (MRI) scans were acquired in 57 men with schizophrenia, whose age at MRI was 19-53 years, and whose symptom onset ranged from age 7 to 29 years; all were inpatients in a state hospital. Volumes of intracranial space, cortical gray matter (GM) and white matter (WM), and cerebrospinal fluid (CSF) in lateral and third ventricles and cortical sulci were derived from MRI scans and corrected by regression analysis for variations attributable to age and head size, quantified in a control sample of healthy community volunteers. The schizophrenic patients had larger volumes of cortical and ventricular CSF and smaller volumes of cortical GM but not WM than age-matched controls, whether or not volumes were adjusted for head size and age norms. Age of onset did not correlate with any of the five age-adjusted brain measures. Neither current age, length of illness, nor symptom severity correlated with age-normalized volumes of cortical GM, sulcal CSF, or ventricular CSF. These observations are consistent with the theory that brain structure deficits 1) first develop prior to symptom onset (perhaps during the prenatal and/or early childhood process of GM development); 2) probably establish a vulnerability to subsequent dysfunctionality; but 3) are nonprogressive.

    View details for Web of Science ID A1996UQ17800002

    View details for PubMedID 8780849

  • Thinning of the corpus callosum in older alcoholic men: A magnetic resonance imaging study ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Lim, K. O., Desmond, J. E., SULLIVAN, E. V. 1996; 20 (4): 752-757


    A brain image averaging technique was applied to three-dimensional magnetic resonance images to identify visually detectable brain volume abnormalities in chronically alcoholic men, compared with healthy control men. This technique, which was based on pixel-by-pixel statistical probability mapping, revealed a dramatic reduction in the area of the corpus callosum in older alcoholics (age 45 years or older), relative to age-matched controls. Subsequent analysis used anatomical landmarks to outline the borders of midsagittal sections of the corpus callosum in a larger group of alcoholics and controls, who spanned the adult age range from 23 to 71 years. This analysis revealed significant reduction, most prominent in the genu and body, of total callosal area in the alcoholic group relative to the control group; the results were the same whether raw area measures or head size plus age adjusted measure were analyzed. Significant thinning of the callosal body in alcoholics is usually attributed to the relatively rare, nutritional-deficient condition, Marchiafava-Bignami disease. However, callosal thinning was present in vivo in chronic alcoholics without clinical symptoms of severe liver disease, amnesia, or alcoholic dementia. These data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic-related subsyndromes, such as Marchiafava-Bignami disease.

    View details for Web of Science ID A1996UT99900021

    View details for PubMedID 8800395

  • Cortical gray matter volume deficits in schizophrenia: A replication SCHIZOPHRENIA RESEARCH Lim, K. O., SULLIVAN, E. V., Zipursky, R. B., Pfefferbaum, A. 1996; 20 (1-2): 157-164


    We sought to replicate an earlier finding of widespread deficit in cortical gray matter in schizophrenia by testing new samples of 22 schizophrenic patients and 27 controls between the ages of 21-46 years. Brain values for both patients and controls were standardized against age and head size norms derived from a larger control group (n = 73) spanning a wider age range (21-70). Compared to the new age-matched controls, the new schizophrenic sample showed a deficit in gray matter volume affecting the cortex as a whole and enlargement of the lateral and third ventricles. Thus, widespread cortical gray matter deficit is a replicable feature of the brain dysmorphology of schizophrenia in young to middle-aged men.

    View details for Web of Science ID A1996UR72100017

    View details for PubMedID 8794504

  • Relationship between alcohol withdrawal seizures and temporal lobe white matter volume deficits ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V., Marsh, L., Mathalon, D. H., Lim, K. O., Pfefferbaum, A. 1996; 20 (2): 348-354


    A previous magnetic resonance imaging study from our laboratory reported significant temporal lobe volume deficits in cortical gray matter, white matter, and anterior hippocampus in chronic alcoholic men relative to controls. In the present study, we reexamined these data and asked whether withdrawal seizure history was predictive of either the hippocampal or the extrahippocampal volume deficits. A review of the medical charts indicated that 11 alcoholics had experienced one or more alcohol-related seizures and 35 were seizure-free; no patient had a seizure disorder unrelated to alcohol. The two alcoholic groups did not differ significantly in age, education, alcohol consumption variables, premorbid intelligence, Memory Quotient, Trail Making, or detection of hidden figures. Although each alcoholic group showed significant bilateral volume deficits of the anterior hippocampus and frontal-parietal and temporal gray matter, relative to controls, the seizure group had significantly smaller temporal lobe white matter volumes than either the control or the seizure-free groups; the latter two groups did not differ from each other. Both alcoholic groups, however, had white matter volume deficits in the frontal-parietal region. Thus, the seizure group accounted for the white matter volume deficits in the temporal lobe previously reported in the full sample of alcoholics. It seems, then, that reduced white matter volume in the temporal lobes may be either a risk factor for or sequela of alcohol withdrawal seizures.

    View details for Web of Science ID A1996UE73700023

    View details for PubMedID 8730229

  • Slow wave sleep and computed tomographic measures of brain morphology in schizophrenia PSYCHIATRY RESEARCH Benson, K. L., SULLIVAN, E. V., Lim, K. O., Lauriello, J., Zarcone, V. P., Pfefferbaum, A. 1996; 60 (2-3): 125-134


    To test the hypothesis that slow wave sleep in schizophrenia is inversely correlated with ventricular system volume, polysomnography and computed tomographic (CT) brain imaging were carried out in 14 psychiatric patients who met Research Diagnostic Criteria for schizophrenia (h = 11) or schizoaffective disorder (n = 3). Three measures of ventricular system volume were analyzed: (1) raw ventricular volume expressed in cm3; (2) ventricle-to-brain ratio; and (3) ventricular volume corrected for normal variation in age and head size expressed as a standardized (z) score. All three quantifications of ventricular volume were significantly and inversely correlated with visually scored measures of stage 3 and stage 4 sleep. This finding suggests that the etiology of slow wave sleep deficits in schizophrenia is related either directly or indirectly to underlying brain dysmorphology.

    View details for Web of Science ID A1996UH31100005

    View details for PubMedID 8723303

  • Cognitive and motor impairments are related to gray matter volume deficits in schizophrenia BIOLOGICAL PSYCHIATRY SULLIVAN, E. V., Shear, P. K., Lim, K. O., Zipursky, R. B., Pfefferbaum, A. 1996; 39 (4): 234-240


    This study examined whether the neuropsychological deficits observed in patients with schizophrenia were related to cortical gray matter volume deficits in these patients. All subjects were men and included 34 patients with DSM-III-R Schizophrenia and 47 age-matched healthy controls. Subjects received a battery of 21 tests, assessing four different functional domains: executive functions, short-term memory and production, declarative memory, and motor ability. MRI volumes were corrected for normal variation in head size and age, and neuropsychological test scores were corrected for normal variation in age. The schizophrenic group had significantly smaller cortical gray matter volumes (p < .05) and lower test scores in all functional domain than the control group (p = .0001). Within the schizophrenic group, lower scores in each domain were significantly correlated with smaller total cortical gray matter volumes; however, no predictable relationships were observed between neuropsychological test performance and the volumes of specific cortical regions.

    View details for Web of Science ID A1996TW73000002

    View details for PubMedID 8645769

  • White matter MR hyperintensities in adult patients with congenital rubella AMERICAN JOURNAL OF NEURORADIOLOGY Lane, B., SULLIVAN, E. V., Lim, K. O., Beal, D. M., Harvey, R. L., Myers, T., Faustman, W. O., Pfefferbaum, A. 1996; 17 (1): 99-103


    To observe and quantify white matter hyperintensities on MR images in adults with schizophrenialike symptoms who had had congenital rubella, in order to elucidate the neuropathologic sequelae of this perinatal viral infection and to explore the potential relationship of these lesions to schizophrenia.Eleven deaf adult patients with documented prenatal rubella virus infection and schizophrenialike symptoms were compared with 19 age-matched patients with early-onset schizophrenia who did not have congenital rubella and with 18 age-matched control subjects. All MR images (obtained at 1.5 T) were evaluated by a neuroradiologist who was blinded to diagnosis and were rated for white matter lesions on a five-point scale: 0 = no lesions; 1 = 1 lesion less than 1 mm in diameter; 2 = 1 to 4 lesions 1 mm or greater; 3 = 5 to 10 lesions; 4 = more than 10 lesions or a single lesion more than 1 cm in diameter. In addition, the white matter hyperintensities were volumed objectively with a manual threshold technique.Ratings of white matter lesions were significantly higher in the rubella patients than in the control subjects: 6 of the 11 patients had ratings greater than 1 compared with 1 of the 18 control subjects and none of the 19 schizophrenic patients. Also, MR images in five rubella patients received ratings at the highest end of the scale of abnormality (3 or 4). The white matter hyperintensities were characterized as bilateral T2 signal hyperintensities in periventricular and subcortical regions, punctate or linear in shape; they were observed predominantly in parietal lobes.This quantitative MR study of adult rubella patients disclosed abnormal white matter lesions that may correspond to neurovascular lesions known neuropathologically. They do not appear to be directly related to schizophrenialike symptoms.

    View details for Web of Science ID A1996TP96800017

    View details for PubMedID 8770257

  • Neuroimaging and the cognitive neuroscience of schizophrenia SCHIZOPHRENIA BULLETIN McCarley, R. W., Hsiao, J. K., Freedman, R., Pfefferbaum, A., Donchin, E. 1996; 22 (4): 703-725


    The Carmel Workshop on Cognitive Psychophysiology began in 1980, and the focus of the 1996 workshop was on schizophrenia. Research into schizophrenia is in the midst of a period of unparalleled advance, driven in large part, by improvements in neuroimaging technology that make detailed examination of in vivo brain structure and function possible. Neuroimaging studies may help provide a bridge between investigations demonstrating molecular and cellular abnormalities in schizophrenia and those demonstrating cognitive dysfunction. The workshop brought together experts in different neuroimaging modalities to present the strengths and advantages of each, as well as the insights each modality might bring into normal and schizophrenic cognitition. It began with a series of tutorials to inform participants of the state of the art in various disciplines. It then broke into four panels, each given a very specific topic assignment related to neuroimaging and/or the cognitive neuroscience of schizophrenia. After 1 1/2 days of discussion, each panel reported its conclusions to the workshop. Group I presented cellular models of the pathophysiology of schizophrenia. Group II examined experimental paradigms for studying cognitive function and schizophrenia. Group III examined technical issues in image processing and combining data across different modalities. Group IV sought to survey the current state of knowledge about the pathophysiology of schizophrenia. The conclusions of each of the groups are presented in this report.

    View details for Web of Science ID A1996VT40400013

    View details for PubMedID 8938923



    Chronic alcoholism is associated with smaller volumes of cortical gray matter and white matter and a complementary increase in brain cerebrospinal fluid (CSF) volumes, relative to age norms. This longitudinal study quantified the extent of brain volume changes associated with abstinence and drinking at three time points in chronic alcoholics. We obtained magnetic resonance imaging (MRI) on 58 alcoholic men after an average of 12 days (MRI-1) and 32 days (MRI-2) of sobriety. In addition, 58 healthy control subjects were scanned at a comparable interval. At MRI-3, 11 controls and 39 alcoholics were rescanned, 2-12 months after MRI-2; 19 alcoholics had abstained, and 20 had resumed drinking. Axial MRI slices were segmented into cortical gray matter, white matter, and CSF and summed over seven slices; lateral and third ventricular volumes were also estimated. MRI volume changes were corrected using an estimate of interscan measurement error caused by head positioning differences, and then divided by the interval to yield rates of change (slopes). From MRI-1 to MRI-2, the alcoholic group showed declines in CSF volumes of the lateral ventricles and posterior cortical sulci, and a trend toward an increase in anterior cortical gray matter volume relative to the control group. From MRI-2 to MRI-3, third ventricular volumes decreased in the abstainers relative to the relapsers and controls; cortical white matter volume decreased in the relapsers. In the relapsers, lifetime consumption of alcohol (as of MRI-1) predicted later vulnerability to white matter volume decline and third ventricular enlargement with resumption of drinking. These data suggest that improvement in cortical gray matter, sulcal, and lateral ventricular volumes occur early in the course of abstinence, and that improvement in third ventricular volume appears later with continued abstinence.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995TA73800014

    View details for PubMedID 8561288



    The effect of normal aging on the volume of the hippocampus and temporal cortex was assessed cross-sectionally with quantitative Magnetic Resonance Imaging (MRI) in 72 healthy men, spanning 5 decades of the adult age range (21 to 70 years). Neither the hippocampal nor cortical white matter volumes were significantly correlated with age. By contrast, left and right temporal lobe gray matter volumes, exclusive of the hippocampal measures, each decreased with age (p < 0.01). Volumes of temporal lobe sulcal CSF and the ventricular system (temporal horns and lateral and third ventricles) significantly increased with age. Measures of verbal and nonverbal working memory showed age-related declines and were related to enlargement of the three ventricular regions, which may be indicative of age-related atrophy of the adjacent cortex but not the hippocampus, at least up to age 70 years.

    View details for Web of Science ID A1995RL48800012

    View details for PubMedID 8544910


    View details for Web of Science ID A1995RH81500004

    View details for PubMedID 7598632



    Brain morphology was quantified with magnetic resonance imaging (MRI) in adult patients with congenital rubella who also had schizophrenialike symptoms. MRIs were compared with those of adult early-onset schizophrenic patients without congenital rubella and age-matched healthy control subjects. The rubella patients had significantly smaller intracranial volumes and shorter stature than the schizophrenic patients or the controls; however, both patient groups had smaller cortical gray matter, but not white matter, volumes than the control group, even when the MRI volumes were corrected for head size and age. In addition, both patient groups showed significant enlargement of the lateral ventricles but not cortical sulci when compared with expected values of normal adults of the same age and head size. Overall, the pattern of dysmorphology was identical in the rubella and the schizophrenic groups. The observations in the rubella group are consistent with a developmental lesion that limits full brain growth, with the small intracranial volume due at least in part to a severe cortical gray matter volume deficit. Thus, the brain dysmorphology of congenital rubella may provide an instance of prenatal viral infection that models the schizophrenic pattern and provides indirect support for a developmental hypothesis of the neuropathogenesis of schizophrenia.

    View details for Web of Science ID A1995RA24400002

    View details for PubMedID 7647161



    This study used a semiautomated image analysis technique to quantify the rate and regional pattern of cerebrospinal fluid (CSF) volume changes in the computed tomographic brain examinations of healthy adults and patients with Alzheimer's disease (AD).Longitudinal, within-subject design, with statistical correction for longitudinal method error (eg, head repositioning effects).Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 41 patients with AD were recruited from the Geriatric Psychiatry Research Unit and the National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 35 healthy control subjects were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans.Even after accounting for an estimate of method error (eg, head positioning effects) across computed tomographic examinations, the patients with AD showed greater annual CSF volume increases than did the control group. This CSF volume enlargement was not uniform across brain regions of interest; rather, the patients with AD showed disproportionate volume increases in the ventricular system and the sylvian fissures. Greater CSF volume changes in the patients with AD were significantly associated with greater cognitive decline on the Mini-Mental State Examination. Furthermore, younger patients with AD showed more rapid progression on computed tomographic scans than did older patients.The rate of CSF volume enlargement is region specific, with the most marked annual rate of change occurring in the ventricular system and the sylvian fissures. In addition, younger patients show more rapid progression in the ventricular and frontal sulcal brain regions of interest than do older patients.

    View details for Web of Science ID A1995QR98600014

    View details for PubMedID 7710375



    Magnetic resonance imaging was used to quantify the volume of the hippocampus in 47 men with chronic alcoholism and 72 healthy male control subjects. The subjects ranged in age from 21 to 70 years, thus permitting a test of whether older alcoholics suffer greater brain tissue volume reduction than do younger ones. Comparison brain regions included temporal lobe gray matter, white matter, and cerebrospinal fluid, as well as measures of the lateral ventricles, third ventricle, and temporal horns. The results of this cross-sectional study showed that the anterior, but not the posterior, portions of the hippocampus in both hemispheres were significantly smaller in the alcoholic than the healthy control group. Furthermore, the bilateral anterior hippocampal volume loss was greater in older than younger alcoholics. Despite the hippocampal volume deficit, these alcoholics did not demonstrate an explicit memory impairment; furthermore, memory test scores did not correlate significantly with hippocampal volumes. In the alcoholics, the age-related volume loss, which was over and above that expected in normal aging, was also evident in the temporal cortex and white matter. Likewise, alcoholic ventricular enlargement was age-related. Analysis of covariance revealed that the anterior hippocampal deficit persisted after accounting for the temporal lobe gray matter volume deficit. Multiple regression analysis revealed that the age-related brain volume abnormalities observed in the alcoholics could not be attributed to duration of alcoholism or total lifetime consumption of alcohol.

    View details for Web of Science ID A1995QG62500018

    View details for PubMedID 7771636


    View details for Web of Science ID A1995QG57400027

    View details for PubMedID 7726091



    In vivo neuroimaging techniques have characterized the global features of brain dysmorphology in schizophrenia. These features include ventriculomegaly and widespread sulcal dilation, which particularly affect the frontal and temporal lobes and involve cortical gray matter rather than white matter. Dysmorphology of specific brain structures such as the basal ganglia and hippocampus, which have been implicated in the pathophysiology of schizophrenia by pharmacological manipulations and post mortem investigations, have not been consistently observed in vivo, perhaps because of differences in imaging and analysis techniques, methods used to control for variance due to age and head size, and sample characteristics. The epidemiology of the observed widespread brain dysmorphology supports a developmental origin, perhaps with limited progressive change beyond that expected in normal aging. Establishing the clinical significance of relatively static structural brain dysmorphologies remains a major challenge that may be best met by use of combined cross-sectional and longitudinal study designs.

    View details for Web of Science ID A1995RL56800008

    View details for PubMedID 7583616



    This study examined the neuropsychological deficits associated with schizophrenia and the interrelationships among multiple dissociable cognitive and motor functions. The tests were selected for their previously demonstrated sensitivity to circumscribed brain pathology and included four functional domains: executive functions, short-term memory and production, motor ability, and declarative memory. Each test composite was divided according to verbal versus nonverbal material or left- versus right-hand performance; this distinction permitted functions principally subserved by the left or right cerebral hemispheres to be tested separately. Data reduction was theoretically driven by the test selection and was achieved first by standardizing the scores of each test for age-related differences observed in the normal control group, and then by calculating test composite scores as an average of the age-corrected Z-scores of the tests comprising a functional composite. The schizophrenic group was impaired equivalently on all composites for both cerebral hemispheres; on average, the Z-scores of the patients were 1 standard deviation below those of the control group. The cognitive test composite scores were highly intercorrelated but showed only weak associations with motor ability. Multiple regression analyses suggested that symptom severity was a significant predictor of the Declarative Memory and Short-Term Memory/Production composite scores after accounting for disease duration, whereas disease duration uniquely contributed to the Executive Functions composite scores after controlling for symptom severity. Even though the schizophrenics as a group showed an equivalent level of deficit across all test composites, 1) the deficits were associated with different aspects of psychiatric symptomatology, 2) the motor deficit was independent of the cognitive deficits, and 3) each neuropsychological domain contributed independently to the deficit pattern. Thus, what appears to be a generalized functional deficit in schizophrenia may actually be, at least in part, combinations of multiple specific deficits.

    View details for Web of Science ID A1994PT24700001

    View details for PubMedID 7661935



    Thirty-two acutely psychotic, male schizophrenic patients received raclopride, at 2, 6, or 12 mg/day, or haloperidol, 15 mg/day for 4 weeks after randomized, double-blind assignment. Twenty-six patients, including 19 who had been assigned one of the three doses of raclopride, completed the study. Raclopride, particularly at 12 mg/day, increased CSF homovanillic acid (HVA) at 4 weeks, and plasma HVA at 2 days, of treatment. The clinical response to raclopride was significantly correlated with plasma raclopride concentrations and baseline plasma HVA concentrations. Although raclopride is a substituted benzamide with atypical properties in animals, these results suggest that the doses of raclopride required for clinical efficacy and elevation of clinical indices of brain dopamine turnover are similar.

    View details for Web of Science ID A1994PR72500008

    View details for PubMedID 7534423



    To model in vivo the dynamic interrelations of head size, gray matter, white matter, and cerebrospinal fluid (CSF) volumes from infancy to old age using magnetic resonance imaging (MRI).Cross-sectional, between-subjects using an age-regression model.A Veterans Affairs medical center and community hospitals.There were 88 male and female subjects aged 3 months to 30 years whose clinical MRI film had been read as normal and 73 healthy male volunteers aged 21 to 70 years who had an MRI performed specifically for this study.These MRI data were quantified using a semiautomated computer technique for segmenting images into gray matter, white matter, and CSF compartments. The cortex was defined geometrically as the outer 45% on each analyzed slice, and the volumes of cortical white matter, gray matter, and CSF were computed. Subcortical (ventricular) CSF volume was computed for the inner 55% of each analyzed slice.In the younger sample, intracranial volume increased by about 300 mL from 3 months to 10 years. The same patterns of change in volume of each compartment across the age range were seen in both sexes: cortical gray matter volume peaked around age 4 years and decreased thereafter; cortical white matter volume increased steadily until about age 20 years; cortical and ventricular CSF volumes remained constant. In the older sample, brain volumes were statistically adjusted for normal variation in head size through a regression procedure and revealed the following pattern: cortical gray matter volume decreased curvilin-early, showing an average volume loss of 0.7 mL/y, while cortical white matter volume remained constant during the five decades; complementary to the cortical gray matter decrease, cortical CSF volume increased by 0.6 mL/y and ventricular volumes increased by 0.3 mL/y.These patterns of growth and change seen in vivo with MRI are largely consistent with neuropathological studies, as well as animal models of development, and may reflect neuronal progressive and regressive processes, including cell growth, myelination, cell death, and atrophy.

    View details for Web of Science ID A1994PG22500008

    View details for PubMedID 8080387

  • ERPS IN SCHIZOPHRENIA - EFFECTS OF ANTIPSYCHOTIC MEDICATION BIOLOGICAL PSYCHIATRY Ford, J. M., White, P. M., Csernansky, J. G., Faustman, W. O., Roth, W. T., Pfefferbaum, A. 1994; 36 (3): 153-170


    Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2, and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.

    View details for Web of Science ID A1994PB80100003

    View details for PubMedID 7948453

  • VOLUMETRIC MRI ASSESSMENT OF TEMPORAL-LOBE STRUCTURES IN SCHIZOPHRENIA BIOLOGICAL PSYCHIATRY Zipursky, R. B., Marsh, L., Lim, K. O., DEMENT, S., Shear, P. K., SULLIVAN, E. V., Murphy, G. M., Csernansky, J. G., Pfefferbaum, A. 1994; 35 (8): 501-516


    This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

    View details for Web of Science ID A1994NJ34700001

    View details for PubMedID 8038294



    Event-related potentials (ERPs) and brain magnetic resonance images (MRIs) were acquired from 28 normal men, age 21-60 years. ERPs were recorded during 3 paradigms designed to elicit automatic or effortful attention, and a combination of both. MRI-derived measures of brain gray matter, white matter and cerebral spinal fluid (CSF) volumes were computed from frontal, parietal and temporal lobes. P300 amplitude correlated significantly with gray matter volumes but not with white matter or CSF volumes. Furthermore, the relationships between P300 amplitude and gray matter volumes reflected functional rather than direct topographical relationships: P300 recorded at Pz during automatically elicited attention correlated significantly with frontal but not parietal lobe gray matter volumes, P300 recorded during effortful attention correlated significantly with parietal but not frontal lobe gray matter volumes, and P300 recorded when both types of attention were invoked correlated significantly with both frontal and parietal gray matter volumes. Startle blinks, also elicited during automatic attention-engaging paradigms, were significantly correlated with frontal but not parietal lobe gray matter volumes. There was no evidence for a direct spatial relationship between P300 amplitude and the gray matter volumes underlying the recording electrode.

    View details for Web of Science ID A1994ND22100006

    View details for PubMedID 7511503



    Because P300 is typically measured from an average of single trials, variations among individual trials may account for P300 amplitude reduction so often seen in patients with schizophrenia. We tested three hypotheses regarding single-trial contribution to small average P300s in schizophrenics: normal P300s are elicited on some trials and no P300s on others, all trials have consistently small P300s, or P300 latency varies over trials. Nineteen schizophrenics and 35 controls were tested on a two-tone auditory oddball event-related potential (ERP) paradigm. ERPs recorded from the parietal electrode (Pz) were subjected to a P300-screening procedure in which a 2 Hz half-sine wave template was moved across the electroencephalogram (EEG) to find the point of best fit. If, for the point of best fit, the EEG:Template covariance was greater in the signal epoch (280-600 msec) than in the noise epoch (610-930 msec), and if the EEG:Template correlation was statistically significant, the trial passed the P300-screen and was deemed to have a P300. Three types of average ERPs were constructed: Traditional Average from all good (artifact-free, correct response) trials, P300-Screen Average from all good trials that also passed the P300-screen, and Latency Adjusted Average by aligning the P300-screen trials at the latency of maximum covariance. Traditional average ERPs were significantly smaller in schizophrenics than in controls. The results of the P300-screen confirmed all three hypotheses: schizophrenics had fewer trials passing the P300-screen, smaller P300s on each trial, and P300s that were more variable in latency across trials.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994MW69800003

    View details for PubMedID 8167215



    This cross-sectional study used a semi-automated analysis technique to quantify regional brain cerebrospinal fluid (CSF) volumes derived from computed tomography (CT) in 84 healthy men ranging from 21 to 82 years of age and 28 patients meeting Research Diagnostic Criteria for alcohol dependence. The goals were to replicate an earlier CT study of an independent sample of alcoholic and control subjects (Pfefferbaum et al., 1988a; Zipursky et al., 1988) and to compare CT assessments of brain changes with magnetic resonance imaging (MRI) assessments made in the same alcoholic patients (Pfefferbaum et al., 1992). Regional brain changes associated with normal aging were derived by regression analysis, using CT data collected from the healthy control subjects. As in the earlier CT study and in the concurrent MRI study, ventricular and sulcal CSF volumes in alcoholic patients were greater than would be expected for their age. Furthermore, the present CT study replicated the previous CT and MRI findings of a positive relationship between age and CSF volume enlargement in alcoholic patients over and above the normal age-related increase in CSF volume, suggesting greater vulnerability of the aging brain to alcohol. Comparison of CT- and MRI-derived estimates of ventricular and cortical sulcal volume revealed high correlations (> 0.80). MRI and CT produced similar absolute ventricular volumes, while MRI produced larger sulcal volume estimates than did CT. The difference in sulcal volume estimate may be due to differences between CT and MRI in slice thickness and sensitivity to partial volume effects.

    View details for Web of Science ID A1993MT42000004

    View details for PubMedID 8177924



    The in vivo distribution of ethanol in normal human brain following the consumption of a moderate amount of alcohol was measured using magnetic resonance spectroscopic imaging. Three subjects were studied, and the spatial distribution of brain ethanol, 60-min postingestion and measured at a spatial resolution of 1.5 cm, was found to be highly nonuniform with the relative ethanol signal in cerebral spinal fluid, gray matter, and white matter determined to be 1.00, 0.72, and 0.37, respectively. These spectroscopic imaging results indicate that whereas in vivo magnetic resonance studies of ethanol are feasible, quantitative studies of alcohol need to account carefully for the various tissue types within the observed volume.

    View details for Web of Science ID A1993ME46800024

    View details for PubMedID 8279668



    Structural brain-imaging measurements based on computed tomography (CT) or magnetic resonance imaging (MRI) are often corrected or adjusted for normal variation in head size. Some methods of head-size correction, such as the ventricle-brain ratio (VBR), are based on taking the brain structure size as a proportion of the estimated head size, while other methods have used a regression model to obtain head-size residualized structure measures. Recently, head-size correction was shown to result in less reliable volumetric measures of brain structures (Arndt et al., 1991). In the present study, MRI was used to examine the effects of head-size correction on the interrater reliability of volumetric measures of gray matter, white matter, and cerebrospinal fluid. Four raters independently scored MRI brain images from 26 subjects, generating separate estimates of head size and region of interest (ROI) size. Two methods were used to correct MRI values for differences in head size, one based on proportions and the other based on linear regression. Results confirmed that head-size correction did produce measures with lower reliability; however, further analysis based on classical measurement theory showed that the lower reliability was attributable not only to increased measurement error variance, but also to reduced true score variance. Subsequent analyses of criterion validity compared the raw (uncorrected) and head-size-corrected ROI measures in terms of their correlations with age in a sample of 43 normal control subjects, and in terms of their ability to differentiate schizophrenic patients (n = 22) from normal control subjects (n = 20). Results indicated that head-size correction often improved criterion validity, producing higher correlations with age and with diagnostic status than those produced by the raw measures. These findings suggest that head-size correction removes irrelevant true-score variance which reduces reliability yet improves the correlations with validity criteria such as age and diagnostic status.

    View details for Web of Science ID A1993LK62400006

    View details for PubMedID 8378488



    This study used a semiautomated analysis technique to quantify differences in regional brain cerebrospinal fluid volumes observed with computed tomography between healthy adults and patients with Alzheimer's disease (AD).Cross-sectional, between-subject design, using an age-regression model.Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 117 patients with probable or definite AD were recruited from the Geriatric Psychiatry Research Unit and National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 114 healthy volunteers were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans and neuropsychological test scores.The computed tomographic estimates of ventricular and sulcal cerebrospinal fluid volumes increased significantly in all sampled brain regions in normal aging and were vastly larger in AD than in normal aging. Furthermore, younger patients with AD had significantly greater cerebrospinal fluid volume enlargement than did older patients with AD compared with healthy controls of their age. When the AD group was divided on the basis of reported age at symptom onset, patients in the early-onset group (onset before age 65 years) were quantitatively more abnormal than and showed a different pattern of abnormality from the patients in the late-onset group. This onset difference was also evident in neuropsychological test performance.This cross-sectional study revealed a number of converging findings that suggested greater abnormality in the early-onset than in the late-onset group of patients with AD. The possibility remains, however, that the two onset groups represent different stages along a continuum of pathologic changes.

    View details for Web of Science ID A1993KV70200007

    View details for PubMedID 8460957



    The purpose of this study was to examine the factor structure of the Wisconsin Card Sorting Test (WCST). The scores of 22 patients with schizophrenia, 20 patients with chronic alcoholism, and 16 normal control subjects were entered into a principal components analysis, which yielded three factors: Perseveration, Inefficient Sorting, and Nonperseverative Errors. WCST performance of seven patients with lesions invading the dorsolateral prefrontal cortex, available from another study, provided criterion validity for the Perseveration factor and, less strongly, for the Inefficient Sorting factor. Two patterns of performance characterized the three patient groups: the schizophrenic group and frontal lobe group had the highest Perseveration factor scores, whereas the alcoholic group had the highest Inefficient Sorting scores; the Nonperseverative Errors factor showed no significant group differences. Construct validity of these factors involved assessing, in all but the frontal group, the degree of overlap (convergent validity) and separation (discriminant validity) of each WCST factor with scores from tests of other cognitive functions. The convergent and discriminant validity of the Perseveration factor, but not the remaining two factors, received support only within the group of schizophrenic patients.

    View details for Web of Science ID A1993KU96900007

    View details for PubMedID 8483976


    View details for Web of Science ID A1992KA26000031

    View details for PubMedID 1435914



    Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.

    View details for Web of Science ID A1992KD40900012

    View details for PubMedID 1471762



    The Rey-Osterrieth complex figure was used to assess the separate influences of the constructional accuracy and the organizational strategy employed while copying the figure on the later, incidental recall of the figure. We tested a model, which hypothesized that subjects who copied the main framework of the figure holistically would be more likely to achieve good copy accuracy scores and to reproduce the figure more accurately at recall than subjects who used a piecemeal approach during copy. Subjects included 68 detoxified, chronic alcoholics (ALC), 28 patients with schizophrenia (SZ), and 69 normal control subjects (NCS). The results showed that the ALC and the SZ groups, on average, had lower accuracy and strategy scores at copy than did the NCS group, and furthermore, that the combined contributions of copy accuracy and copy strategy accounted for group differences at recall. A path analysis revealed that, for all three groups, copy strategy had a significant direct effect on copy accuracy. Moreover, copy accuracy and copy strategy made independent contributions to recall accuracy within the ALC and NCS groups; by contrast, within the SZ group, copy strategy made an independent contribution to recall performance but copy accuracy did not. These results suggest that (1) organizational strategy can influence constructional accuracy at both copy and recall; (2) copy accuracy and strategy have the potential to influence recall independently; and (3) the recall deficit in ALC could be attributed to abnormalities in both accuracy and strategy at copy, whereas in SZ it could be attributed only to strategy abnormalities. The deficits observed on the complex figure test in the ALC and SZ were primarily nonmnemonic and were related to ability in figure construction and organizational strategy.

    View details for Web of Science ID A1992JW49300003

    View details for PubMedID 1420646

  • P3 AND SCHIZOPHRENIA ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Ford, J. M., Pfefferbaum, A., Roth, W. 1992; 658: 146-162

    View details for Web of Science ID A1992JL81200010

    View details for PubMedID 1353949



    Magnetic resonance imaging was used to investigate whether the structural brain differences commonly observed in patients with schizophrenia as compared with normal control subjects are specific to gray or white matter, and furthermore whether such abnormalities are localizable to circumscribed cortical regions. Accordingly, 22 patients meeting DSM-III-R criteria for schizophrenia and 20 healthy community volunteers, all 23 to 45 years old, received magnetic resonance imaging scans. Seven axial magnetic resonance imaging sections of 5-mm thickness were segmented into cerebrospinal fluid, gray matter, and white matter compartments and used for volumetric quantification. For the healthy control subjects, age correlated significantly with the percentage of all magnetic resonance imaging sections taken up by gray matter but not white matter. After correcting for the normal effect of age, the schizophrenic group was found to have significantly less gray matter than the control group but no difference in white matter; ventricular volume was 34% greater in the schizophrenic group. The schizophrenic group had less gray matter in all six cortical subregions analyzed; these differences attained statistical significance for all but the parietal measure. These findings have implications for studies of localized gray matter abnormalities and suggest that regional brain volume measurements need to be expressed in the context of possible widespread gray matter volume deficits in schizophrenia.

    View details for Web of Science ID A1992HG92500003

    View details for PubMedID 1567274



    Using in vivo magnetic resonance (MR) images, the percentages of gray matter, white matter, and cerebrospinal fluid (CSF) in the brains of 8 young and 6 elderly normal male community volunteers were quantified. Compared with the young men, the elderly men had a significantly lower percentage of gray matter (p less than .01) and higher percentage of CSF (p less than .01). The percentage of white matter was not significantly different between the two groups. This finding suggests that the age-related decrease in brain tissue is chiefly due to loss of gray matter.

    View details for Web of Science ID A1992GY68000010

    View details for PubMedID 1730845



    Multilead event-related potentials (ERPs), elicited by auditory and visual stimuli requiring a button press response and by a startling noise requiring no response, were recorded from male alcoholics and age-matched male controls (26-60 years old). Single-trial analyses of blink responses to the startling stimuli indicated that alcoholics startle less frequently but with equivalent amplitude as the controls. In contrast, single-trial analyses of P3 indicated that alcoholics generate a P3 as often as controls, but that their individual P3s are smaller. Alcoholics who reported a positive family history of problem drinking had larger startle blink amplitudes and smaller auditory and visual P3s than did alcoholics who reported a negative family history. Hierarchical regression analysis was used to demonstrate that smaller P3s in family history positive alcoholics were independent of lifetime alcohol consumption.

    View details for Web of Science ID A1991GL40900018

    View details for PubMedID 1755518



    This study presents a structural and functional description of a case of striatonigral degeneration (SND) and emphasizes neuropsychological findings. The patient, a 55-year-old woman with progressive and relatively intractable rigidity and bradykinesia, particularly of the right side, was studied with brain MR scans and with a wide variety of sensory, motor, and cognitive tests known to be subserved by specific brain regions. T2-weighted MR images revealed curvilinear areas of high signal in the lateral putamen at low magnetic field strength (0.3T) and adjacent regions of marked low signal in the posterior-lateral putamen at high magnetic field (1.5T). High signal changes in the insular cortex were also noted on the high field images. Letter fluency and short-term memory as well as motor speed, strength, and sequencing were selectively impaired. Taken together, the data of this case suggest that structural involvement of the putamen resulted in dysfunctions usually associated with the primary motor cortex and orbitofrontal cortex, while sparing functions of other frontal regions as well as temporal and parietal cortices.

    View details for Web of Science ID A1991GK47600011

    View details for PubMedID 1955531



    Seventeen young (mean age = 20.2 years old) and 16 elderly (mean age = 72.6 years old) women were tested with event-related potential (ERP) paradigms designed to elicit responses in reaction time tasks and to a startling noise burst. EEG was analyzed from 17 standard 10-20 electrode sites. Reaction time and performance data suggested that the elderly did not perform worse than the young. Nevertheless, the physiological responses of the elderly differed significantly from those of the young. While the task-dependent P3s at Pz were smaller in the elderly than in the young, the automatic P3 was smaller yet. The distribution of both types of P3 across the scalp was more uniform in the elderly than in the young. Single-trial analyses revealed that the P3 amplitude differences at Pz were not due to latency dispersal of single trials. Single-trial startle eye blink responses to intense noise bursts during the automatic paradigm were considerably less frequent in the elderly, although their individual startle blinks were actually larger. The data demonstrate that the electrophysiological responses of the elderly are different from the young both in tasks eliciting automatic responses and in tasks requiring controlled processing.

    View details for Web of Science ID A1991FL58200005

    View details for PubMedID 1711455



    Event-related potentials (ERPs) and electrodermal activity were studied in 14 medicated schizophrenics, 17 unmedicated schizophrenics, and 23 age- and education-matched controls. Subjects were run in three auditory stimulus paradigms differing from the usual ERP paradigms in having interstimulus intervals greater than 12 sec to permit measurement of the longer latency skin conductance response (SCR). In every paradigm medicated but not unmedicated schizophrenics had smaller N120 amplitudes and fewer SCRs than controls. In addition, medicated schizophrenics showed reduced P200 amplitude and latency, longer P320 latency, and reduced skin conductance levels in certain paradigms. These effects cannot easily be attributed to different mental states of medicated and unmedicated patients, since their Brief Psychiatric Rating Scale scores were almost the same. It is more probable that antipsychotic and antiparkinsonian drugs reduced electrodermal activity through anticholinergic mechanisms and that the antipsychotic drugs attenuated N120 through other biological mechanisms.

    View details for Web of Science ID A1991FG08800007

    View details for PubMedID 1675890



    Neuroimaging studies of schizophrenia have identified abnormalities in neuroanatomy, regional brain metabolism and receptor physiology. Computerized tomographic (CT) studies have demonstrated gross ventricular and sulcal enlargement. These findings are probably nonprogressive, and it is not yet clear whether they are present only in a subgroup of patients; whether they represent a reduction in tissue from a previously normal condition or an abnormality in brain development; and what relationship they have to genetic risk for schizophrenia, clinical features, or longterm prognosis. Magnetic resonance imaging (MRI) studies, which offer higher resolution and greater flexibility in imaging plane, are currently focussing on specific neuroanatomic sites, such as the limbic system, basal ganglia and frontal cortex, implicated by neuropathological or clinical studies in the pathophysiology of schizophrenia. Positron emission tomographic (PET) scanning now enables investigators to study brain metabolism and receptor physiology. Evidence to date suggests that there may be significant abnormalities in the pattern of cerebral glucose utilization as well as in the density of dopamine receptors in patients with schizophrenia. Much future work is needed to determine the sensitivity and specificity of these observations as well as the extent to which they are affected by changes in clinical state, attention and medication exposure.

    View details for Web of Science ID A1991FA66100009

    View details for PubMedID 2039761

  • HEPATOBILIARY MR IMAGING - 1ST HUMAN-EXPERIENCE WITH MNDPDP RADIOLOGY Lim, K. O., Stark, D. D., Leese, P. T., Pfefferbaum, A., Rocklage, S. M., Quay, S. C. 1991; 178 (1): 79-82


    The first human MR imaging results for the hepatobiliary contrast agent manganese(II)N,N'-dipyridoxylethylenediamine-N,N'-diacetate 5,5'-bis(phosphate) (MnDPDP) are reported. MnDPDP is a paramagnetic contrast agent specific for hepatobiliary imaging. An imaging study was performed to investigate the presence of contrast enhancement or facilitated visualization of normal structures. Twelve healthy subjects receiving MnDPDP at doses of 3, 10, or 15 mumol/kg were imaged after injection for approximately 30 minutes at 1-5-minute intervals. Transaxial abdominal images were obtained at 1.5 T in a single breath-hold interval of 21 seconds with use of a spin-echo pulse sequence (repetition time = 150 msec, echo time = 20 msec). Liver parenchyma enhancement was observed 1 minute after injection and persisted for at least 30 minutes. Clearance into the gallbladder was visualized within 15 minutes. Enhancement was dose-dependent; a dose of 10 mumol/kg produced a 75%-100% signal enhancement of the liver at 10 minutes after injection.

    View details for Web of Science ID A1991EP11700015

    View details for PubMedID 1898539

  • FILTER FREQUENCY IN P-3 EXPERIMENTS BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Ford, J. M., Roth, W. T. 1990; 28 (12): 1070-1071

    View details for Web of Science ID A1990EP89400012

    View details for PubMedID 2289003

  • A QUANTITATIVE-ANALYSIS OF CT AND COGNITIVE MEASURES IN NORMAL AGING AND ALZHEIMERS-DISEASE PSYCHIATRY RESEARCH-NEUROIMAGING Pfefferbaum, A., SULLIVAN, E. V., Jernigan, T. L., Zipursky, R. B., Rosenbloom, M. J., Yesavage, J. A., Tinklenberg, J. R. 1990; 35 (2): 115-136


    Patients with presumptive Alzheimer's disease (AD) and healthy community volunteers received computed tomographic (CT) brain scans and cognitive tests. The CT scans were quantitatively analyzed with a semiautomated thresholding technique to derive volumetric measures of cerebrospinal fluid (CSF)-to-tissue ratios in six regions of interest (ROIs): lateral ventricles; vertex sulci, frontal sulci, Sylvian fissures, parieto-occipital sulci, and third ventricle. Regression analysis was performed on CT data from 85 older volunteers (ages 51-82) to generate age norms for each ROI. Within this group, tissue loss, as measured by the % CSF in each ROI, was highly correlated with age, although each ROI showed different rates of change over age. For all ROIs, the AD group had significantly more tissue loss than expected in normal aging. In addition, AD patients with a presenescent onset (before age 65) tended to have greater vertex sulcal and frontal sulcal tissue reduction than AD patients with a senescent onset (age 65 or after). When regional tissue reduction, corrected for age, was correlated with cognitive test scores, two sets of double dissociations emerged within the AD group: large CT z scores (i.e., decreased tissue and increased CSF) of frontal sulci, but not of the third ventricle, correlated with low Comprehension and Boston Naming Test scores, whereas large CT z scores of the third ventricle, but not of the frontal sulci, correlated with low scores on Digit Symbol and Picture Arrangement. These results suggest that heterogeneity of structural and functional integrity exists among patients with AD.

    View details for Web of Science ID A1990EU28600003

    View details for PubMedID 2100804


    View details for Web of Science ID A1990DQ19400003

    View details for PubMedID 1694485



    The advent of computed tomography (CT) of the brain has facilitated the study of brain asymmetries in normal individuals and in patients with various diseases. A computerized volumetric approach to quantifying CT scan data is used to demonstrate that imperfect alignment of the subject's head in the CT scanner can be a major source of artifact in the assessment of cerebral asymmetry. An approach for estimating the extent of misalignment of the head in the scanner is described. This approach can be used to take variations in head alignment into account when studying cerebral asymmetries. When volumetric measures were used, left-handed subjects (n = 5) were found to have a significantly lower left/right ratio of total cerebral hemispheric tissue than right-handed subjects (n = 41). The amount of asymmetry in the lateral ventricles was found to depend on their total size. A method for controlling for the effect of size when measuring asymmetry of the lateral ventricles is described. In both right- and left-handed subjects, the left lateral ventricles were significantly larger than the right. A magnetic resonance (MR) scan was performed with standard alignment and with a deliberate 10 degrees misalignment, using a volunteer subject. These data are presented to demonstrate how artifactual cerebral asymmetries can be generated by head tilt and to test the quantification procedures developed.

    View details for Web of Science ID A1990DT48100007

    View details for PubMedID 2367612



    Limbic system structures are of central interest in many neuropsychiatric disorders. Magnetic resonance imaging (MRI) has a unique potential for imaging limbic system structures in vivo, but methodological constraints can limit the usefulness and interpretation of the collected image data. In this article, we present approaches for the acquisition and quantification of high resolution MR images of the limbic system. We used a long TR, cardiac gated, flow compensated, spin echo sequence to collect 22, 3-mm thick contiguous sections encompassing the limbic system. The sections were oriented relative to standard internal neuroanatomical landmarks. The sequence provided good gray matter/white matter/cerebrospinal fluid (CSF) and CSF/bone contrast; the latter is necessary for quantifying intracranial size and total CSF volume. Using operationalized criteria, we achieved high interrater reliability in volumetric measurement of temporal horn and hippocampus. This technique was then used to examine the effect of normal aging by comparing eight young (mean = 24 years) and seven old (mean = 73 years) healthy community members. We were able to demonstrate a significant age-related increase in temporal horn volume and a trend toward an age-related decrease in hippocampal volume.

    View details for Web of Science ID A1990DT48100002

    View details for PubMedID 2367609



    Magnetic resonance imaging (MRI) offers the potential for identifying, in vivo, specific brain abnormalities associated with schizophrenia. The detection of small morphological differences in areas such as the prefrontal cortex, limbic structures, and basal ganglia requires attention to a number of technical and methodological details. The effects of age, height, sex, head size, and overall tissue loss are of particular concern and are discussed. MRI acquisition and processing techniques for improving gray/white tissue contrast and image resolution are described, as are techniques for quantitative, volumetric measurement of localized regions of interest and specific brain structures as well as of the brain as a whole. Techniques for evaluating frontal lobes, temporal lobes, and basal ganglia integrity are reviewed, and recent observations on these brain regions in patients with schizophrenia are described.

    View details for Web of Science ID A1990EL87100013

    View details for PubMedID 2287935



    Eighteen schizophrenics who were not taking medication, 13 schizophrenics who were taking medication, and 37 age-matched controls were tested with event-related potential paradigms designed to elicit P3 response automatically or effortfully (ie, with a choice reaction time task). Electroencephalograms were recorded from the 19 standard 10-20 electrode sites. Compared with controls, both groups of schizophrenics had reduced P3 amplitudes for both effortful and automatic paradigms. P3 latencies were delayed relative to controls for the medication-taking schizophrenics in the effortful paradigms. Negative symptoms derived from the Brief Psychiatric Rating Scale within 1 week of event-related potential testing correlated negatively with both auditory and visual P3 amplitude in the subjects who were not taking medication. There was no evidence that P3 is smaller over left temporal electrode sites in schizophrenics, as has been reported by others. P3 amplitude reduction in schizophrenia is a robust psychobiological phenomenon that is present regardless of medication status or task demands.

    View details for Web of Science ID A1989AY08200009

    View details for PubMedID 2573328



    Magnetic resonance brain scans were obtained from 10 chronic alcoholics within 2 weeks of alcohol withdrawal, and 19 to 28 days later. Age-matched control subjects were scanned at comparable intervals. At the initial scan, the alcoholics had larger lateral ventricles than the controls; at the second scan, their ventricles were significantly smaller than at the first scan. Among the controls, there was no mean change in the size of the lateral ventricles between the first and second scan. This study demonstrates reversibility in ventricular enlargement with short-term abstinence from alcohol. The role of rehydration in this process and the possibility of further changes with continued abstinence remain to be tested.

    View details for Web of Science ID A1989AW39200013

    View details for PubMedID 2688465



    An interactive computer method for quantifying CSF, white matter, and gray matter in magnetic resonance (MR) axial brain scans is presented. A stripping algorithm is used to remove the skull and scalp from each axial section. The images are then filtered to correct for radiofrequency inhomogeneity image artifacts. Late echo images are subtracted from or added to early echo images to enhance fluid/tissue and gray/white tissue contrast, respectively. Thresholds for fluid/tissue and gray/white separation are set interactively. A boundary pixel locking algorithm is used to handle ambiguities due to partial voluming between the fluid and tissue compartments. The MR brain scans from five healthy, young, normal men were obtained using a standard neuroanatomical reference technique. These data were processed and percentages computed for fluid, gray matter and white matter compartments. The gray/white ratios compare favorably with those determined in a published postmortem brain study.

    View details for Web of Science ID A1989AG41700006

    View details for PubMedID 2745775


    View details for Web of Science ID A1988Q372300012

    View details for PubMedID 2460883



    Quantification of ventricular and sulcal volumes from the computed tomographic (CT) scans of 45 schizophrenic patients and 57 normal controls was carried out using a semi-automated computerized approach. The sizes of all cerebrospinal fluid spaces measured were significantly related to age in the control population. An age regression model was used to compare patients and controls. Schizophrenics had slightly larger ventricles and considerably larger sulci than controls. Enlargement of the ventricles and sulci was not correlated with measures of negative symptoms or neuropsychological impairment. The CT scans of eight very ill chronically institutionalized schizophrenics were also analyzed. Their CT findings did not differ significantly from the larger group of schizophrenics studied. Our results show that the cerebral atrophy found in schizophrenia is diffuse in nature and does not relate clearly to measures of disease severity or chronicity.

    View details for Web of Science ID A1988P224900004

    View details for PubMedID 3382323

  • OSCILLATORY POTENTIALS AS A MARKER FOR DOPAMINERGIC DISEASE DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Hock, P., Schechter, G., Pfefferbaum, A., Berger, P. A., Maurice, R. 1988; 69 (3): 255-261


    In an effort to find electrophysiologic correlates of dopaminergic disease in man, we measured oscillatory potentials of the electroretinogram in normal and unmedicated schizophrenic subjects, and in rabbits given D1 agonist or antagonist drugs. We found highly reproducible oscillatory potentials in twelve male schizophrenics that were indistinguishable from those in nine male normal volunteers. We also found little electroretinographic difference among four rabbits given intramuscular injections of SKF 38393 (a D1 agonist) and four control animals injected with saline. However, four animals given SCH 23390 (a D1 antagonist) showed diminution of the b-wave and selective suppression of the second oscillatory potential. This effect was more prominent in oscillatory potentials generated by 5-Hz flicker than by a single flash. These rabbit data suggest that further efforts at finding clinical correlations may be worthwhile, possibly with trial of flicker oscillatory potentials, and they support the concept that different oscillatory potentials have different generators.

    View details for Web of Science ID A1988P573500006

    View details for PubMedID 3048944


    View details for Web of Science ID A1988N733300002

    View details for PubMedID 3406327


    View details for Web of Science ID A1988N733300001

    View details for PubMedID 3406326



    Computerized tomographic (CT) brain scans were obtained in severely ill, chronic schizophrenic patients hospitalized in a long-term in-patient facility of a Veterans Administration hospital, and compared to CT brain scans from an age, sex and education-matched normal control population. In contrast to results obtained in our previous studies with younger, less severely ill, chronic schizophrenic patients, the current study population exhibited significantly increased rankings of third ventricular size and of fronto-tempero-sylvian atrophy, compared to normal control subjects.

    View details for Web of Science ID A1988M523700009

    View details for PubMedID 3258997



    A computerized tomographic (CT) brain scan and assessments of lifetime alcohol consumption, body size, and cognitive performance were performed in 37 male alcoholics, aged 26-62 years. Hematocrit and mean corpuscular volume (MCV) were also measured. CT data were analyzed using a semiautomated scoring system yielding measures of percentage of fluid at the ventricles and cortical sulci. Normative brain CT data from 57 community controls spanning the adult age range allowed Z-score assessment of deviation from age norms for each alcoholic. Across the entire group, alcoholics had significantly enlarged ventricles and sulci for their age. Enlargement at both sites correlated significantly with lifetime alcohol consumption. Sulcal enlargement in alcoholics was found across all ages. In contrast, ventricular enlargement was apparent only in older alcoholics and became increasingly exaggerated with age. Measures of body size, hematocrit, and MCV correlated with ventricular but not sulcal enlargement, suggesting that nutritional factors play a role in ventricular enlargement. Associations between neuropsychological performance and CT changes or alcohol consumption were less pronounced and at times counterintuitive. The findings support a modest dose-effect relationship between ethanol exposure and changes in brain morphology, and suggest that ventricles and sulci show a different time course of response. The role of nutritional status needs to be more closely investigated.

    View details for Web of Science ID A1988M164500016

    View details for PubMedID 3279864


    View details for Web of Science ID A1988T061000043

    View details for PubMedID 3153515



    Sixty-six normal adults ranging in age from 20 to 85 years were presented with stimuli containing explicit instructions to initiate or to inhibit a motor response (the words 'push' or 'wait'). In one task, the effect of stimulus probability was investigated by varying probability between 0.25 and 0.75 for both Go and No-go stimuli. In another task, the effect of visual noise was investigated by degrading the stimuli with ampersands on half of the trials. Regression analysis was used to examine the effects of age on P3 amplitude and latency for each stimulus type. The effects of stimulus variables on P3, independent of age, were examined by standardizing each subject's data to those expected for a 20 year old. P3 latency to all stimuli and RT to Go stimuli increased with age. The latency of P3s to No-go stimuli was less sensitive to age than Go stimuli. P3 amplitude at Cz and Pz (but not Fz) diminished with age. P3s to Go stimuli were maximal at Pz and earlier than P3s to No-go stimuli. P3s to No-go stimuli were maximal at Cz. These differences between Go and No-go stimuli remained true under visual noise and probability manipulations. Visual noise prolonged the latency of Go and No-go P3. Less probable Go and No-go stimuli elicited larger and later P3s than more probable stimuli. Decreasing the probability of the No-go stimulus enhanced its central distribution.

    View details for Web of Science ID A1988L794200007

    View details for PubMedID 2446846

  • LATE EVENT-RELATED POTENTIAL CHANGES IN ALCOHOLICS ALCOHOL Pfefferbaum, A., Rosenbloom, M., Ford, J. M. 1987; 4 (4): 275-281


    The P3 component of the event-related potential (ERP) was recorded during a Go/No-Go task from 42 alcoholic subjects, abstinent for 11-63 days, and 66 normal adult volunteers. In two different tasks, ERPs were elicited by visually presented words which provided explicit response instructions to Go (PUSH) or No-Go (WAIT). In the Noise Task, half of both Go and No-Go stimuli were degraded with ampersands (&P&U&S&H&, &W&A&I&T&). In the Probability Task, the probability of the Go stimulus was 25% and No-Go 75% on one run and the proportion reversed on another run. For both tasks, the amplitude of alcoholics' P3 was smaller than that of controls to the Go but not to the No-Go stimulus. There was a similar, but less pronounced trend for P3 latency to be delayed in alcoholic subjects for the Go, but not No-Go stimuli for the Noise Task. The P3 changes in alcoholics are consistent with those seen in several disease states which produce cognitive impairment.

    View details for Web of Science ID A1987J909400009

    View details for PubMedID 3620096

  • Event-related potentials to deviations of pitch and of timing. Electroencephalography and clinical neurophysiology. Supplement Nordby, H., Roth, W. T., Pfefferbaum, A. 1987; 40: 241-245

    View details for PubMedID 3480129

  • Electroretinographic assessment in schizophrenia. Electroencephalography and clinical neurophysiology. Supplement Schechter, G., Hock, P., Rodgers, K., Pfefferbaum, A., Marmor, M. F., Berger, P. A. 1987; 40: 746-751

    View details for PubMedID 3480203



    Ten young women were tested with an ERP paradigm that used the words 'left,' 'right,' 'LEFT,' 'RIGHT' as stimuli. The stimulus sequence was presented as several separate runs with varying response instructions. Subjects were instructed to respond according to the meaning of the stimulus in the (WORD task), to the case in which the stimulus was written (CASE task), or to both the case and meaning of the stimulus (CASE/WORD) task. In each task, half the trials called for a response that was incompatible with the stimulus. For the WORD task, compatible and incompatible trials were presented as separate blocks of trials. For all 3 tasks an additional stimulus sequence was presented in which the words were degraded with superimposed visual random noise. Reaction time (RT) in the CASE/WORD task was more than 100 msec later than in the other tasks. In the WORD and CASE/WORD tasks, RT was delayed more than 100 msec when the response was incompatible with the stimulus. Degrading the stimulus additionally delayed RT by about 100 msec. In the WORD and CASE tasks, error RTs were earlier than correct RTs. P3 latency was measured with a single-trial latency adjustment algorithm. P3 latency was delayed in the CASE/WORD task compared to the other 2 tasks. P3 was delayed by degrading the stimuli. Contrary to some previous reports, P3 was delayed by about 70 msec when incompatible responses were required, but only in the WORD task. Taken together with error and RT data, these P3 latency data are consistent with the notion that the task causes subjects to adopt different strategies and hence different types of processing (i.e., serial vs. parallel). Depending on the type of processing, P3 may appear to be affected by response incompatibility.

    View details for Web of Science ID A1986E561700007

    View details for PubMedID 2428593

  • AUTONOMIC CHARACTERISTICS OF AGORAPHOBIA WITH PANIC ATTACKS BIOLOGICAL PSYCHIATRY Roth, W. T., Telch, M. J., Taylor, C. B., SACHITANO, J. A., Gallen, C. C., KOPELL, M. L., MCCLENAHAN, K. L., Agras, W. S., Pfefferbaum, A. 1986; 21 (12): 1133-1154


    We compared electrodermal and heart rate measures of autonomic activation between patients meeting DSM-III criteria for agoraphobia with panic attacks and controls in terms of tonic level, reactivity to various types of stimuli, recovery, habituation, and spontaneous variability. The most striking differences between groups in the laboratory were higher tonic levels of skin conductance and heart rate among patients. Patients' heart rates were also tonically elevated in a test situation outside the laboratory. Certain measures of habituation and spontaneous variability also differed between groups, but there were only weak and inconsistent differences in reactivity to, or recovery from, stimuli with diverse qualities of novelty, startlingness, intensity, or phobicity. The elevated activation levels may be signs of a chronic state or may be phobic responses to the testing situations. A minority of patients failed to show these elevated levels.

    View details for Web of Science ID A1986D850400004

    View details for PubMedID 3756263



    Presented here is a modification of a previously developed, computed, semiautomated system for quantifying the amount of CSF and tissue on brain CT scans. The technique automatically strips skull from brain and applies a two-dimensional high-pass filter to reduce spectral-shift artifact. The resultant images are presented along with the raw images, section by section, on a screen for fluid-tissue differentiation by a human scorer. This is accomplished by adjusting a one-bit display of the filtered image until a satisfactory separation threshold is found. Data can be summed within or across sections to provide measures of CSF volume in specific regions of interest such as the ventricles and sulci. A major advantage is the improved accuracy of sulcal measurement. This method has been applied to scans of 57 community volunteers, 20-84 years old. High correlations have been established between rankings performed by an experienced clinician and automated rankings (r = 0.88 with rankings based on ventricular size, and r = 0.83 with rankings based on sulcal size). Furthermore, significant correlations were found between computed measures of ventricular size and age and between sulcal widening and age.

    View details for Web of Science ID A1986D210700004

    View details for PubMedID 3734197

  • Applications of cognitive ERPs in psychiatric patients. Electroencephalography and clinical neurophysiology. Supplement Roth, W. T., Duncan, C. C., Pfefferbaum, A., Timsit-Berthier, M. 1986; 38: 419-438

    View details for PubMedID 3466780

  • FLUORODEOXYGLUCOSE-18 PET IN SCHIZOPHRENIA PSYCHIATRY RESEARCH Jernigan, T. L., Sargent, T., Pfefferbaum, A., Kusubov, N., Stahl, S. M. 1985; 16 (4): 317-329


    Six chronic schizophrenic patients and six age-matched controls were studied with 18fluorodeoxyglucose (18FDG) positron emission tomography (PET). All patients were scanned when they had been free of medication for at least 2 weeks. Comparisons were made between the groups on regional ratios of cortical 18FDG, with manual and automated measures. Only one of eight regions, the right temporal cortical region, showed a significant group difference, and this effect was not significant when adjustment was made for multiple comparisons. Secondary analyses suggest that ventricular enlargement and age may be associated with a relatively "hypofrontal" pattern of 18FDG.

    View details for Web of Science ID A1985AYD8300006

    View details for PubMedID 3878971



    Three experiments investigating the effects of response production and inhibition on the N2 and P3 components of the ERP are reported. In the first experiment, 12 young female volunteers were presented with the words "push' and "wait' (semantic stimuli). On a separate series of trials, they were presented with arbitrary symbols assigned the same meanings (symbolic stimuli). For each stimulus series half of the stimuli were degraded. To obtain an estimate of reliability of the data, each task was repeated. Data were collected from Fz, Cz and Pz electrode sites. The P3 amplitude had a parietal maximum when the stimuli instructed subjects to respond (Go). The P3 was equal at central and parietal sites when the stimuli instructed the subjects to withhold a response (No-Go). This topographic pattern was obtained for all stimulus manipulations, simple and degraded stimuli, words and symbols, and for the first and second runs. The N2 was a frontal maximum component that was larger to the No-Go than to the Go stimuli. This result was also robust to the manipulations. A second experiment investigated the dependency of these findings on an overt motor response. In this experiment, the symbolic and semantic stimulus series were each presented twice. The subjects counted the Go stimuli and did not count the No-Go stimuli for one presentation and pressed the reaction time button as in experiment 1 for the other presentation. While counting (compared to button pressing) delayed the N2 and P3 peaks, counting and pressing produced similar results, including the Go/No-Go P3 distribution effects. A third experiment investigated the sensitivity of these findings to the orientation of the symbols instructing the subjects to respond or withhold the response. Again the pattern of results was robust to this manipulation.

    View details for Web of Science ID A1985AHE7000006

    View details for PubMedID 2580694


    View details for Web of Science ID A1985AQM7100001

    View details for PubMedID 4048349


    View details for Web of Science ID A1984TA47400062

    View details for PubMedID 6588878



    Patients with dementia, schizophrenia and depression were tested with analogous auditory and visual event-related potential (ERP) paradigms designed to elicit a large P3. The patient groups were compared to age normative predictions derived from a large control sample for a number of ERP and behavioral variables. The results were similar for the auditory and visual paradigms. P3 latency was prolonged two or more S.D.s beyond that predicted by age for less than one-half of the demented patients. This latency prolongation was significant for the group as a whole but would result in too many false negatives if used diagnostically for individuals. Furthermore, increased P3 latency was not specific, as the schizophrenic patients also had later P3s. The amplitude of P3 was reduced in the demented patients, but it was also smaller in other patient groups. The only variable which distinguished the demented patients from both controls and from the other patients was the single trial P3 latency/RT correlation. The demented patients, as a group, had significantly lower P3 latency/RT correlations, but this effect also was not sensitive enough to be diagnostic for individuals. The data from these two paradigms suggest that the P3 amplitude and latency abnormalities observed reflect a common, rather than a diagnostically specific deficit. This study is in contrast to some others which report much more sensitivity and specificity in the use of P3 latency in the diagnosis of dementia. Differences in task demands, patient samples and ERP analysis techniques might explain some of the discrepancy.

    View details for Web of Science ID A1984SN71300002

    View details for PubMedID 6200305

  • ERPS AND PSYCHOPATHOLOGY .1. BEHAVIORAL PROCESS ISSUES ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Roth, W. T., Tecce, J. J., Pfefferbaum, A., Rosenbloom, M., Callaway, E. 1984; 425 (JUN): 496-522


    The clinical study of ERPs has an inherent defect--a self-selection of clinical populations that hampers equating of clinically defined groups on factors extraneous to the independent variables. Such ex post facto studies increase the likelihood of confounding variables in the interpretation of findings. Hence, the development of lawful relationships between clinical variables and ERPs is impeded and the fulfillment of description, explanation, prediction, and control in brain science is thwarted. Proper methodologies and theory development can increase the likelihood of establishing these lawful relationships. One methodology of potential value in the clinical application of ERPs, particularly in studies of aging, is that of divided attention. Two promising theoretical developments in the understanding of brain functioning and aging are the distraction-arousal hypothesis and the controlled-automatic attention model. The evaluation of ERPs in the study of brain-behavior relations in clinical populations might be facilitated by the differentiation of concurrent, predictive, content, and construct validities.

    View details for Web of Science ID A1984TA47400054

    View details for PubMedID 6588871



    Normal adult volunteer subjects ranging in age from 18 to 90 years participated in a study in which analogous auditory and visual paradigms, with infrequently occurring target and non-target events, were used to elicit event-related potentials (ERPs) with a prominent P3 component. Of the 135 subjects participating, 66 completed both auditory and visual paradigms. The amplitude and latency of P3 were analyzed using average ERPs, single trials (adaptive filter) and principal components analysis (PCA). Age regressions were calculated using measures derived from average ERPs and single trials. Single trial measures were better than average ERP measures in demonstrating age-related changes in P3 latency. There was a significant increase in P3 latency with age of 1-1.5 msec/year. The range of normal P3 latency for a given age (1 S.E. of the regression = 40 msec for the visual target stimuli) was much larger than obtained by other investigators. The visual paradigm produced higher P3 latency/age correlations than the auditory paradigm (visual target r = 0.52, non-target r = 0.42; auditory target r = 0.32, non-target r = 0.33). Within individuals, the amplitude and latency of P3 generated by auditory and visual stimuli were highly correlated, though the visual paradigm produced larger and later P3s than the auditory paradigm. There is an apparent change in the scalp topography of P3 with age. In young adults, P3s to target stimuli have a markedly parietal distribution. The distribution of P3 becomes more uniformly distributed from Pz to Fz with age. This may be due to changes in overlapping components such as the slow wave (SW) rather than to changes in the amplitude of P3 per se.

    View details for Web of Science ID A1984SN71300001

    View details for PubMedID 6200311



    We measured the trabecular bone volume (TBV) of 62 iliac crest biopsies taken from women admitted to lymphoma protocols at Stanford University between 1970-1981. All subjects were active, cycling premenopausal women, with bone marrows that were negative for tumor. Disease status was stage III or less in 90% of the subjects. Trabecular bone volume was negatively correlated with age, and the annual predicted loss of bone was 0.14-0.18% TBV, or 0.7% of the original bone volume. In addition, there was a substantial range of normal TBV at any given age, evident even during adolescence. This study demonstrates that TBV is lost from iliac crest throughout adult life. The large spread in TBV indicates further that factors operating during adolescence or even earlier may have an important impact on skeletal mass.

    View details for Web of Science ID A1983RA53800003

    View details for PubMedID 6616313



    Twelve young female subjects were presented with a series of horizontal line-pairs of same or different length in a two-alternative, forced-choice RT task, with 60 of each type pair in each block of trials. In one block (Easy) lines differed by 30%, in another block (Difficult) lines differed by 7%. Subjects were first given 60 practice trials with the Easy discrimination and with the instruction that speed and accuracy should be emphasized equally. For the next block of trials, accuracy was emphasized with a monetary bonus for accurate performance. Finally, in the last block of trials, speed was emphasized with a monetary bonus for speedy performance. Additionally, a penalty was incurred for RTs that exceeded a criterion level based on each individual subject's performance. The order of Easy and Difficult discrimination blocks was maintained within a subject but balanced across subjects. From the latency-adjusted P3s recorded from Pz, we obtained P3 latencies, amplitudes and single-trial P3 latency/RT correlations. RT to correct and incorrect trials and error data were also collected. P3 was considerably larger during the Speed than Accuracy conditions. The single-trial P3 latency/RT correlation was higher in Speed than in Accuracy runs. RT was 235 msec faster and P3 was 40 msec earlier during the Speed than during the Accuracy runs. On the other hand, discrimination difficulty delayed P3 and RT about equally, 28 and 43 msec respectively. This pattern suggests that speed instructions and discrimination difficulty affect stimulus processing time and response production time differently.

    View details for Web of Science ID A1983QB97500010

    View details for PubMedID 6185317



    Ten healthy old and 10 healthy young subjects each received a series of trials in a memory retrieval task similar to that devised by Sternberg (1967). On each trial the subject saw a memory set of 2 or 4 digits (set size) followed by a probe. The task was to indicate whether the probe was a positive or negative instance (response type) of the memory set for that trial. On half the trials, the probe digits were degraded by a mask of random dots (stimulus quality). For both young and old subjects, RT was later to probes following the larger set size, later to degraded probes, and later to negative probes. For the young subjects only, P3 latency was delayed by the same variables affecting RT although to a lesser degree. P3 latency in the elderly responded quite differently: it was unaffected by set size or response type. However, P3 was somewhat delayed by the degraded probes suggesting that the failure to reflect set size or ceiling effect in the elderly. The correlation between single-trial P3 latency and RT in the elderly is lower than in the young. The data are discussed in terms of age-related differences in the meaning of P3 latency.

    View details for Web of Science ID A1982PH34000007

    View details for PubMedID 6179758

  • CT MEASURES OF CEREBROSPINAL-FLUID VOLUME IN ALCOHOLICS AND NORMAL VOLUNTEERS PSYCHIATRY RESEARCH Jernigan, T. L., ZATZ, L. M., Ahumada, A. J., Pfefferbaum, A., Tinklenberg, J. R., Moses, J. A. 1982; 7 (1): 9-17


    Cranial computed tomography (CT) scans were obtained in 46 male chronic alcoholics and 31 normal male volunteers. Automated methods were used to estimate the cerebrospinal fluid (CSF) volume in various intracranial zones. Measures of the ventricular fluid volume, the volume of fluid in cortical areas on CT sections at the level of the ventricles, and the sulcal fluid volumes on two convexity sections were computed. The alcoholic group, excluding subjects with chronic liver disease, had significantly more fluid than the control group on all sulcal measures. The group difference on the ventricular measure fell short of significance. Within the alcoholic group, no significant correlation was found between the number of years of alcoholism and any fluid measure when normal age effects were taken into account. A striking degree of variability in the sulcal volumes was observed within the alcoholic group, with many subjects showing normal values while a large group showed markedly elevated values. Further studies will be necessary to determine the significance of these variations.

    View details for Web of Science ID A1982PE56600002

    View details for PubMedID 6957902



    Event-related brain potentials were collected from 10 young (M = 22 years) and 10 elderly (M = 77 years) women. Stimuli were random sequences of 1000- and 1500-Hz tone pips in a two alternative, forced choice, reaction time task. Trials were sorted and averaged according to the sequence of the preceding four tones: continuations of repetitions (AAAAA) and alternations (ABABA) and discontinuations of repetitions (BBBBA) and alternations (BABAA). For both groups the P300 component of the event-related brain elicited larger P300s than did discontinuations of alternations, an effect especially large for the elderly women. Mean reaction time did not differ between the two groups, although P300 latencies were significantly longer for the elderly group. Results are discussed in terms of age-related differences in response strategies and sensitivity of P300 latency to response strategy.

    View details for Web of Science ID A1982PN59300010

    View details for PubMedID 7130643


    View details for Web of Science ID A1982ND79500007

    View details for PubMedID 7071296


    View details for Web of Science ID A1981MU57700008

    View details for PubMedID 6977630

  • LITHIUM EFFECT ON PARATHYROID-HORMONE AMERICAN JOURNAL OF PSYCHIATRY DAVIS, B. M., Pfefferbaum, A., Krutzik, S., Davis, K. L. 1981; 138 (4): 489-492


    Lithium has been reported to raise serum calcium and lower serum phosphate concentrations and to increase urinary calcium excretion. Because these changes may be effects of parathyroid hormone (PTH), PTH was measured in 19 patients receiving lithium. PTH was significantly higher in these patients than in 150 normal subjects. For all patients serum calcium concentrations correlated significantly with serum lithium concentrations. These results indicate that lithium may cause biochemical hyperparathyroidism. Secondary hyperparathyroidism in certain patients with lithium nephrotoxicity is also possible.

    View details for Web of Science ID A1981LJ25500015

    View details for PubMedID 7212107


    View details for Web of Science ID A1981MS99100005

    View details for PubMedID 7311534



    Because patients with bipolar affective illness have generally been viewed as poor candidates for psychotherapy, many clinicians have relied on lithium prophylaxis as the major treatment modality. However, even with lithium prophylaxis many patients still relapse, often in settings providing little support for maintenance treatment. This report presents the results of a long-term therapy group composed exclusively of bipolar manic-depressive patients, many of whom had histories of poor adherence ot lithium maintenance. The group met weekly and was conducted with an interpersonal, interactional "here and now" format. Patients attended an average of 47 sessions. Members were initially somewhat aloof and remote and minimized their problems. Over the course of their participation, members became more open and began to discuss their concerns about their illness and lithium maintenance treatment; during this time they functioned much as members in any long-term psychotherapy group. In the two-year period prior to entering the group, patients averaged 16.8 weeks of hospitalization; in the subsequent two-year period they averaged 3.6 weeks of hospitalization. Groups of this kind may offer a simple, cost-effective adjunct to lithium maintenance treatment and may provide the advantages and opportunities of psychotherapy to a group of patients generally seen as resistant to such approaches.

    View details for Web of Science ID A1981LU66700008

    View details for PubMedID 7258419



    Event-related potentials in two auditory target detection paradigms and two auditory paradigms without overt tasks were studied in 22 schizophrenic, 21 depressed, and 28 matched control subjects meeting Research Diagnostic Criteria. In the target detection paradigms, schizophrenics showed a pattern of reduced N120 amplitude and shorter P200 latency to frequently occurring tones, and reduced P300 and Slow Wave amplitude to infrequent target and nontarget tones. This pattern is consistent with impaired selective attention for stimuli. For depressed patients these variables were generally intermediate between those of schizophrenics and controls. In the other paradigms N120 latency was greater for schizophrenics, and P200 amplitude was less for depressed patients.

    View details for Web of Science ID A1981LM54300009

    View details for PubMedID 6939010



    To determine the significance of social factors in racial intolerance, the authors studied the relationship between relational behavior and ethnicity, group status and role, peer acceptance, and group cohesion in an adolescent correctional institution. Results portray three distinct patterns of adaptation. Hispanics (Chicanos) formed a highly cohesive group that required considerable conformity to group norms; policy was implemented by a leadership capable of relating well to all ethnic groups. Whites formed a disorganized and fragmented group, led by individuals who engaged in racially antagonistic behavior. The highly cohesive black group and their leadership were simultaneously in the forefront of both racial cooperation and racial conflict.

    View details for Web of Science ID A1981MA30300008

    View details for PubMedID 7258381



    Auditory brain stem and cortical evoked potentials were recorded from 15 schizophrenics and 15 controls. There were significant cortical evoked potential differences between the two groups. However, brain stem evoked potentials were almost identical, suggesting that the cortical evoked potential differences are not due to peripheral factors such as inability to match sensory thresholds or defects in auditory acuity.

    View details for Web of Science ID A1980JK81900003

    View details for PubMedID 7417612



    Fifteen schizophrenics and 15 age-matched controls were compared on 3 auditory event-related potential (ERP) paradigms that elicited a variety of components. In one paradigm, tones were given at 0.75, 2.25 and 6.75 sec interstimulus intervals; in another, infrequently occurring targets in a reaction-time task were interspersed with frequent background stimuli; and, in a third, noise bursts or tones were delivered in a random sequence at either 70 or 100 dB SPL. The sensitivity of some of the ERP components in distinguishing schizophrenics from controls depended on the conditions under which the component was elicited. N1 amplitude was smaller in the schizophrenics than in the controls after longer interstimulus intervals. P2 amplitude was smaller in the schizophrenics than in the controls after longer interstimulus intervals. P2 amplitude was smaller in the schizophrenics only at higher stimulus intensities. P2 latency was shorter in schizophrenics except in the paradigm that varied interstimulus intervals. P3 amplitude, however, was much smaller in schizophrenics than controls ragardless of whether P3 was elicited by targets in a task or was elicited by 100 dB SPL stimuli. The loud stimuli also elicited blink reflexes that coincided with N1, but these reflexes did not vary by clinical group. Neither the amplitude of the slow wave following targets nor the sustained potential that accompanies prolonged auditory stimuli differed between schizophrenics and controls.

    View details for Web of Science ID A1980JE94500002

    View details for PubMedID 6153330



    Fifteen schizophrenics and 15 age-matched controls performed a reaction time (RT) task. A Bernoulli sequence of 85 dB SPL, 50 msec, 800 c/sec (P = 0.85) and 1200 c/sec (P = 0.15) tones was presented with an interstimulus interval of 1 sec. Subjects were instructed to press a button quickly upon hearing the 1200 c/sec tone. If a subject failed to respond within 650 msec, a 50 msec white noise burst occurred. In averages synchronized with target tones and computed without respect to RT, P3 was maximal at PZ with a mean latency of 330 msec for both schizophrenics and controls. P3 amplitude at PZ, however, averaged 6 muV in schizophrenics and 14 muV in controls (P < 0.001). Both mean RT and mean within-subject variance were greater in schizophrenices than controls. Other kinds of averages were computed to investigate the possibility that the amplitude differences were associated with different RTs or with differences in P3 latency variability in underlying trails. Averages of trials associated with short RTs (100--286 msec) had larger P3s than averages associated with long RTs (287--600 msec) (P < 0.01). Within each RT range, however, schizophrenic P3s were smaller than control P3s. Neither response-synchronized averaging nor adaptive filtering eliminated P3 amplitude differences between groups, indicating that P3 latency variability cannot account for these differences. We hypothesize that the smaller P3s in schizophrenics represent a deficit in reactivity to unexpected stimuli that is compatible with normal RT performance.

    View details for Web of Science ID A1980KH37100007

    View details for PubMedID 6158431

  • P300 and reaction time in schizophrenics and controls. Progress in brain research Roth, W. T., Pfefferbaum, A., HORVATH, T. B., KOPELL, B. S. 1980; 54: 522-525

    View details for PubMedID 7220962



    Eight healthy old and 12 healthy young women had event-related potentials (ERPs) recorded during the performance of a memory retrieval task. For each subject the single trial data recorded at Pz were analyzed using Woody's adaptive filter technique. The old subjects differed from the young in several respects: P3 amplitude at Pz was smaller, P3 latency and reaction time (RT) were greater, the relationship between P3 latency and RT was considerably altered. The adaptive filter increased the amplitude of P3 but the age-related amplitude difference persisted, suggesting that this difference is not due to increased latency variability with age. The old subjects had lower single trial P3-RT correlations and longer elapsed time from P3 peak to the response than did the young subjects. Both groups had greater RTs for outset items ('negative' responses) than for inset items ('positive' responses). For the young subjects P3 latency was also greater for the outset compared to the inset items but the difference was not found for the old subjects. Thus, the relationship between P3 latency and RT is altered in the aged--P3 and RT are less tightly coupled than in the young.

    View details for Web of Science ID A1980KD59600005

    View details for PubMedID 6158402



    Twelve elderly and 12 young women were subjects in a reaction-time task designed to elicit middle and late event-related potentials (ERP). The aged subjects differed from the young in respect to the later occurring ERP components: P2 was larger and later; P3 was later and had a different scalp distribution; the slow wave (SW) was smaller. In contrast, no age-related differences were found for N1 amplitude or latency. It is suggested that the diminution in SW amplitude contributes to the change in scalp distribution of P3 amplitude seen with age. The relationship of reaction time and P3 latency of single trials was examined by the adaptive filter technique. There was no difference between the old and young subjects as both groups revealed signficant, positive P3 latency-reaction time correlations.

    View details for Web of Science ID A1980KD59600006

    View details for PubMedID 6158403

  • BETA-ENDORPHIN AND SCHIZOPHRENIA ARCHIVES OF GENERAL PSYCHIATRY Berger, P. A., Watson, S. J., Akil, H., Elliott, G. R., Rubin, R. T., Pfefferbaum, A., Davis, K. L., BARCHAS, J. D., Li, C. H. 1980; 37 (6): 635-640


    To study the effects of beta-endorphin in chronic schizophrenia, nine male patients participated in a double-blind crossover comparison of a single intravenous 20-mg injection of beta-endorphin and saline. Bolus injection of beta-endorphin from an albumin-coated syringe produced markedly higher plasma concentrations than did slow intravenous infusion from a non-albumin-coated syringe. Beta-endorphin intravenously injected in nine patients produced a statistically significant increase in serum prolactin levels. In one patient, both 10 mg of morphine sulfate and 20 mg of beta-endorphin produced similar increases in the alpha power of the EEG. In eight patients, beta-endorphin administration was associated with a statistically significant but not clinically obvious improvement in schizophrenic symptoms.

    View details for Web of Science ID A1980JW99000003

    View details for PubMedID 7387335

  • Clinical application of sustained auditory evoked potentials. Progress in brain research Pfefferbaum, A., Roth, W. T., Ford, J. M., HORVATH, T. B., KOPELL, B. S. 1980; 54: 526-530

    View details for PubMedID 7220963

  • Effects of stimulus intensity on P300. Progress in brain research Roth, W. T., Doyle, C. M., Pfefferbaum, A., KOPELL, B. S. 1980; 54: 296-300

    View details for PubMedID 7220929

  • On the utility of P3 latency and RT for studying cognitive processes. Progress in brain research Ford, J. M., Mohs, R. C., Pfefferbaum, A., KOPELL, B. S. 1980; 54: 661-667

    View details for PubMedID 7220982

  • Acute and chronic effects of ethanol on event-related potentials. Advances in experimental medicine and biology Pfefferbaum, A., HORVATH, T. B., Roth, W. T., Clifford, S. T., KOPELL, B. S. 1980; 126: 625-639

    View details for PubMedID 7405699


    View details for Web of Science ID A1980JM40600018

    View details for PubMedID 7361940

  • CHOLINOMIMETICS AND MEMORY - EFFECT OF CHOLINE CHLORIDE ARCHIVES OF NEUROLOGY Davis, K. L., Mohs, R. C., Tinklenberg, J. R., Hollister, L. E., Pfefferbaum, A., KOPELL, B. S. 1980; 37 (1): 49-52


    Young normal subjects received 16 g of choline chloride in a double-blind A-B-A design. Short- and long-term memory function was evaluated. Comparison of group means indicated that choline chloride did not significantly affect short-term memory or long-term memory. However, individual subjects may have had some aspects of long-term memory affected by choline chloride treatments. The results suggest that the effect of lower doses of choline on long-term memory should be evaluated.

    View details for Web of Science ID A1980JB37100012

    View details for PubMedID 7350901

  • EFFECTS OF ETHANOL AND MEPERIDINE ON AUDITORY EVOKED-POTENTIALS DRUG AND ALCOHOL DEPENDENCE Pfefferbaum, A., Roth, W. T., Tinklenberg, J. R., Rosenbloom, M. J., KOPELL, B. S. 1979; 4 (5): 371-380


    The effects of ethanol and meperidine on the auditory evoked potential (AEP) to stimuli of different intensities were investigated. Sixteen normal male volunteers received ethanol, 0.8 ml/kg, 100 mg meperidine, and a placebo on different days in a double-blind study. AEPs were recorded from Fz, Cz and Pz electrode placements. The stimuli were 500 msec 1000 Hz tones at 50, 60, 70 and 80 dB sound pressure level presented in a pseudo-random sequence. Meperidine had no significant effect on AEP variables. Ethanol reduced AEP activity between 24 and 250 msec but had no effect on the sustained potential measured between 300 and 450 msec.

    View details for Web of Science ID A1979GY68200001

    View details for PubMedID 510179



    The authors used an ecological approach to analyze the interaction of ethnicity, environment, personality, and ideology that led to racial intolerance, ethnic strife, and the existence of a self-styled neo-Nazi group in a correctional institution for youthful offenders. Staff members completed a questionnaire on which they rated the behavior of each of 320 inmates toward his own and other ethnic groups. The inmate's membership, if any, in a "power" subgroup was also noted. Results indicated a correlation between antagonistic patterns of ethnic relations and receptivity to racial propaganda and ideology. Further research focusing on the perceived ethnic relations climate is necessary to determine whether the patterns found in this institution are typical and to ascertain explanations for this correlation.

    View details for Web of Science ID A1979HT07000010

    View details for PubMedID 495797

  • State-trait considerations of event-related potential markers of psychopathology. Psychopharmacology bulletin Pfefferbaum, A., Roth, W. T., KOPELL, B. S. 1979; 15 (1): 36-39

    View details for PubMedID 419247



    Ten chronic alcoholics (10+ year alcoholic drinking history) and ten age and sex matched controls were tested on an ERP paradigm which elicited a large P3 component. The N1 and P2 sensory evoked potential components did not differ in amplitude or latency between the two groups. The latency of the P3 was significantly longer for the alcoholics than the controls for both a response and non-response stimulus. This finding is consistent with the results seen in a variety of dementias and is offered as evidence of the dementing effects of prolonged alcoholism in this group of subjects. While the P3 latencies were prolonged for the alcoholics, their reaction times were not different from the controls. Single trial analysis using Woody's adaptive filter also demonstrated that the single trial estimates for the 3 latency were significantly prolonged for the alcoholics. The single trial correlation between the P3 latency and each trial's corresponding reaction time was significantly greater for the alcoholics than for the controls.

    View details for Web of Science ID A1979HY33700001

    View details for PubMedID 91494

  • EEG EFFECTS OF PHYSOSTIGMINE AND CHOLINE CHLORIDE IN HUMANS PSYCHOPHARMACOLOGY Pfefferbaum, A., Davis, K. L., COULTER, C. L., Mohs, R. C., Tinklenberg, J. R., KOPELL, B. S. 1979; 62 (3): 225-233


    Seventeen normal volunteers received either 0.5 mg, 1.5 mg, or 2.5 mg physostigmine i.v. in a placebo-drug-placebo single-blind design. EEG was recorded simultaneously and analyzed by computerized spectral analysis. Eleven healthy elderly volunteers (mean age = 69.1 years) with mild memory impairment were treated with placebo, followed by oral choline chloride (either 8 g/day for 3 weeks, or 16 g/day for 1 week), and then, again, placebo. Recordings of spontaneous EEG and EEG event-related potentials (contingent negative variation) were obtained during both placebo and choline treatments. The larger doses of physostigmine produced an increase in low frequency activity and a slowing of the peak alpha frequency. Oral choline chloride had no effect on the EEG as measured by spectral analysis, but appears to have differential effects on contingent negative variation (CNV) amplitude and reaction time, depending upon the initial CNV amplitude.

    View details for Web of Science ID A1979GW41600004

    View details for PubMedID 111288

  • GROUP-PSYCHOTHERAPY AS AN ADJUNCT TO LITHIUM MAINTENANCE AMERICAN JOURNAL OF PSYCHIATRY Shakir, S. A., Volkmar, F. R., Bacon, S., Pfefferbaum, A. 1979; 136 (4): 455-456

    View details for Web of Science ID A1979GQ52400022

    View details for PubMedID 426116

  • HUMAN EEG RESPONSE TO BETA-ENDORPHIN PSYCHIATRY RESEARCH Pfefferbaum, A., Berger, P. A., Elliott, G. R., Tinklenberg, J. R., KOPELL, B. S., BARCHAS, J. D., Li, C. H. 1979; 1 (1): 83-88


    Beta-endorphin, morphine, and saline were given intravenously to a single schizophrenic subject on separate occasions in a double-blind design. EEG spectral analyses performed on data collected before and after drug injection demonstrated that beta-endorphin and morphine produced similar increases in alpha power within 5 to 15 minutes after injection. This effect could be distinguished from two placebo (saline) injections. These data suggest that intravenous beta-endorphin can produce changes in the central nervous system in humans.

    View details for Web of Science ID A1979HN77000011

    View details for PubMedID 298341



    We used an event-related brain potential (ERP) technique developed by Hillyard et al. (1973) to test abilities to attenuate irrelevant stimuli and to detect target stimuli. Subjects, 12 healthy old (80.3 years) and 12 healthy young adults (22.0 years), heard 1500 Hz tones in one ear and 800 Hz tones in the other ear. Infrequently, the pitch of either tone was raised. During one run, infrequent tones in the right ear were targets, and in the other run those in the left ear were targets. Subjects counted targets. For both groups, an early component of the ERP (N1) was larger to tones in the attended ear than in the unattended ear, and a later component (P3) was largest to the target. This suggests that both groups can attenuate irrelevant stimuli and can use stimulus probability information in this task. That P3 was later for old subjects suggests that they take longer to decide stimulus relevance.

    View details for Web of Science ID A1979GU67100010

    View details for PubMedID 429773



    Neurophysiological changes in the central nervous system were demonstrated with EEG even-related potentials in healthy, aged women. Compared to young women, the aged women showed decreased amplitude of the late sustained potential (SP), increased P2 latency, disruption of the normal stimulus intensity-response amplitude function of P2 and increased amplitude of the P1 component. These age-related changes are interpreted as neurophysiological reflections of CNS deterioration found in non-senile elderly persons.

    View details for Web of Science ID A1979GD90100009

    View details for PubMedID 88334


    View details for Web of Science ID A1978ES94700003

    View details for PubMedID 652905



    Sixteen college-educated male subjects were given an object description task during placebo conditions and while intoxicated with marijuana extract cookies calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol, a dose within the range of usual social use. The task was scored for fluency, flexibility, elaboration, and uniqueness, all of which represent associational thinking and are considered to be components of creativity. Marijuana did not enhance any of these measures.

    View details for Web of Science ID A1978FA84600008

    View details for PubMedID 650201


    View details for Web of Science ID A1978FR95200013

    View details for PubMedID 693759

  • PHYSOSTIGMINE - IMPROVEMENT OF LONG-TERM-MEMORY PROCESSES IN NORMAL HUMANS SCIENCE Davis, K. L., Mohs, R. C., Tinklenberg, J. R., Pfefferbaum, A., KOPELL, B. S., Hollister, L. E. 1978; 201 (4352): 272-274


    Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine.

    View details for Web of Science ID A1978FF63800020

    View details for PubMedID 351807

  • MARIHUANA AND MEMORY INTRUSIONS JOURNAL OF NERVOUS AND MENTAL DISEASE Pfefferbaum, A., DARLEY, C. F., Tinklenberg, J. R., Roth, W. T., KOPELL, B. S. 1977; 165 (6): 381-386


    Sixteen college-educated male subjects were tested on free-recall lists during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol and during placebo conditions. On each testing day subjects studied six lists using a regular overt rehearsal procedure and six lists using an association-overt rehearsal procedure in which they were to rehearse alound both list items and associations to those items. Both marijuana and the association-rehearsal procedure reduced the number of correct recalls and increased the number of intrusions (nonlist items which were incorrectly recalled as having been on the list to be learned). The intrusions were divided into three categories: a) words found on prior lists; b) associates spoken during the rehearsal; or c) totally new works not previously mentioned. Marijuana significantly increased the number of new intrusions; the association-rehearsal procedure did not. This result suggests that one of the effects of marijuana on cognitive functions in humans is to increase the number of intrusive thoughts and this may be the mechanism involved in some of the thought disorder observed with marijuana intoxication.

    View details for Web of Science ID A1977EF05800003

    View details for PubMedID 591936



    The case history of a 54-year-old man with concomitant narcolepsy, paranoid psychosis, and tardive dyskinesia is presented. These disorders may all result from alteration in catecholamines, serotonin, and/or acetylcholine in the central nervous system. The interactions of the various psychopharmacological agents usually used to treat the disorders when they occur separately are considered in terms of current neurotransmitter hypotheses. The management of this case creates a pharmacological dilemma; the agents used for treatment of each of the disorders separately exacerbate one or both of the other two syndromes.

    View details for Web of Science ID A1977DC69300011

    View details for PubMedID 845600


    View details for Web of Science ID A1975AU99500018

    View details for PubMedID 171700


    View details for Web of Science ID A1972O311300042

    View details for PubMedID 4643983

  • Enhancement of the average evoked response to tone onset and cessation. Psychophysiology Pfefferbaum, A., Buchsbaum, M., Gips, J. 1971; 8 (3): 332-339

    View details for PubMedID 5093976


    View details for Web of Science ID A1971K375400013

    View details for PubMedID 5094937


    View details for Web of Science ID A1971J548100011

    View details for PubMedID 5149062


    View details for Web of Science ID A1970H009700012

    View details for PubMedID 5454262

Conference Proceedings

  • A profile of neuropsychological deficits in alcoholic women Sullivan, E. V., Fama, R., Rosenbloom, M. J., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2002: 74-83


    Neuropsychological deficits, most notable in executive, visuospatial, and functions of gait and balance, are detectable in alcoholic men even after a month of sobriety. Less well established are the severity and profile of persisting deficits in alcoholic women. The authors used an extensive test battery to examine cognitive and motor functions in 43 alcoholic women who were sober, on average, for 3.6 months. Functions most severely affected in alcoholic women involved visuospatial and verbal and nonverbal working memory processes as well as gait and balance. Areas of relative sparing were executive functions, declarative memory, and upper-limb strength and speed. The authors found that lifetime alcohol consumption was related to impairment severity on Block Design (Wechsler Adult Intelligence Scale-Revised, D. Wechsler, 1981) and verbal and nonverbal working memory, suggesting a dose effect of alcohol abuse. The alcohol-related deficits in working memory, visuospatial, and balance implicate disruption of prefrontal, superior parietal, and cerebellar brain systems.

    View details for DOI 10.1037//0894-4105.16.1.74

    View details for Web of Science ID 000173794700009

    View details for PubMedID 11853359

  • Magnetic resonance relaxometry reveals central pontine abnormalities in clinically asymptomatic alcoholic men Sullivan, E. V., Pfefferbaum, A. BLACKWELL PUBLISHING. 2001: 1206-1212


    Central pontine myelinolysis (CPM) is a rare, debilitating, life-threatening condition, associated with chronic alcoholism, rapid correction of hyponatremia, and advanced age. It is unknown, however, whether older alcoholic patients who by age and diagnosis are at risk for CPM have objectively determined neuroimaging evidence of preclinical CPM that could be valuable in understanding its development and in initiating appropriate treatment. Accordingly, we examined central pontine magnetic resonance (MR) transverse relaxation time (T2), which reflects myelin and axonal integrity when measured in white matter and is prolonged with pathology that causes increased free water content in tissue.The subjects were 46 alcoholic men who were abstinent from alcohol for about 1 month and were asymptomatic for CPM, 9 men and 1 woman with alcoholic Korsakoff's syndrome (KS), and 74 healthy control men. All subjects received coronally acquired dual-echo MR imaging (MRI), from which T2 times were calculated in central pons. MRI films were read clinically and independently of relaxometry results. Hematological and neuropsychological data were also available for many subjects.Only the KS group showed prolonged T2 times; however, pontine T2 prolongation increased significantly with older age in the asymptomatic alcoholics but not controls. Clinical radiological readings detected pontine signal hyperintensity in five KS subjects (two without dementia and three with dementia), one control, and no alcoholic patient. Hematologic indexes of macrocytic anemia and nutritional deficiency and neuropsychological measures of verbal and nonverbal fluency correlated with prolonged T2 times in alcoholic men.This CPM-like condition, manifest as prolonged T2, may occur with higher incidence than previously thought in clinically asymptomatic alcoholism and may contribute to neuropsychological compromise of initiation and production. Preclinical detection of abnormal pontine signal properties with MR relaxometry may identify patients at high risk for developing CPM.

    View details for Web of Science ID 000170458200017

    View details for PubMedID 11505052

  • Sex differences in corpus callosum size: relationship to age and intracranial size SULLIVAN, E. V., Rosenbloom, M. J., Desmond, J. E., Pfefferbaum, A. ELSEVIER SCIENCE INC. 2001: 603-611


    This quantitative MRI study reports measurement of corpus callosum area taken from midsagittal brain images in 51 healthy men and 41 healthy women, spanning the adult age range (22 to 71 years). Men had larger brains and corpora callosa than women, but callosal size did not correlate with age in either sex. Intracranial (i.c.) volume (ICV) and midsagittal i.c. area (ICA) of brain were used in covariate, regression, and ratio analyses to determine whether sex differences in the corpus callosum endured with statistical adjustment for sex differences in maximally attained brain size. With the exception of one ratio measure, the different statistical adjustments for the contribution of sex differences in brain size to corpus callosum size all indicated that men had larger corpora callosa than women for their brain size. A subsample of men and women selected to be matched on i.c. volume and age confirmed this statistical observation. Sexual dimorphism in the corpus callosum is not a simple artifact of sex differences in brain size and may reflect differences in connectivity necessitated by differences in brain size.

    View details for Web of Science ID 000169912200011

    View details for PubMedID 11445261

  • Motor sequencing deficits in schizophrenia: A comparison with Parkinson's disease Sullivan, E. V., Fama, R., Shear, P. K., Cahn-Weiner, D. A., Stein, M., Zipursky, R. B., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2001: 342-350


    Motor abnormalities occur in schizophrenia (SZ) and may arise from striatal dysfunction. This study examined whether the pattern of performance on simple and complex motor abilities in SZ was similar to that of patients with Parkinson's disease (PD). Quantitative tests of speeded movement and motor and cognitive sequencing were used to assess 25 SZ, 16 PD, and 84 normal controls (NCs). Sequencing performance was also examined with motor rigidity taken into account. Compared with the NC group, the SZ and PD groups were impaired on measures of motor rigidity and motor sequencing. With rigidity accounted for, the SZ group was significantly more impaired than the PD group on motor sequencing; cognitive and motor processes contributed to the motor deficit. Cognitive sequencing performance predicted motor sequencing performance in PD but not SZ. Although both SZ and PD resulted in significant motor and cognitive sequencing deficits, the pattern and correlates of these deficits differ, suggesting that the affected neural systems underlying motor deficits in SZ are different from those involved in PD.

    View details for DOI 10.1037//0894-4105.15.3.342

    View details for Web of Science ID 000170947000003

    View details for PubMedID 11499989

  • N1 and P300 abnormalities in patients with schizophrenia epilepsy, and epilepsy with schizophrenialike features Ford, J. M., Mathalon, D. H., Kalba, S., Marsh, L., Pfefferbaum, A. ELSEVIER SCIENCE INC. 2001: 848-860


    The scalp-recorded N1 and P300 components of the event-related brain potential (ERP) are commonly reduced in patients with schizophrenia but not in patients with epilepsy. Epilepsy patients with interictal chronic schizophrenialike features (EPI-SZ) provide a comparison group for determining whether the ERP amplitude abnormalities seen in schizophrenic patients are associated with shared clinical features of EPI-SZ and schizophrenic patients or overlapping pathophysiologies, or are specific to a distinct schizophrenia etiology.Patients with schizophrenia (n = 24) were compared with normal control subjects (n = 32) and patients with epilepsy syndromes on visual and auditory oddball ERP paradigms. Epilepsy patients included those with chronic interictal schizophrenialike features (n = 6) and those without (n = 16).Auditory P300 amplitude was reduced in both schizophrenic and EPI-SZ patients, whose positive or negative symptoms did not differ. In contrast, N1 amplitude was reduced only in schizophrenic patients. Delays in both N1 and P300 were associated with epilepsy patients and EPI-SZ but not schizophrenic patients.The schizophrenialike symptoms in epilepsy probably represent a phenocopy of schizophrenia with common clinical features and some common pathophysiologies but distinct etiologies. P300 amplitude appears to be sensitive to schizophrenialike features, regardless of whether they occur in the context of schizophrenia or epilepsy. N1 amplitude reduction appears to be specific to schizophrenia, suggesting its sensitivity to the distinct etiology of schizophrenia.

    View details for Web of Science ID 000168559100004

    View details for PubMedID 11343681

  • Neuroimaging in alcoholism: Ethanol and brain damage Mann, K., Agartz, I., Harper, C., Shoaf, S., RAWLINGS, R. R., Momenan, R., Hommer, D. W., Pfefferbaum, A., SULLIVAN, E. V., Anton, R. F., Drobes, D. J., George, M. S., Bares, R., Machulla, H. J., Mundle, G., Reimold, M., Heinz, A. WILEY-BLACKWELL. 2001: 104S-109S


    This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

    View details for Web of Science ID 000168846000019

    View details for PubMedID 11391058

  • Progressive brain volume changes and the clinical course of schizophrenia in men - A longitudinal magnetic resonance imaging study Mathalon, D. H., SULLIVAN, E. V., Lim, K. O., Pfefferbaum, A. AMER MEDICAL ASSOC. 2001: 148-157


    We sought to determine whether the brain dysmorphology previously observed cross-sectionally in people with schizophrenia progresses over time and whether such progression is related to the severity of the illness course.Men with chronic schizophrenia (n = 24) and control men (n = 25) received 2 brain magnetic resonance imaging scans, on average 4 years apart. Changes in brain volume were adjusted for head-repositioning error and expressed as slopes (cubic centimeters per year). Clinical course severity for the schizophrenic patients was assessed using the mean of time 1 and time 2 Brief Psychiatric Rating Scale (BPRS) scores and the percentage of time the patient was hospitalized during the interscan interval.Schizophrenic patients exhibited faster volume decline than control subjects in right frontal gray matter and bilateral posterior superior temporal gray matter, as well as faster cerebrospinal fluid volume expansion in right frontal sulci, left lateral ventricle, and bilateral prefrontal and posterior superior temporal sulci. Faster rates of frontal sulcal expansion were related to greater BPRS total and positive symptom scores and longer time hospitalized. Prefrontal gray matter decline and sulcal expansion were associated with greater BPRS negative symptom scores and longer time hospitalized. Temporal lobe gray matter decline was associated with greater BPRS total and negative symptom scores.This controlled study revealed that patients with chronic schizophrenia exhibited accelerated frontotemporal cortical gray matter decline and cortical sulcal and lateral ventricular expansion. Further, greater clinical severity was associated with faster rates of frontotemporal brain volume changes. These observations are consistent with a progressive pathophysiological process but need to be replicated in a larger sample.

    View details for Web of Science ID 000166842600005

    View details for PubMedID 11177116

  • Sex differences in the effects of alcohol on brain structure Pfefferbaum, A., Rosenbloom, M., Deshmukh, A., SULLIVAN, E. V. AMER PSYCHIATRIC PUBLISHING, INC. 2001: 188-197


    This study investigated whether alcoholic women manifest deficits in cortical gray and white matter volumes and ventricular enlargement similar to those seen in alcoholic men.Volumetric measures of intracranium, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of 42 women and 44 men with DSM-III-R alcoholism and age-matched healthy comparison groups (37 women and 48 men). Groups of alcoholic men and women were matched on age and length of sobriety, but men had a 2.5 times higher lifetime alcohol consumption than women.Women, regardless of diagnosis, had less cortical gray and white matter and smaller third ventricles than men, consistent with sex-related differences in intracranial volume. Alcoholics had larger volumes of cortical sulci and lateral and third ventricles than comparison subjects. Diagnosis-by-sex interactions for cortical white matter and sulcal volumes were due to abnormalities in alcoholic men but not alcoholic women, relative to same-sex comparison subjects. This interaction persisted for cortical sulci after covarying for lifetime alcohol consumption. Slopes relating cortical gray matter and sulcal volumes to age were steeper in alcoholic than in comparison men. Slopes relating lateral ventricle volume to age were steeper in alcoholic than in comparison women. In alcoholic women, longer sobriety was associated with larger white matter volumes.Alcoholic men and women show different brain morphological deficits, relative to same-sex comparison subjects. However, age and alcoholism interact in both sexes, which puts all older alcoholics at particular risk for the negative sequelae of alcoholism.

    View details for Web of Science ID 000166761400007

    View details for PubMedID 11156800

  • Cerebellar volume decline in normal aging, alcoholism, and Korsakoff's syndrome: Relation to ataxia SULLIVAN, E. V., Deshmukh, A., Desmond, J. E., Lim, K. O., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2000: 341-352


    The authors used magnetic resonance imaging to measure gray and white matter volumes in cerebellar hemispheres and 4 vermian regions in 61 normal control (NC) men aged 23-72 years, 25 men with uncomplicated alcoholism (ALC), and 8 men and 1 woman with alcoholic Korsakoff s syndrome (KS). NC and ALC took quantitative gait and balance tests. Gray but not white matter volume declined with normal age in both hemispheres and anterior-superior vermis. ALC had gray but not white matter cerebellar hemisphere volume deficits, whereas KS had deficits in both tissue types. ALC and KS had gray and white matter volume deficits in anterior superior but not posterior inferior vermis. ALC had a 1 SD ataxia deficit, significantly and selectively correlated with white matter volume in anterior superior vermis. Regional distribution but not severity of cerebellar volume deficits is similar in alcoholic individuals whether or not complicated by KS and relates to ataxia.

    View details for Web of Science ID 000088253400002

    View details for PubMedID 10928737

  • Extent, pattern, and correlates of remote memory impairment in Alzheimer's disease and Parkinson's disease Fama, R., Sullivan, E. V., Shear, P. K., Stein, M., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2000: 265-276


    Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.

    View details for DOI 10.1037//0894-4105.14.2.265

    View details for Web of Science ID 000087480700010

    View details for PubMedID 10791866

  • Structural brain correlates of verbal and nonverbal fluency measures in Alzheimer's disease Fama, R., Sullivan, E. V., Shear, P. K., Cahn-Weiner, D. A., Marsh, L., Lim, K. O., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2000: 29-40


    This study examined the relationships between regional brain volumes and semantic, phonological, and nonverbal fluency in 32 participants with Alzheimer's disease (AD). Object but not animal semantic fluency correlated with frontal and temporal gray matter volumes. Phonological fluency was not significantly associated with any brain volume examined. Nonverbal fluency was selectively associated with bilateral frontal gray matter volumes. Hippocampal volumes, although markedly reduced in these patients, were not related to any of the fluency measures. Results lend evidence to the importance of the frontal lobes in the directed generation of nonverbal and verbal exemplars by AD patients. Furthermore, both left- and right-hemisphere regions contribute to the generation of verbal and nonverbal exemplars.

    View details for Web of Science ID 000085020000003

    View details for PubMedID 10674796

  • Brain structural and cognitive correlates of clock drawing performance in Alzheimer's disease Cahn-Weiner, D. A., SULLIVAN, E. V., Shear, P. K., Fama, R., Lim, K. O., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. CAMBRIDGE UNIV PRESS. 1999: 502-509


    The Clock Drawing Test (CDT) is widely used in the assessment of dementia and is known to be sensitive to the detection of deficits in neurodegenerative disorders such as Alzheimer's disease (AD). CDT performance is dependent not only on visuospatial and constructional abilities, but also on conceptual and executive functioning; therefore, it is likely to be mediated by multiple brain regions. The purpose of the present study was to identify component cognitive processes and regional cortical volumes that contribute to CDT performance in AD. In 29 patients with probable AD, CDT performance was significantly related to right-, but not left-hemisphere, regional gray matter volume. Specifically, CDT score correlated significantly with the right anterior and posterior superior temporal lobe volumes. CDT scores showed significant relationships with tests of semantic knowledge, executive function, and visuoconstruction, and receptive language. These results suggest that in AD patients, CDT performance is attributable to impairment in multiple cognitive domains but is related specifically to regional volume loss of right temporal cortex.

    View details for Web of Science ID 000083339700003

    View details for PubMedID 10561930

  • Brain gray and white matter transverse relaxation time in schizophrenia Pfefferbaum, A., SULLIVAN, E. V., Hedehus, M., Moseley, M., Lim, K. O. ELSEVIER IRELAND LTD. 1999: 93-100


    Recent in vivo diffusion brain imaging studies of schizophrenic patients have revealed microstructural abnormalities, with low diffusion anisotropy present throughout much of cortical white matter. Brain anisotropy is produced when proton movement reflects physically restricted water movement, for example, by myelin sheaths. Conditions that increase self-diffusion, such as edema, may also alter the longitudinal and transverse relaxation time of protons, and it is possible that such changes could explain the observed anisotropy diminution seen in schizophrenia. To test this possibility, we calculated pixel-by-pixel transverse relaxation time (T2) and proton density (PD) maps for gray matter and white matter across eight 5-mm-thick axial slices of fast spin echo MRI in 10 control men (age 30-57 years) and 10 men with schizophrenia (age 32-64 years). Schizophrenics had significantly longer mean white matter T2 (84.0 vs. 81.9 ms, P<0.03) and gray matter T2 (95.1 vs. 92.2, P = 0.003); their mean white and gray matter PD values were not significantly different from those of controls. Correlations were not significant between anisotropy and T2 in either grey or white matter but were significant between anisotropy and PD in white matter. T2 relaxation times are longer in schizophrenics than in controls in both gray and white matter whereas anisotropy reduction is restricted to white matter. Taken together, these results suggest that the process producing prolonged T2 does not fully account for the abnormally low anisotropy observed selectively in white matter in this group of schizophrenic patients.

    View details for Web of Science ID 000082888500003

    View details for PubMedID 10515464

  • P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia Ford, J. M., Mathalon, D. H., Marsh, L., Faustman, W. O., Harris, D., Hoff, A. L., Beal, M., Pfefferbaum, A. ELSEVIER SCIENCE INC. 1999: 94-101


    Relationships between illness severity and neurobiologic abnormalities in schizophrenia were studied in subpopulations varying in clinical severity.Auditory ERPs were collected from 28 severely ill, chronically hospitalized schizophrenic men from a state hospital; 29 moderately ill inpatient and outpatient schizophrenic men from a veterans hospital; and 30 healthy male subjects from the community as controls. Clinical symptoms were evaluated in patients using the Brief Psychiatric Rating Scale (BPRS).Both schizophrenic patient groups had smaller P300 amplitude than the control subjects. Severely ill patients had smaller P300s than moderately ill patients and scored higher on three BPRS factor scores as well as BPRS Total. Among severely ill patients, P300 amplitude was unrelated to clinical symptoms. Among moderately ill patients, P300 was related to Withdrawal/Retardation, Anxiety/Depression, and BPRS Total. After combining patients, Thinking Disturbance emerged as an additional correlate of P300. Group differences in P300 could not be accounted for by group differences in symptom severity using analysis of covariance.Reduced P300 amplitude marks the diagnosis of schizophrenia, but also reflects individual differences in severity, including positive symptoms. Previous failures to find relationships between positive symptoms and P300 may have been due to a restricted range of clinical severity.

    View details for Web of Science ID 000081103400012

    View details for PubMedID 10394478

  • Selective cortical and hippocampal volume correlates of Mattis Dementia Rating Scale in Alzheimer disease Fama, R., SULLIVAN, E. V., Shear, P. K., Marsh, L., Yesavage, J. A., Tinklenberg, J. R., Lim, K. O., Pfefferbaum, A. AMER MEDICAL ASSOC. 1997: 719-728


    To examine whether each of the 5 Mattis Dementia Rating Scale (DRS) scores related to magnetic resonance imaging-derived volumes of specific cortical or limbic brain regions in patients with Alzheimer disease (AD).Relations between DRS measures and regional brain volume measures were tested with bivariate and multivariate regression analyses.The Aging Clinical Research Center of the Stanford (Calif) University Department of Psychiatry and Behavioral Science and the Geriatric Psychiatry Rehabilitation Unit of the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif.Fifty patients with possible or probable AD. Magnetic resonance imaging data from 136 healthy control participants, age 20 to 84 years, were used to correct brain volumes for normal variation arising from intracranial volume and age.The DRS scores and volumes of regional cortical gray matter and of the hippocampus.Memory scores of the patients with AD were selectively related to hippocampal volumes. Attention and construction scores were related to several anterior brain volume measures, with attention showing a significantly greater association to right than left hemisphere measures. Initiation/perseveration scores were not significantly correlated with any measure of regional gray matter volume, but performance was related to prefrontal sulcal widening, with a greater association with the left than right sulcal volume.Certain DRS subtests are predictably correlated with selective regional brain volumes in AD. The specific relation between memory and hippocampal volumes and the nonsignificant relations between memory and regional cortical volumes suggest a dissociation between cortical and hippocampal contributions to explicit memory performance.

    View details for Web of Science ID A1997XE00100008

    View details for PubMedID 9193207

  • Similar extent of brain dysmorphology in severely ill women and men with schizophrenia Lauriello, J., Hoff, A., Wieneke, M. H., Blankfeld, H., Faustman, W. O., Rosenbloom, M., DEMENT, S., SULLIVAN, E. V., Lim, K. O., Pfefferbaum, A. AMER PSYCHIATRIC PUBLISHING, INC. 1997: 819-825


    The purpose of this study was to determine whether women with chronic, severe schizophrenia manifest a widespread deficit in cortical gray matter and ventricular enlargement similar to that seen in men with schizophrenia and whether this deficit is related to age at onset of illness, length of illness, or current illness severity.Volumetric measures of head size, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of chronic inpatient schizophrenic women (N = 19) and men (N = 18) and healthy comparison women (N = 19) and men (N = 18). Sex and group differences were assessed by using a two-factor analysis of variance of brain measures. Age was entered as a covariate in assessments of associations between brain measures and age at onset and length of illness.The schizophrenic patients as a group had less cortical gray matter but comparable white matter and significantly more lateral and third ventricular CSF than the comparison group. Compared to the combined groups of men, women, regardless of diagnosis, had smaller heads, less cortical gray and white matter, and less sulcal, lateral, and third ventricular CSF. There were no group-by-sex interactions, suggesting that in schizophrenia these aspects of gross volumetric morphology in male and female brains are affected equally. There was no relationship between cortical gray matter deficit or ventricular enlargements and age at symptom onset or length of illness in either men or women with schizophrenia, when variance due to age was accounted for statistically.The process that contributes to cortical gray matter deficit in schizophrenia appears to affect men and women to a similar extent.

    View details for Web of Science ID A1997XA58700015

    View details for PubMedID 9167510

  • Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics Pfefferbaum, A., SULLIVAN, E. V., Mathalon, D. H., Lim, K. O. WILEY-BLACKWELL. 1997: 521-529


    This study used magnetic resonance imaging to quantify the extent and pattern of tissue volume deficit and cerebrospinal fluid volume enlargement in younger versus older chronic alcoholics relative to normal controls. In the present analysis, we divided our previously reported group of 62 alcoholic men into a younger group (n = 33, age mean = 37.5 +/- 4.5, and range = 26 to 44 years) and an older group (n = 29, age mean = 52.7 +/- 6.0, and range = 45 to 63 years) to examine whether, in addition to extent, the two age groups differed in pattern of tissue type and regional brain volume abnormalities quantified with magnetic resonance imaging. Brain volumes were adjusted for normal variation in head size and age established from a group of healthy controls and were expressed as Z-scores. The younger group had significant cortical gray, but not white, matter volume deficits and sulcal and ventricular enlargement relative to age-matched controls. The older group had volume deficits in both cortical gray and white matter and sulcal and ventricular enlargement that significantly exceeded the younger alcoholic group. An analysis of six cortical regions revealed that, although both age groups had gray matter volume deficits throughout the cortex, the older alcoholic group had a selectively more severe deficit in prefrontal gray matter relative to the younger alcoholic group. Similarly, the cortical white matter volume deficit in the older alcoholics was especially severe in the prefrontal and frontal regions. The differences in brain dysmorphology between the two alcoholic groups cannot easily be attributed to potential alcohol history differences typically related to age because the two groups had similar disease durations and amounts of lifetime alcohol consumption. These results provide in vivo evidence that the frontal lobes are especially vulnerable to chronic alcoholism in older men.

    View details for Web of Science ID A1997WZ64500020

    View details for PubMedID 9161613

  • ELDERLY MEN AND WOMEN ARE LESS RESPONSIVE TO STARTLING NOISES - N1, P3 AND BLINK EVIDENCE Ford, J. M., Roth, W. T., Isaacks, B. G., White, P. M., Hood, S. H., Pfefferbaum, A. ELSEVIER SCIENCE BV. 1995: 57-80


    Previously we observed that the P3 component of the event-related brain potential (ERP) elicited by startling noises, and to a lesser extent P3 to target tones, is reduced in the elderly (Ford & Pfefferbaum, 1991). In the current experiment, we tried to eliminate possible effects of age-related hearing deficits on the responses to noises by filtering them to include only frequencies heard best by the elderly (0-1000 Hz) and by setting noise intensity relative to each subject's threshold (sensation level, SL). Twelve younger (mean 22 years) and 12 older (mean 69 years) men and women listened to three sequences of tones (80%, 500 Hz, 70 dB SPL) and noises (20%). One type of noise occurred in each sequence (wide band noise set to 107 dB SPL, narrow band noise set to 107 dB SPL, or narrow band noise set to approximately 65 dB SL). The order of the three sequences was counterbalanced across age and sex. Younger subjects blinked to the noise 4-5 times more often than older subjects and had N1 and P3 amplitudes that were 2-3 times larger, regardless of the noise type. N1 amplitude to the background frequent tones and non-startle blinks did not differ between groups. Thus, even when noises were narrow band and set relative to each subject's threshold, older subjects were less responsive to startling auditory stimuli than were younger.

    View details for Web of Science ID A1995QE66900001

    View details for PubMedID 7734630


    View details for Web of Science ID A1991HB51400033

    View details for PubMedID 1915027



    Dipole source localization promises to enhance knowledge about the structural and functional processes underlying differences in scalp-recorded ERPs observed between normal and patient populations. In this paper the Cuffin and Cohen (1) four-compartment model of volume conduction is used to examine the effects of variations in size of different compartments on scalp-recorded potentials. Using single discrete current dipoles located various distances from the center of the head, the effect of varying the thickness of the superficial extra-sulcal subarachnoid layer of CSF and the thickness of the skull are examined. Changing the thickness of the CSF layer alters amplitude recorded at the scalp and also alters the topographic distribution of the potential; these effects are more pronounced the closer the dipole source is to the surface. Changes in skull thickness have similar, but even greater effects.

    View details for Web of Science ID A1990DX05900018

    View details for PubMedID 2222852

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