Bachelor of Science, University of Florida (2005)
Doctor of Philosophy, University of Florida (2010)
Jean Tang, Postdoctoral Faculty Sponsor
The hippocampus is a very important structure in memory formation and retrieval, as well as in various neurological disorders such as Alzheimer's disease, epilepsy and depression. It is composed of many intricate subregions making it difficult to study the anatomical changes that take place during disease. The hippocampal hilus may have a unique neuroanatomy in humans compared to that in monkeys and rodents, with field CA3h greatly enlarged in humans compared to that in rodents, and a white-matter pathway, called the endfolial pathway, possibly only present in humans. In this study we have used newly developed 7.0T whole brain imaging sequence, balanced steady-state free precession (bSSFP) that can achieve 0.4mm isotropic images to study, in vivo, the anatomy of the hippocampal hilus. A detailed hippocampal subregional segmentation was performed according to anatomic atlases segmenting the following regions: CA4, CA3, CA2, CA1, SRLM (stratum radiatum lacunosum moleculare), alveus, fornix, and subiculum along with its molecular layer. We also segmented a hypointense structure centrally within the hilus that resembled the endfolial pathway. To validate that this hypointense signal represented the endfolial pathway, we acquired 0.1mm isotropic 8-phase cycle bSSFP on an excised specimen, and then sectioned and stained the specimen for myelin using an anti-myelin basic protein antibody (SMI 94). A structure tensor analysis was calculated on the myelin-stained section to show directionality of the underlying fibers. The endfolial pathway was consistently visualized within the hippocampal body in vivo in all subjects. It is a central pathway in the hippocampus, with unknown relevance in neurodegenerative disorders, but now that it can be visualized noninvasively, we can study its function and alterations in neurodegeneration.
View details for DOI 10.1016/j.neuroimage.2015.02.029
View details for Web of Science ID 000353203400001
View details for PubMedID 25701699
An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MRI scans of a single healthy adult human subject were acquired both at 3T and 7T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.
View details for DOI 10.1016/j.neuroimage.2015.01.004
View details for Web of Science ID 000352224100046
View details for PubMedID 25596463
Emerging high-field diffusion weighted MR imaging protocols, along with tractography, can elucidate microstructural changes associated with brain disease at the sub-millimeter image resolution. Epilepsy and other neurological disorders are accompanied by structural changes in the hippocampal formation and associated regions; however, these changes can be subtle and on a much smaller scale than the spatial resolution commonly obtained by current clinical magnetic resonance (MR) protocols in vivo.We explored the possibility of studying the organization of fresh tissue with a 17.6 Tesla magnet using diffusion MR imaging and tractography. The mesoscale organization of the temporal lobe was estimated using a fresh unfixed specimen obtained from a subject who underwent anterior temporal lobectomy for medically refractory temporal lobe epilepsy (TLE). Following ex vivo imaging, the tissue was fixed, serial-sectioned, and stained for correlation with imaging.We resolved tissue microstructural organizational features in the temporal lobe from diffusion MR imaging and tractography in fresh tissue.Fresh ex vivo MR imaging, along with tractography, revealed complex intra-temporal structural variation corresponding to neuronal cell body layers, dendritic fields, and axonal projection systems evident histologically. This is the first study to describe in detail the human temporal lobe structural organization using high-field MR imaging and tractography. By preserving the 3-dimensional structures of the hippocampus and surrounding structures, specific changes in anatomy may inform us about the changes that occur in TLE in relation to the disease process and structural underpinnings in epilepsy-related memory dysfunction.
View details for DOI 10.1016/j.nicl.2015.07.005
View details for PubMedID 26413472
High spatial and angular resolution diffusion weighted imaging (DWI) with network analysis provides a unique framework for the study of brain structure in vivo. DWI-derived brain connectivity patterns are best characterized with graph theory using an edge weight to quantify the strength of white matter connections between gray matter nodes. Here a dimensionless, scale-invariant edge weight is introduced to measure node connectivity. This edge weight metric provides reasonable and consistent values over any size scale (e.g. rodents to humans) used to quantify the strength of connection. Firstly, simulations were used to assess the effects of tractography seed point density and random errors in the estimated fiber orientations; with sufficient signal-to-noise ratio (SNR), edge weight estimates improve as the seed density increases. Secondly to evaluate the application of the edge weight in the human brain, ten repeated measures of DWI in the same healthy human subject were analyzed. Mean edge weight values within the cingulum and corpus callosum were consistent and showed low variability. Thirdly, using excised rat brains to study the effects of spatial resolution, the weight of edges connecting major structures in the temporal lobe were used to characterize connectivity in this local network. The results indicate that with adequate resolution and SNR, connections between network nodes are characterized well by this edge weight metric. Therefore this new dimensionless, scale-invariant edge weight metric provides a robust measure of network connectivity that can be applied in any size regime.
View details for DOI 10.1371/journal.pone.0131493
View details for PubMedID 26173147
The objectives of this study were to acquire ultra-high resolution images of the brain using balanced steady-state free precession (bSSFP) at 7.0 T and to identify the potential utility of this sequence.Eight volunteers participated in this study after providing informed consent. Each volunteer was scanned with 8 phase cycles of bSSFP at 0.4-mm isotropic resolution using 0.5 number of excitations and 2-dimensional parallel acceleration of 1.75 × 1.75. Each phase cycle required 5 minutes of scanning, with pauses between the phase cycles allowing short periods of rest. The individual phase cycles were aligned and then averaged. The same volunteers underwent scanning using 3-dimensional (3D) multiecho gradient recalled echo at 0.8-mm isotropic resolution, 3D Cube T2 at 0.7-mm isotropic resolution, and thin-section coronal oblique T2-weighted fast spin echo at 0.22 × 0.22 × 2.0-mm resolution for comparison. Two neuroradiologists assessed image quality and potential research and clinical utility.The volunteers generally tolerated the scan sessions well, and composite high-resolution bSSFP images were produced for each volunteer. Rater analysis demonstrated that bSSFP had a superior 3D visualization of the microarchitecture of the hippocampus, very good contrast to delineate the borders of the subthalamic nucleus, and relatively good B1 homogeneity throughout. In addition to an excellent visualization of the cerebellum, subtle details of the brain and skull base anatomy were also easier to identify on the bSSFP images, including the line of Gennari, membrane of Liliequist, and cranial nerves. Balanced steady-state free precession had a strong iron contrast similar to or better than the comparison sequences. However, cortical gray-white contrast was significantly better with Cube T2 and T2-weighted fast spin echo.Balanced steady-state free precession can facilitate ultrahigh-resolution imaging of the brain. Although total imaging times are long, the individually short phase cycles can be acquired separately, improving examination tolerability. These images may be beneficial for studies of the hippocampus, iron-containing structures such as the subthalamic nucleus and line of Gennari, and the basal cisterns and their contents.
View details for Web of Science ID 000337297800004
View details for PubMedID 24473366
For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of ∼12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction.
View details for DOI 10.1152/jn.00911.2012
View details for Web of Science ID 000324095300004
View details for PubMedID 23678009
Humans and wildlife are exposed to environmental pollutants that have been shown to interfere with the thyroid hormone system and thus may affect brain development. Our goal was to expose pregnant rats to propylthiouracil (PTU) to measure the effects of a goitrogen on white matter development in offspring using magnetic resonance imaging (MRI) and volumetric analysis. We exposed pregnant Sprague Dawley (SD) rats to 3 or 10 ppm PTU from gestation day 7 (GD7) until postnatal day 25 (P25) to determine the effects on white matter (WM), gray matter (GM), and hippocampus volumes in offspring. We sacrificed offspring at P25 but continued the life of some offspring to P90 to measure persistent effects in adult animals. P25 offspring exposed to 10 ppm PTU displayed lowered levels of triiodothyronine (T3) and thyroxine (T4); cerebral WM, GM, and total brain volumes were significantly lower than the volumes in control animals. P90 adults exposed to 10 ppm PTU displayed normal T3 levels but lowered T4 levels; WM, GM, total brain, and hippocampal volumes were significantly lower than the volumes in control adults. Both P25 and P90 rats exposed to 10 ppm PTU displayed significant reductions in percent WM as well as heterotopias in the corpus callosum. Exposure to 3 ppm PTU did not produce any significant effects. These results suggest that MRI coupled with volumetric analysis is a powerful tool in assessing the effects of thyroid hormone disruption on white matter development and brain structure. This approach holds great promise in assessing neurotoxicity of xenobiotics in humans and wildlife.
View details for DOI 10.1016/j.neuro.2012.08.008
View details for PubMedID 22975424
Structural changes in limbic regions are often observed in individuals with temporal lobe epilepsy (TLE) and in animal models. However, the brain structural changes during the evolution into epilepsy remain largely unknown. Therefore, the purpose of this study was to define the temporal changes in limbic structures after experimental status epilepticus (SE) during the latency period of epileptogenesis in vivo, with quantitative diffusion tensor imaging (DTI) and T2 relaxometry in an animal model of chronic TLE. A pair of fifty micron electrodes was implanted into the ventral hippocampus in twelve male adult rats. Self-sustaining SE was induced with electrical stimulation in eleven rats. Three rats served as age-matched controls. In vivo diffusion tensor and T2 magnetic resonance imaging (MRI) was performed at 11.1 Tesla, pre- and post-implantation of electrodes and 3, 5, 7, 10, 20, 40 and 60 days post-SE to assess structural changes. Spontaneous seizures were identified with continuous time-locked video-monitoring. Following imaging in vivo, fixed, excised brains were MR imaged at 17.6 Tesla. Subsequently, histological analysis was correlated with MRI results. Following SE, 8/11 injured rats developed spontaneous seizures. Unique to these 8 rats, early T2, diffusivity and anisotropy changes were observed in vivo within the parahippocampal gyrus (contralateral) and fimbria (bilateral). In excised brains, bilateral increase in anisotropy was observed in the dentate gyrus, corresponding to mossy fiber sprouting as determined by Timm staining. Using T2 relaxometry and DTI, specific transient and long-term structural changes were observed only in rats that developed spontaneous limbic seizures.
View details for DOI 10.1016/j.expneurol.2010.03.031
View details for Web of Science ID 000279128400029
View details for PubMedID 20394745
An understanding of the in vivo spatial emergence of abnormal brain activity during spontaneous seizure onset is critical to future early seizure detection and closed-loop seizure prevention therapies. In this study, we use Granger causality (GC) to determine the strength and direction of relationships between local field potentials (LFPs) recorded from bilateral microelectrode arrays in an intermittent spontaneous seizure model of chronic temporal lobe epilepsy before, during, and after Racine grade partial onset generalized seizures. Our results indicate distinct patterns of directional GC relationships within the hippocampus, specifically from the CA1 subfield to the dentate gyrus, prior to and during seizure onset. Our results suggest sequential and hierarchical temporal relationships between the CA1 and dentate gyrus within and across hippocampal hemispheres during seizure. Additionally, our analysis suggests a reversal in the direction of GC relationships during seizure, from an abnormal pattern to more anatomically expected pattern. This reversal correlates well with the observed behavioral transition from tonic to clonic seizure in time-locked video. These findings highlight the utility of GC to reveal dynamic directional temporal relationships between multichannel LFP recordings from multiple brain regions during unprovoked spontaneous seizures.
View details for DOI 10.1016/j.jneumeth.2010.03.007
View details for Web of Science ID 000278290900017
View details for PubMedID 20304005
While temporal lobe epilepsy (TLE) has been treatable with anti-seizure medications over the past century, there still remain a large percentage of patients whose seizures remain untreatable pharmacologically. To better understand and treat TLE, our laboratory uses several in vivo analytical techniques to estimate connectivity in epilepsy. This paper reviews two different connectivity-based approaches with an emphasis on application to the study of epilepsy. First, we present effective connectivity techniques, such as Granger causality, that has been used to assess the dynamic directional relationships among brain regions. These measures are used to better understand how seizure activity initiates, propagates, and terminates. Second, structural techniques, such as magnetic resonance imaging, can be used to assess changes in the underlying neural structures that result in seizure. This paper also includes in vivo epilepsy-centered examples of both effective and anatomical connectivity analysis. These analyses are performed on data collected in vivo from a spontaneously seizing animal model of TLE. Future work in vivo on epilepsy will no doubt benefit from a fusion of these different techniques. We conclude by discussing the interesting possibilities, implications, and challenges that a unified analysis would present.
View details for DOI 10.1109/TNSRE.2008.2006220
View details for Web of Science ID 000267493300003
View details for PubMedID 19273040