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1.  A Two-level Multimodality Imaging Bayesian Network Approach For Classification of Partial Epilepsy: Preliminary Data 
NeuroImage  2013;71:224-232.
Quantitative neuroimaging analyses have demonstrated gray and white matter abnormalities in group comparisons of different types of non-lesional partial epilepsy. It is unknown to what degree these type-specific patterns exist in individual patients and if they could be exploited for diagnostic purposes. In this study, a two-level multi-modality imaging Bayesian network approach is proposed that uses information about individual gray matter volume loss and white matter integrity to classify non-lesional temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial-temporal sclerosis and frontal lobe epilepsy (FLE).
25 controls, 19 TLE-MTS, 22 TLE-no and 14 FLE were studied on a 4T MRI and T1 weighted structural and DTI images acquired. Spatially normalized gray matter (GM) and fractional anisotropy (FA) abnormality maps (binary maps with voxels 1 SD below control mean) were calculated for each subject. At the first level, each group’s abnormality maps were compared with those from all the other groups using Graphical-Model-based Morphometric Analysis (GAMMA). GAMMA uses a Bayesian network and a Markov random field based contextual clustering method to produce maps of voxels that provide the maximal distinction between two groups and calculates a probability distribution and a group assignment based on this information. The information was then combined in a second level Bayesian network and the probability of each subject to belong to one of the three epilepsy types calculated.
The specificities of the two level Bayesian network to distinguish between the three patient groups were 0.87 for TLE-MTS and TLE-no and 0.86 for FLE, the corresponding sensitivities were 0.84 for TLE-MTS, 0.72 for TLE-no and 0.64 for FLE
The two-level multi-modality Bayesian network approach was able to distinguish between the three epilepsy types with a reasonably high accuracy even though the majority of the images were completely normal on visual inspection.
PMCID: PMC3619666  PMID: 23353601
TLE; FLE; classifier; Bayesian network; epilepsy; DTI; gray matter volume
2.  Different Structural Correlates for Verbal Memory Impairment in Temporal Lobe Epilepsy with and Without Mesial Temporal Lobe Sclerosis 
Human Brain Mapping  2011;33(2):489-499.
Memory impairment is one of the most prominent cognitive deficits in temporal lobe epilepsy (TLE). The overall goal of this study was to explore the contribution of cortical and hippocampal (subfield) damage to impairment of auditory immediate recall (AIMrecall), auditory delayed recall (ADMrecall), and auditory delayed recognition (ADMrecog) of the Wechsler Memory Scale III (WMS-III) in TLE with (TLE–MTS) and without hippocampal sclerosis (TLE-no). It was hypothesized that volume loss in different subfields determines memory impairment in TLE–MTS and temporal neocortical thinning in TLE-no.
T1 whole brain and T2-weighted hippocampal magnetic resonance imaging and WMS-III were acquired in 22 controls, 18 TLE–MTS, and 25 TLE-no. Hippocampal subfields were determined on the T2 image. Free surfer was used to obtain cortical thickness averages of temporal, frontal, and parietal cortical regions of interest (ROI). MANOVA and stepwise regression analysis were used to identify hippocampal subfields and cortical ROI significantly contributing to AIMrecall, ADMrecall, and ADMrecog.
In TLE–MTS, AIMrecall was associated with cornu ammonis 3 (CA3) and dentate (CA3&DG) and pars opercularis, ADMrecall with CA1 and pars triangularis, and ADMrecog with CA1. In TLE-no, AIMrecall was associated with CA3&DG and fusiform gyrus (FUSI), and ADMrecall and ADMrecog were associated with FUSI.
The study provided the evidence for different structural correlates of the verbal memory impairment in TLE–MTS and TLE-no. In TLE–MTS, the memory impairment was mainly associated by subfield-specific hippocampal and inferior frontal cortical damage. In TLE-no, the impairment was associated by mesial–temporal cortical and to a lesser degree hippocampal damage.
PMCID: PMC3259857  PMID: 21438080
TLE; CA1; CA3; dentate gyrus; MRI; recognition; recall; mesial temporal sclerosis; fusiform
3.  Influences of lobar gray matter and white matter lesion load on cognition and mood 
Psychiatry research  2010;181(2):90.
Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer’s disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD) and segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together depressed mood and cognitive impairment are caused by different pathological correlates.
PMCID: PMC2814971  PMID: 20074914
white matter lesion; gray matter atrophy; depression; mood; cognition; MRI
4.  Involvement of the thalamocortical network in TLE with and without mesiotemporal sclerosis 
Epilepsia  2009;51(8):1436-1445.
The thalamus plays an important role in seizure propagation in temporal lobe epilepsy (TLE). This study investigated how structural abnormalities in the focus, ipsilateral thalamus and extrafocal cortical structures relate to each other in TLE with mesiotemporal sclerosis (TLE-MTS) and without hippocampal sclerosis (TLE-no).
T1 and high-resolution T2 images were acquired on a 4T magnet in 29 controls, 15 TLE-MTS cases, and 14 TLE-no. Thalamus volumes were obtained by warping a labeled atlas onto each subject’s brain. Deformation-based morphometry was used to identify regions of thalamic volume loss and FreeSurfer for cortical thickness measurements. CA1 volumes were obtained from high-resolution T2 images. Multiple regression analysis and correlation analyses for voxel- and vertex-based analyses were performed in SPM2 and FreeSurfer.
TLE-MTS had bilateral volume loss in the anterior thalamus, which was correlated with CA1 volume and cortical thinning in the mesiotemporal lobe. TLE-no had less severe volume loss in the dorsal lateral nucleus, which was correlated with thinning in the mesiotemporal region but not with extratemporal thinning.
The findings suggest that seizure propagation from the presumed epileptogenic focus or regions close to it into the thalamus occurs in TLE-MTS and TLE-no and results in circumscribed neuronal loss in the thalamus. However, seizure spread beyond the thalamus seems not to be responsible for the extensive extratemporal cortical abnormalities in TLE.
PMCID: PMC2888933  PMID: 20002143
Extrafocal cortical thinning; Mesiotemporal sclerosis; Thalamus; Temporal lobe epilepsy
5.  Subfield atrophy pattern in temporal lobe epilepsy with and without mesial sclerosis detected by high-resolution MRI at 4 Tesla: Preliminary results 
Epilepsia  2009;50(6):1474-1483.
High-resolution magnetic resonance imaging (MRI) at 4 Tesla depicts details of the internal structure of the hippocampus not visible at 1.5 Tesla, and so allows for in vivo parcellation of different hippocampal subfields. The aim of this study was to test if distinct subfield atrophy patterns can be detected in temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) and without (TLE-no) hippocampal sclerosis.
High-resolution T2-weighted hippocampal images were acquired in 34 controls: 15 TLE-MTS and 18 TLE-no. Entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, and CA3, and dentate (CA3&DG) volumes were determined using a manual parcellation scheme.
TLE-MTS had significantly smaller ipsilateral CA1, CA2, CA3&DG, and total hippocampal volume than controls or TLE-no. Mean ipsilateral CA1 and CA3&DG z-scores were significantly lower than ipsilateral CA2, ERC, and SUB z-scores. There were no significant differences between the various subfield or hippocampal z-scores on either the ipsi- or the contralateral side in TLE-no. Using a z-score ≤ −2.0 to identify severe volume loss, the following atrophy patterns were found in TLE-MTS: CA1 atrophy, CA3&DG atrophy, CA1 and CA3& DG atrophy, and global hippocampal atrophy. Significant subfield atrophy was found in three TLE-no: contralateral SUB atrophy, bilateral CA3&DG atrophy, and ipsilateral ERC and SUB atrophy.
Using a manual parcellation scheme on 4 Tesla high-resolution MRI, we found the characteristic ipsilateral CA1 and CA3&DG atrophy described in TLE-MTS. Seventeen percent of the TLE-no had subfield atrophy despite normal total hippocampal volume. These findings indicate that high-resolution MRI and subfield volumetry provide superior information compared to standard hippocampal volumetry.
PMCID: PMC2804395  PMID: 19400880
Hippocampus; Magnetic resonance imaging; Subfield; Atrophy; Temporal lobe epilepsy
6.  Selective Effect of Age, Apo e4, and Alzheimer’s Disease on Hippocampal Subfields 
Hippocampus  2009;19(6):558-564.
Histopathological studies and animal models suggest that different physiological and pathophysiological processes exert different subfield specific effects on the hippocampus. High-resolution images at 4T depict details of the internal structure of the hippocampus allowing for in vivo volumetry of hippocampal subfields. The aims of this study were (1) to determine patterns of hippocampal subfield volume loss due to normal aging and Apo e4 carrier state, (2) to determine subfield specific volume losses due to preclinical (MCI) and clinical Alzheimer’s disease (AD) and their modification due to age and Apo e4 carrier state. One hundred fifty seven subjects (119 cognitively healthy elderly controls, 20 MCI and 18 AD) were studied with a high resolution T2 weighted imaging sequence obtained at 4T aimed at the hippocampus. Apo e4 carrier state was known in 95 subjects (66 controls, 14 MCI, 15 AD). Subiculum (SUB), CA1, CA1–CA2 transition zone (CA1–2 transition), CA3- dentate gyrus (CA3&DG) were manually marked. Multiple linear regression analysis was used to test for effects of age, Apo e4 carrier state and effects of MCI and AD on different hippocampal subfields. Age had a significant negative effect on CA1 and CA3&DG volumes in controls (P < 0.05). AD had significantly smaller volumes of SUB, CA1, CA1–2 transition, and MCI had smaller CA1–2 transition volumes than controls (P < 0.05). Apo e4 carrier state was associated with volume loss in CA3&DG compared to non-Apo e4 carriers in healthy controls and AD. Based on these findings, we conclude that subfield volumetry provides regional selective information that allows to distinguish between different normal and pathological processes affecting the hippocampus and thus for an improved differential diagnosis of neurodegenerative diseases affecting the hippocampus.
PMCID: PMC2802542  PMID: 19405132
CA1; dentate; volumetry; neurodegeneration; MCI
7.  Patterns of Reduced Cortical Thickness in Late Life Depression and Relationship to Psychotherapeutic Response 
Cortical atrophy has been associated with late life depression (LLD) and recent findings suggest that reduced right hemisphere cortical thickness is associated with familial risk for major depressive disorder but cortical thickness abnormalities in LLD have not been explored. Further, cortical atrophy has been posited as a contributor to poor antidepressant treatment response in LLD but the impact of cortical thickness on psychotherapy response is unknown. This study was conducted to evaluate patterns of cortical thickness in LLD and in relation to psychotherapy treatment outcomes.
Participants included 22 individuals with LLD and 12 age matched comparison subjects. LLD participants completed 12 weeks of psychotherapy and treatment response was defined as a 50% reduction in depressive symptoms. All participants participated in Magnetic Resonance Imaging (MRI) of the brain and cortical mapping of grey matter tissue thickness was calculated.
LLD individuals demonstrated thinner cortex than controls prominently in the right frontal, parietal, and temporal brain regions. Eleven participants (50%) exhibited positive psychotherapy response after 12 weeks of treatment. Psychotherapy non-responders demonstrated thinner cortex in bilateral posterior cingulate and parahippocampal cortices, left paracentral, precuneus, cuneus, and insular cortices, and the right medial orbito-frontal and lateral occipital cortices relative to treatment responders.
Our findings suggest more distributed right hemisphere cortical abnormalities in LLD than have been previously reported. Additionally, our findings suggest that reduced bilateral cortical thickness may be an important phenotypic marker of individuals at higher risk for poor response to psychotherapy.
PMCID: PMC3732520  PMID: 23567394
8.  Evidence for brainstem network disruption in temporal lobe epilepsy and sudden unexplained death in epilepsy 
NeuroImage : Clinical  2014;5:208-216.
The symptoms witnessed in unexplained death in epilepsy (SUDEP) suggest a breakdown of central autonomic control. Since the brainstem plays a crucial role in autonomic control, the objectives of this study were 1. To investigate if temporal lobe epilepsy (TLE) is associated with brainstem atrophy and to characterize it using graph Analysis 2. To compare the findings with those in two probable TLESUDEP. T1 images were obtained from 17 controls, 30 TLE (16 with mesial-temporal-sclerosis (TLE-MTS) and 14 without (TLE-no)) and from 2 patients who died of SUDEP. The brainstem was extracted, warped onto a brainstem atlas and Jacobian determinants maps (JDM) calculated. SPM8 was used to compare the JDMs at the group level, z-score maps were calculated for single subject analysis. Brainstem regions encompassing autonomic structures were identified based on macroscopic landmarks and mean z-scores from 5 × 5 × 5 voxel cubes extracted to calculate a new measure called atrophy-similarity index (ASI) for graph analysis. TLE-MTS had volume loss in the dorsal mesencephalon. The SUDEP cases had severe and more extensive volume loss in the same region. Nodal degrees and participation coefficients were decreased and local efficiency increased in SUDEP compared to controls. TLE is associated with volume loss in brainstem regions involved in autonomic control. Structural damage in these regions might increase the risk for a fatal dysregulation during situations with increased demand such as following severe seizures.
Patients with temporal lobe epilepsy (TLE) were studied.Two had died of Sudden Unexplained Death in Epilepsy (TLE-SUDEP)The brainstem was studied with deformation-based morphometry and graph analysis TLE has volume loss in the dorsal mesencephalon.TLE-SUDEP have more extensive brainstem damage and evidence for network breakdown.
PMCID: PMC4110882  PMID: 25068110
Deformation based morphometry; TLEgraph analysis; autonomic control; SUDEP
9.  Grey and white matter abnormalities in temporal lobe epilepsy with and without mesial temporal sclerosis 
Journal of neurology  2013;260(9):10.1007/s00415-013-6974-3.
Temporal lobe epilepsy with (TLE-mts) and without (TLE-no) mesial temporal sclerosis display different patterns of cortical neuronal loss, suggesting that the distribution of white matter damage may also differ between the sub-groups. The purpose of this study was to examine patterns of white matter damage in TLE-mts and TLE-no and to determine if identified changes are related to neuronal loss at the presumed seizure focus. The 4 T diffusion tensor imaging (DTI) and T1-weighted data were acquired for 22 TLE-mts, 21 TLE-no and 31 healthy controls. Tract-based spatial statistics (TBSS) was used to compare fractional anisotropy (FA) maps and voxel-based morphometry (VBM) was used to identify grey matter (GM) volume atrophy. Correlation analysis was conducted between the FA maps and neuronal loss at the presumed seizure focus. In TLE-mts, reduced FA was identified in the genu, body and splenium of the corpus callosum, bilateral corona radiata, cingulum, external capsule, ipsilateral internal capsule and uncinate fasciculus. In TLE-no, FA decreases were identified in the genu, the body of the corpus callosum and ipsilateral anterior corona radiata. The FA positively correlated with ipsilateral hippocampal volume. Widespread extra-focal GM atrophy was associated with both sub-groups. Despite widespread and extensive GM atrophy displaying different anatomical patterns in both sub-groups, TLE-mts demonstrated more extensive FA abnormalities than TLE-no. The microstructural organization in the corpus callosum was related to hippocampal volume in both patients and healthy subjects demonstrating the association of these distal regions.
PMCID: PMC3845492  PMID: 23754695
Temporal lobe epilepsy; FA; DTI; TBSS; VBM; DARTEL
10.  Measuring longitudinal change in the hippocampal formation from in vivo high-resolution T2-weighted MRI 
NeuroImage  2012;60(2):1266-1279.
The hippocampal formation (HF) is a brain structure of great interest because of its central role in learning and memory, and its associated vulnerability to several neurological disorders. In vivo oblique coronal T2-weighted MRI with high in-plane resolution (~0.5 mm×0.5 mm), thick slices (~2.0 mm), and a field of view tailored to imaging the hippocampal formation (denoted HF-MRI in this paper) has been advanced as a useful imaging modality for detailed hippocampal morphometry. Cross-sectional analysis of volume measurements derived from HF-MRI has shown the modality’s promise to yield sensitive imaging-based biomarker for neurological disorders such as Alzheimer’s disease. However, the utility of this modality for making measurements of longitudinal change has not yet been demonstrated. In this paper, using an unbiased deformation-based morphometry (DBM) pipeline, we examine the suitability of HF-MRI for estimating longitudinal change by comparing atrophy rates measured in the whole hippocampus from this modality with those measured from more common isotropic (~1 mm3) T1-weighted MRI in the same set of individuals, in a cohort of healthy controls and patients with cognitive impairment. While measurements obtained from HF-MRI were largely consistent with those obtained from T1-MRI, HF-MRI yielded slightly larger group effect of greater atrophy rates in patients than in controls. The estimated minimum sample size required for detecting a 25% change in patients’ atrophy rate in the hippocampus compared to the control group with a statistical power β=0.8 was N=269. For T1-MRI, the equivalent sample size was N=325. Using a dataset of test–retest scans, we show that the measurements were free of additive bias. We also demonstrate that these results were not a confound of certain methodological choices made in the DBM pipeline to address the challenges of making longitudinal measurements from HF-MRI, using a region of interest (ROI) around the HF to globally align serial images, followed by slice-by-slice deformable registration to measure local volume change. Additionally, we present a preliminary study of atrophy rate measurements within hippocampal subfields using HF-MRI. Cross-sectional differences in atrophy rates were detected in several subfields.
PMCID: PMC3667607  PMID: 22306801
Hippocampus; Subfields; T1-weighted; T2-weighted; MRI; Longitudinal; Atrophy; MCI; Evaluation; Medial temporal lobe; Deformation-based morphometry; DBM sample size
11.  Different associations of white matter lesions with depression and cognition 
BMC Neurology  2012;12:83.
To test the hypothesis that white matter lesions (WML) are primarily associated with regional frontal cortical volumes, and to determine the mediating effects of these regional frontal cortices on the associations of WML with depressive symptoms and cognitive dysfunction.
Structural brains MRIs were performed on 161 participants: cognitively normal, cognitive impaired but not demented, and demented participants. Lobar WML volumes, regional frontal cortical volumes, depressive symptom severity, and cognitive abilities were measured. Multiple linear regression analyses were used to identify WML volume effects on frontal cortical volume. Structural equation modeling was used to determine the MRI-depression and the MRI-cognition path relationships.
WML predicted frontal cortical volume, particularly in medial orbirtofrontal cortex, irrespective of age, gender, education, and group status. WML directly predicted depressive score, and this relationship was not mediated by regional frontal cortices. In contrast, the association between WML and cognitive function was indirect and mediated by regional frontal cortices.
These findings suggest that the neurobiological mechanisms underpinning depressive symptoms and cognitive dysfunction in older adults may differ.
PMCID: PMC3482604  PMID: 22920586
Leukoaraiosis; Depression; Cognition; Frontal lobe; Mediation
12.  Patterns Of Altered Cortical Perfusion And Diminished Subcortical Integrity In Posttraumatic Stress Disorder: A MRI Study 
NeuroImage  2010;54S1:S62-S68.
Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010; 67(3):296–303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion and diffusion MRI together may provide a signature for a PTSD marker.
PMCID: PMC2945438  PMID: 20483375
13.  Insomnia severity is associated with a decreased volume of the CA3/Dentate Gyrus Hippocampal Subfield 
Biological psychiatry  2010;68(5):494-496.
Prolonged disruption of sleep in animal studies is associated with decreased neurogenesis in the dentate gyrus. Our objective was to determine if insomnia severity in a sample of PTSD and controls was associated with decreased volume in the CA3/dentate hippocampal subfield.
Volumes of hippocampal subfields in seventeen veteran males positive for PTSD (41 ±12 years) and nineteen age-matched male veterans negative for PTSD were measured using 4 Tesla MRI. Subjective sleep quality was measured by the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index (PSQI).
Higher scores on the ISI, indicating worse insomnia, were associated with smaller volumes of the CA3/dentate subfields (r= −.48, p < 0.01) in the combined sample. Adding the ISI score as a predictor for CA3/dentate volume to a hierarchical linear regression model after first controlling for age and PTSD symptoms accounted for a 13 % increase in incremental variance (t= −2.47, p= 0.02).
The findings indicate for the first time in humans that insomnia severity is associated with volume loss of the CA3/dentate subfields. This is consistent with animal studies showing that chronic sleep disruption is associated with decreased neurogenesis and dendritic branching in these structures.
PMCID: PMC2921477  PMID: 20598672
sleep; hippocampus; magnetic resonance imaging; neurogenesis; dentate gyrus; posttraumatic stress disorder
14.  Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis 
Journal of Neurology  2010;258(4):603-612.
MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE.
PMCID: PMC3065637  PMID: 20976465
Temporal lobe epilepsy; Mesial temporal sclerosis; NAA; Spectroscopy
15.  Hippocampal Atrophy Patterns in Mild Cognitive Impairment and Alzheimer’s Disease 
Human brain mapping  2010;31(9):1339-1347.
Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer’s disease (AD), and other diseases. High-resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.
Ninety-one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high-resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1–CA2 transition zone (CA1-2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited.
Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1-2, and total hippocampal volumes. MCI had smaller CA1-2 volumes. Discriminant analysis and power analysis showed that CA1-2 was superior to total hippocampal volume for distinction between controls and MCI.
The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus.
PMCID: PMC2943433  PMID: 20839293
hippocampal subfields; Alzheimer’s disease; manual parcellation; MRI
16.  BMI and Neuronal Integrity in Healthy, Cognitively Normal Elderly: A Proton Magnetic Resonance Spectroscopy Study 
Obesity (Silver Spring, Md.)  2009;18(4):743-748.
Recent studies associated excess body weight with brain structural alterations, poorer cognitive function, and lower prefrontal glucose metabolism. We found that higher BMI was related to lower concentrations of N-acetyl-aspartate (NAA, a marker of neuronal integrity) in a healthy middle-aged cohort, especially in frontal lobe. Here, we evaluated whether NAA was also associated with BMI in a healthy elderly cohort. We used 4 Tesla proton magnetic resonance spectroscopy (1H MRS) data from 23 healthy, cognitively normal elderly participants (69.4 ± 6.9 years; 12 females) and measured concentrations of NAA, glutamate (Glu, involved in cellular metabolism), choline-containing compounds (Cho, involved in membrane metabolism), and creatine (Cr, involved in high-energy metabolism) in anterior (ACC) and posterior cingulate cortices (PCC). After adjustment for age, greater BMI was related to lower NAA/Cr and NAA/Cho ratios (β < −0.56, P < 0.008) and lower Glu/Cr and Glu/Cho ratios (β < −0.46, P < 0.02) in ACC. These associations were not significant in PCC (β > −0.36, P > 0.09). The existence of an association between NAA and BMI in ACC but not in PCC is consistent with our previous study in healthy middle-aged individuals and with reports of lower frontal glucose metabolism in young healthy individuals with elevated BMI. Taken together, these results provide evidence that elevated BMI is associated with neuronal abnormalities mostly in frontal brain regions that subserve higher cognitive functions and impulse control. Future studies need to evaluate whether these metabolite abnormalities are involved in the development and maintenance of weight problems.
PMCID: PMC2847061  PMID: 19816410
17.  Magnetic Resonance Imaging of Hippocampal Subfields in Posttraumatic Stress Disorder 
Archives of general psychiatry  2010;67(3):296-303.
Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD.
To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus.
Case-control study.
A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41[12] years) and 19 age-matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community.
High-resolution magnetic resonance imaging at 4 T.
Main Outcome Measure
Volumes of hippocampal subfields.
Posttraumatic stress disorder was associated with 11.4%(1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5%(0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields.
The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures.
PMCID: PMC2848481  PMID: 20194830
18.  Reduced Extrahippocampal NAA in Mesial Temporal Lobe Epilepsy 
Epilepsia  2002;43(10):1210-1216.
Structural and metabolic abnormalities in the hippocampal region in medial temporal lobe epilepsy (mTLE) are well described; less is known about extrahippocampal changes. This study was designed to characterize extrahippocampal metabolic abnormalities in mTLE with magnetic resonance spectroscopy in combination with tissue segmentation and volumetry of gray and white matter.
Multislice magnetic resonance spectroscopic imaging (1H-MRSI) in combination with tissue segmentation was performed on 16 patients with mTLE and 12 age-matched healthy volunteers. The data were analyzed by using a regression-analysis model that estimated the metabolite concentrations in 100% cortical gray and 100% white matter in the frontal lobe and nonfrontal brain. The segmented image was used to calculate the fraction of gray and white matter in these regions.
mTLE had significantly lower N-acetyl aspartate (NAA) in ipsi- and contralateral frontal gray (p = 0.03) and in ipsi- and contralateral nonfrontal white matter (p = 0.008) compared with controls. Although there were no associated volumetric deficits in frontal gray and white matter, ipsilateral nonfrontal gray matter (p = 0.003) was significantly smaller than that in controls.
mTLE is associated with extrahippocampal metabolic abnormalities and volumetric deficits, but these do not necessarily affect the same regions.
PMCID: PMC2753247  PMID: 12366737
Epilepsy; Spectroscopy; Extrahippocampal; Volumetry
19.  Spectroscopic Metabolic Abnormalities in mTLE with and without MRI Evidence for Mesial Temporal Sclerosis Using Hippocampal Short-TE MRSI 
Epilepsia  2003;44(7):977-980.
Long echo time (TE) spectroscopy reliably identifies the epileptogenic hippocampus in mesial temporal lobe epilepsy. Short-TE spectroscopy gives additional metabolic information but may have more artifacts. The aim of this study was to test (a) lateralization of the seizure focus by short-TE spectroscopy, and (b) value of myoinositol (MI) in the identification of the epileptogenic hippocampus.
Twenty-four patients with temporal lobe epilepsy: 16 with mesial temporal sclerosis (TLE-MTS), eight patients with normal magnetic resonance imaging (MRI; TLE-No), and 16 controls were studied with hippocampal 2D short-TE magnetic resonance spectroscopic imaging (MRSI).
In TLE-MTS, the ipsilateral N-acetylaspartate (NAA) was decreased compared with contralateral (p = 0.03) or controls (p = 0.007). Additionally, the ipsilateral MI was decreased compared with controls (p = 0.012). TLE-No values showed no side differences and were not different from controls. Abnormalities in the anterior hippocampus correctly lateralized the epileptogenic hippocampus in ≤82% of TLE-MTS and in ≤80% of the TLE-No.
The accuracy of short-TE MRSI at 1.5 T for focus lateralization in mTLE is comparable to that of long-TE MRSI. MI might be helpful for focus lateralization, but more information about the factors influencing the MI concentration is needed.
PMCID: PMC2744693  PMID: 12823584
Epilepsy; Spectroscopy; Short echo time; Myoinositol
20.  Identification of the Epileptogenic Lobe in Neocortical Epilepsy with Proton MR Spectroscopic Imaging 
Epilepsia  2004;45(12):1580-1589.
The aim of this study was to evaluate the usefulness of multislice magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation for the identification of the epileptogenic focus in neocortical epilepsy (NE).
Twenty patients with NE (10 with MRI-visible malformations, 10 with normal MRI) and 19 controls were studied. In controls, N-acetylaspartate NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter, and thresholds were determined by calculating the 95% prediction intervals (PIs) for NAA/Cr and NAA/Cho. Voxels with NAA/Cr or NAA/Cho values less than the 95% PI were defined as “pathological.” Z-scores were calculated. Depending on the magnitude of those z-scores, we used two different methods (score-localization or forced-localization) to identify in a given subject the lobe with the highest percentage of pathological voxels, which was supposed to represent the epileptogenic lobe.
MRSI correctly identified the lobe containing the epileptogenic focus as defined by EEG in 65% of the NE patients. MRSI localization of the focus was correct in 70% of the patients with an MRI-visible malformation and in 60% of the patients with normal MRI. Of the patients, 15% had metabolically abnormal brain regions outside the epileptogenic lobe, and 35% of the patients had evidence for secondary hippocampal damage.
MRSI may be helpful for the identification of the epileptogenic focus in NE patients, even in NE with normal MRI.
PMCID: PMC2744685  PMID: 15571516
Neocortical epilepsy; MRS; Focus identification; Malformation
21.  Voxel-based T2 Relaxation Rate Measurements in Temporal Lobe Epilepsy (TLE) with and without Mesial Temporal Sclerosis 
Epilepsia  2007;48(2):220-228.
Quantitative measurements of T2 relaxation in the hippocampus for focus lateralization in mesial temporal lobe epilepsy (mTLE) are well established. Less is known to what degree such relaxation abnormalities also affect regions beyond the ipsilateral hippocampus. Therefore, the aim of this study was to characterize extent and distribution pattern of extrahippocampal relaxation abnormalities in TLE with (TLE-MTS) and without MRI evidence of mesial-temporal sclerosis (TLE-no).
Double spin echo images (TE1/2: 20/80 ms) acquired in 24 TLE-MTS and 18 TLE-no were used to calculate relaxation rate maps. These maps were analyzed by SPM2 and by selecting regions of interest (ROI) in the hippocampus and several extrahippocampal brain regions.
In TLE-MTS, the results of the SPM and ROI analysis were in good agreement and showed the most severe relaxation rate decreases in the ipsilateral hippocampus but also in other ipsilateral temporal regions, orbitofrontal, and parietal regions and to a lesser degree in contralateral frontal regions. The relaxation rate decreases in TLE-no were confined to small regions in the ipsilateral anterior inferior and medial temporal lobe in the SPM analysis while ROI analysis showed additional regions in the ipsilateral hippocampus, amygdala, and anterior cingulate.
TLE-MTS showed extensive, widespread but predominantly ipsilateral temporal and also extratemporal T2 relaxation rate decreases. In contrast, the findings of the SPM and ROI analyses in TLE-no suggested that if relaxation rate decreases are present, they are less uniform and generally milder than in TLE-MTS. This further supports the hypothesis that TLE-no is a distinct clinicopathological entity from TLE-MTS and probably heterogeneous in itself.
PMCID: PMC2744642  PMID: 17295614
TLE; Extratemporal; Voxel-based; Mesiotemporal sclerosis; Normal MRI; Relaxation rate
22.  Metabolic characteristics of cortical malformations causing epilepsy 
Journal of neurology  2005;252(9):1082-1092.
Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM.
Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age-matched controls. In controls, NAA, Cr, Cho, NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone.
30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr.
In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.
PMCID: PMC2709485  PMID: 15868069
cortical malformation; MR-spectroscopy; NAA; epilepsy
23.  Patterns of White Matter Atrophy in Frontotemporal Lobar Degeneration 
Archives of neurology  2007;64(11):1619-1624.
Structural magnetic resonance imaging (MRI) has been used to investigate the in vivo pathology of frontotemporal lobar degeneration. However, few neuroimaging studies have focused on white matter (WM) alterations in this disease.
To use volumetric MRI techniques to identify the patterns of WM atrophy in vivo in 2 clinical variants of frontotemporal lobar degeneration—fronto-temporal dementia (FTD) and semantic dementia—and to compare the patterns of WM atrophy with those of gray matter (GM) atrophy in these diseases.
Structural MRIs were obtained from patients with FTD (n=12) and semantic dementia (n=13) and in cognitively healthy age-matched controls (n=24). Regional GM and WM were classified automatically from high-resolution T1-, T2-, and proton density-weighted MRIs with Expectation-Maximization Segmentation and compared between the groups using a multivariate analysis of covariance model that included age and WM lesion volumes as covariates.
Patients with FTD had frontal WM atrophy and frontal, parietal, and temporal GM atrophy compared with controls, who had none. Patients with semantic dementia had temporal WM and GM atrophy and patients with FTD had frontal GM atrophy. Adding temporal WM volume to temporal GM volume significantly improved the discrimination between semantic dementia and FTD.
These results show that patients with frontotemporal lobar degeneration who are in relatively early stages of the disease (Clinical Dementia Rating score, 1.0-1.2) have WM atrophy that largely parallels the pattern of GM atrophy typically associated with these disorders.
PMCID: PMC2443735  PMID: 17998444
25.  Ways toward an early diagnosis in Alzheimer’s disease: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 
With the increasing life expectancy in developed countries, the incidence of Alzheimer’s disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non-AD dementias would not benefit from an AD-specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.
PMCID: PMC1864941  PMID: 17476317
Positron-emission tomography; Single photon emission tomography; Magnetic resonance imaging; Biochemical biomarker; Genetic biomarker

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