De fi ning the human hippocampus in cerebral magnetic resonance images — An overview of current segmentation protocols
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paper_title: Preservation of hippocampal volume throughout adulthood in healthy men and women

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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 (≥50 years) and considering menopause and hormone replacement therapy.
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paper_title: Quantitative Cerebral Anatomy in Depression: A Controlled Magnetic Resonance Imaging Study

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• Magnetic resonance imaging was used to examine cerebral anatomy in 48 inpatients with severe depression who were referred for electroconvulsive therapy and in 76 normal control subjects. The magnetic resonance imaging measures included determinations of regional cerebral volumes and ratings of the frequency and severity of cortical atrophy, lateral ventricular enlargement, and subcortical hyperintensity. The mean total frontal lobe volume was found to be 7% smaller in the inpatients with severe depression (235.88 mL) than in the normal control subjects (254.32 mL)—a difference that was statistically significant even after adjusting for the effects of age, sex, education, and intracranial size. No group differences were observed in the volumes of the cerebral hemispheres, the temporal lobes, or the amygdala-hippocampal complex, nor in the frequency of cortical atrophy. Neither did the groups differ with respect to the total volumes of the lateral and third ventricles, nor in the frequency of lateral ventricular enlargement. Patients with depression had a significantly higher frequency of subcortical hyperintensity in the periventricular white matter, with an odds ratio of 5.32.
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paper_title: Adult Hippocampal Neurogenesis, Synaptic Plasticity and Memory: Facts and Hypotheses

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The demonstration that progenitor cells in regions of the adult mammalian brain such as the dentate gyrus of the hippocampus can undergo mitosis and generate new cells that differentiate into functionally integrated neurons throughout life has marked a new era in neuroscience. In recent years, a wide range of investigations has been directed at understanding the physiological mechanisms and functional relevance of this form of brain plasticity. Our current knowledge of adult hippocampal neurogenesis indicates that the production of new cells in the brain follows a multi-step process during which newborn cells are submitted to various regulatory factors that influence cell proliferation, maturation, fate determination and survival. As details of the dynamics of morphological maturation and functional integration of newborn neurons in corticohippocampal circuits have become clearer, an increasing number of studies have examined how environmental and/or behavioural factors can modulate neurogenesis and affect hippocampal-dependent learning and memory. In this article we present an overview of recent literature that relates neurogenesis to hippocampal function on the basis of correlative studies investigating the modulation of neurogenesis by learning and behavioural experience, and the consequences of the loss of hippocampal neurogenesis for memory function. We also highlight experimental evidence that immature neurons exhibit unique electrophysiological characteristics and therefore may constitute a specific cell population particularly inclined to undergo activity-dependent plasticity. Moreover, we review recent work that reveals an unsuspected mechanistic link between synaptic plasticity and the proliferation and survival of new hippocampal neurons. From the present background of research, we argue that the incorporation of functional adult-generated neurons into existing neural networks provides a higher capacity for plasticity, which may favour the encoding and storage of certain types of memories. Depending on their birth date and maturation stage, new neurons might be implicated in the encoding/storage process of the task at hand or may help future learning experience. Finally, we highlight critical issues to be addressed in order to decipher the exact contribution of newly generated neurons to cognitive functions.
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paper_title: Segmentation of subcortical brain structures using fuzzy templates

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We propose a novel method to automatically segment subcortical structures of human brain in magnetic resonance images by using fuzzy templates. A set of fuzzy templates of the structures based on features such as intensity, spatial location, and relative spatial relationship among structures are first created from a set of training images by defining the fuzzy membership functions and by fusing the information of features. Segmentation is performed by registering the fuzzy templates of the structures on the test image and then by fusing them with the tissue maps of the test image. The final decision is taken in order to optimize the certainty in the intensity, location, relative position, and tissue content of the structure. Our method does not require specific expert definition of each structure or manual interactions during segmentation process. The technique is demonstrated with the segmentation of five structures: thalamus, putamen, caudate, hippocampus, and amygdala; the performance of the present method is comparable with previous techniques.
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paper_title: Adult hippocampal neurogenesis in depression

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The development of new treatments for depression is predicated upon identification of neural substrates and mechanisms that underlie its etiology and pathophysiology. The heterogeneity of depression indicates that its origin may lie in dysfunction of multiple brain regions. Here we evaluate adult hippocampal neurogenesis as a candidate mechanism for the etiology of depression and as a substrate for antidepressant action. Current evidence indicates that adult hippocampal neurogenesis may not be a major contributor to the development of depression, but may be required for some of the behavioral effects of antidepressants. We next revisit the functional differentiation of the hippocampus along the septo-temporal axis within the context of adult hippocampal neurogenesis and suggest that neurogenesis in the ventral dentate gyrus may be preferentially involved in regulation of emotion. Finally, we speculate on how increased adult hippocampal neurogenesis may modulate dentate gyrus function to confer the behavioral effects of antidepressants.
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paper_title: Segmentation of the hippocampus from brain MRI using deformable contours

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Abstract The application of a discrete dynamic contour model for segmentation of the hippocampus from brain MRI has been investigated. Solutions to several common problems of dynamic contours in this case and similar cases have been developed. A new method for extracting the discontinuous boundary of a structure with multiple edges near the structure has been developed. The method is based on detecting and following edges by external forces. The reliability of the final contour and the model stability have been improved by using a continuous mapping of the external energy and limiting movements of the contour. The problem of optimizing the internal force weight has been overcome by making it dependent on the amount of the external force. Finally, the results of applying the proposed algorithm, which implements the above modifications, to multiple applications have been evaluated.
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paper_title: To ignore or explore: Top--down modulation of novelty processing

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Attending to novelty is a critical element of human behavior and learning. Novel events can serve as task-irrelevant distracters or as potential sources of engagement by interesting or important aspects of one's environment. An optimally functioning brain should have the capacity to respond differentially to novel events depending on the circumstances in which they occur. In the present study, a subject-controlled variant of the visual novelty oddball paradigm was employed under two different conditions in which novel stimuli were characterized either as distracters from a main task or as potentially meaningful “invitations” to explore the environment. Differences in context, derived from varying the emphasis of task instructions, strongly modulated both the behavioral and electrophysiological response to novelty. This modulation was not observed for processing earlier than the P3 component. Subjects who encountered novel events that served as distracters limited the amount of attention and processing resources they appropriated. Remarkably, under this condition, there were no differences in overall P3 amplitude, late positive slow-wave activity, or viewing duration between rare novel and frequent standard events. In contrast, subjects who encountered novel events as potential opportunities to explore augmented the attention and processing resources directed toward these events (as reflected by a larger P3 amplitude, late positive slow-wave activity, and longer viewing durations). Our results suggest that the processing of novelty within the visual modality involves several stages, including: (1) the relatively automatic detection of unfamiliar, novel stimuli (indexed by the N2); (2) the voluntary allocation of resources determined by the broader context in which a novel event occurs (indexed by the P3); and (3) the sustained processing of novelty (indexed by late positive slow-wave activity). This study provides evidence of the brain's ability to generate differential responses to novel events according to the circumstances under which they are encountered. It also points to a greater degree of top--down modulation of the processing of novelty than has been previously emphasized. We suggest that less commonly studied variables, such as subject control, may provide additional insight into the different ways in which novelty is processed.
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paper_title: Brain Morphometric Abnormalities in Geriatric Depression: Long-Term Neurobiological Effects of Illness Duration

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OBJECTIVE: The authors’ goal was to compare regional brain volumes in depressed elderly subjects with those of nondepressed elderly subjects by using voxel-based morphometry. METHOD: They used statistical parametric mapping to analyze magnetic resonance imaging scans from 30 depressed patients 59 to 78 years old and 47 nondepressed comparison subjects 55 to 81 years old. RESULTS: Depressed patients had smaller right hippocampal volume than comparison subjects. The volume of the hippocampal-entorhinal cortex was inversely associated with the number of years since the first lifetime episode of depression. CONCLUSIONS: These data provide further evidence of structural brain abnormalities in geriatric depression, particularly in patients with a longer course of illness.
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paper_title: Hippocampal volume is as variable in young as in older adults: Implications for the notion of hippocampal atrophy in humans

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Abstract Previous studies in humans have shown the presence of an age-related reduction of hippocampal (HC) volume, as well as the presence of reduced HC volume in psychiatric populations suffering from schizophrenia, depression or post-traumatic stress disorder. Altogether, these data suggested that aging or psychiatric disease can have neurotoxic effects on the hippocampus, and lead to HC atrophy. However, these two sets of findings imply that HC volume in young healthy adults should present less variability than HC volume in older adults and psychiatric populations. In the present study, we assessed HC volume in 177 healthy men and women aged from 18 to 85 years of age. We show that the dispersion around the mean of HC volume is not different in young and older adults, so that 25% of young healthy adults present HC volume as small as the average participants aged 60 to 75 years. This shows that HC volume is as variable in young as in older adults and suggests that smaller HC volume attributed to the aging process in previous studies could in fact represent HC volume determined early in life. We also report that within similar age groups, the percentage of difference in HC volume between the individuals with the smallest HC volume (smallest quartile) and the group average is greater than the percentage of difference reported to exist between psychiatric populations and normal control in recent meta-analyses. Taken together, these results confront the notion of hippocampal atrophy in humans and raise the possibility that pre-determined inter-individual differences in HC volume in humans may determine the vulnerability for age-related cognitive impairments or psychopathology throughout the lifetime.
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paper_title: Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium

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Previous structural neuroimaging studies of bipolar disorder have reported conflicting findings in limbic structures. Medication heterogeneity of patient samples may have contributed to these inconsistencies. Using structural magnetic resonance imaging we assessed whether lithium treatment was associated with differences in amygdala and hippocampal volumes in a sample of bipolar adults. A total of 49 magnetic resonance imaging scans were collected from patients who were currently treated with or without lithium. Amygdala and hippocampal volumes were analyzed using tensor-based morphometry. Statistical between-group comparisons of deformation maps showed that patients treated with lithium exhibited significantly increased volumes of the amygdala and hippocampus compared with patients who were not taking lithium. Our findings may help to explain previous inconsistencies in the bipolar literature.
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paper_title: Neuroimaging and Early Diagnosis of Alzheimer Disease: A Look to the Future

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Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. Current consensus statements have emphasized the need for early recognition and the fact that a diagnosis of AD can be made with high accuracy by using clinical, neuropsychologic, and imaging assessments. Magnetic resonance (MR) or computed tomographic (CT) imaging is recommended for the routine evaluation of AD. Coronal MR images can be useful to document or quantify atrophy of the hippocampus and entorhinal cortex, both of which occur early in the disease process. Both volumetric and subtraction MR techniques can be used to quantify and monitor dementia progression and rates of regional atrophy. MR measures are also increasingly being used to monitor treatment effects in clinical trials of cognitive enhancers and antidementia agents. Positron emission tomography (PET) and single photon emission CT offer value in the differential diagnosis of AD from other cortical and subcortical dement...
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paper_title: Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study

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Rationale ::: The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients.
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paper_title: A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis

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Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs ( 54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the >54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35–54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.
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paper_title: Fully automatic segmentation of the hippocampus and the amygdala from MRI using hybrid prior knowledge

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The segmentation of macroscopically ill-defined and highly variable structures, such as the hippocampus Hc and the amygdala Am, from MRI requires specific constraints. Here, we describe and evaluate a hybrid segmentation method that uses knowledge derived from a probabilistic atlas and from anatomical landmarks based on stable anatomical characteristics of the structures. Combined in a previously published semi-automatic segmentation method, they lead to a fast, robust and accurate fully automatic segmentation of Hc and Am. The probabilistic atlas was built from 16 young controls and registered with the "unified segmentation" of SPM5. The algorithm was quantitatively evaluated with respect to manual segmentation on two MRI datasets: the 16 young controls, with a leave-one-out strategy, and a mixed cohort of 8 controls and 15 subjects with epilepsy with variable hippocampal sclerosis. The segmentation driven by hybrid knowledge leads to greatly improved results compared to that obtained by registration of the thresholded atlas alone: mean overlap for Hc on the 16 young controls increased from 78% to 87% (p < 0.001) and on the mixed cohort from 73% to 82% (p < 0.001) while the error on volumes decreased from 10% to 7% (p < 0.005) and from 18% to 8% (p < 0.001), respectively. Automatic results were better than the semi-automatic results: for the 16 young controls, average overlap increased from 84% to 87% (p < 0.001) for Hc and from 81% to 84% (p < 0.002) for Am, with equivalent improvements in volume error.
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paper_title: Image registration via level-set motion: Applications to atlas-based segmentation

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Image registration is an often encountered problem in various fields including medical imaging, computer vision and image processing. Numerous algorithms for registering image data have been reported in these areas. In this paper, we present a novel curve evolution approach expressed in a level-set framework to achieve image intensity morphing and a simple non-linear PDE for the corresponding coordinate registration. The key features of the intensity morphing model are that (a) it is very fast and (b) existence and uniqueness of the solution for the evolution model are established in a Sobolev space as opposed to using viscosity methods. The salient features of the coordinate registration model are its simplicity and computational efficiency. The intensity morph is easily achieved via evolving level-sets of one image into the level-sets of the other. To explicitly estimate the coordinate transformation between the images, we derive a non-linear PDE-based motion model which can be solved very efficiently. We demonstrate the performance of our algorithm on a variety of images including synthetic and real data. As an application of the PDE-based motion model, atlas based segmentation of hippocampal shape from several MR brain scans is depicted. In each of these experiments, automated hippocampal shape recovery results are validated via manual "expert" segmentations.
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paper_title: Amygdala and Hippocampal Volumes in Familial Early Onset Major Depressive Disorder

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Background Abnormalities in the amygdala and hippocampus have been implicated in the pathogenesis of major depressive disorder (MDD). To our knowledge, no prior study has examined amygdala-hippocampus anatomy in pediatric patients with familial MDD (at least one first degree relative with MDD). Methods Thirty-two psychotropic-naive patients with familial MDD, aged 8–21 years (12 males and 20 females), and 35 group-matched healthy participants (13 males and 22 females) underwent volumetric magnetic resonance imaging in order to evaluate hippocampal and amygdala volumes. Results Patients with familial MDD had significantly smaller left hippocampal (p = .007, effect size [d] = .44) and right hippocampal volumes (p = .025, d = .33) than controls. No differences were noted in amygdala volumes between groups (right: p > .05, left: p > .05). No correlations between hippocampal or amygdala volumes and demographic or clinical variables were noted. Conclusions Reduced hippocampal volume may be suggestive of a risk factor for developing MDD.
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paper_title: Development and preliminary psychometric properties of an instrument for the measurement of childhood trauma: The early trauma inventory

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Research on the effects of childhood trauma has been limited by the lack of a comprehensive, reliable, and valid instrument that assesses the occurrence of early traumatic experiences. This paper presents the development and preliminary psychometric properties of an instrument, the Early Trauma Inventory (ETI), for the assessment of reported childhood trauma. The clinician-administered ETI is a 56-item interview for the assessment of physical, emotional, and sexual abuse, as well as general traumatic experience (including items which range from parental loss to natural disaster). For each item of the ETI, frequency of abuse/trauma by developmental stage, onset and termination of abuse/trauma, perpetrator of the abuse/trauma, and impact on the individual are assessed. Initial analyses indicate acceptable inter-rater reliability, test-retest reliability, and internal consistency for the ETI. Comparisons between the ETI and other instruments for the assessment of trauma, as well as instruments for the measurement of symptoms related to abuse, such as dissociation and PTSD, demonstrated good convergent validity. Validity was also demonstrated based on the ability of the ETI to discriminate patients with PTSD from comparison subjects. Based on these findings, the ETI appears to be a reliable and valid instrument for the measurement of reported childhood trauma. Depression and Anxiety 12:1‐12, 2000. © 2000 Wiley-Liss, Inc.
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paper_title: A Volumetric Study of Hippocampus and Amygdala in Depressed Patients With Subjective Memory Problems

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MRI was used to measure amygdalar and hippocampal volumes in 14 nondemented depressed patients who persistently complained of “memory” difficulties and in 14 control subjects. Mild neuropsychological impairment had been detected in 5 patients before the study but had later improved. The volume of the left amygdala was smaller in depressed subjects, and there was a trend for smaller left hippocampus in the 5 patients who had exhibited mild cognitive impairment. The authors conclude that subjective memory complaints in depressed patients do not translate into a clinical picture of dementia, but that abnormalities in the amygdala and hippocampus may be relevant in explaining affective and cognitive symptoms.
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paper_title: Automatic calculation of hippocampal atrophy rates using a hippocampal template and the boundary shift integral

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We describe a method of automatically calculating hippocampal atrophy rates on T1-weighted MR images without manual delineation of hippocampi. This method was applied to a group of Alzheimer's disease (AD) (n = 36) and control (n = 19) subjects and compared with manual methods (manual segmentation of baseline and repeat-image hippocampi) and semi-automated methods (manual segmentation of baseline hippocampi only). In controls, mean (S.D.) atrophy rates for manual, semi-automated, and automated methods were 18.1 (53.5), 15.3 (50.2) and 11.3 (50.4) mm(3) loss per year, respectively. In AD patients these rates were 174.6 (106.5) 159.4 (101.2) and 172.1 (123.1) mm 3 loss per year, respectively. The automated method was a significant predictor of disease (p=0.001) and gave similar group discrimination compared with both semi-automated and manual methods. The automated hippocampal analysis in this small study took approximately 20min per hippocampal pair on a 3.4GHz Intel Xeon server, whereas manual delineation of each hippocampal pair took approximately 90 min of operator-intensive labour. This method may be useful diagnostically or in studies where analysis of many scans may be required. (c) 2006 Elsevier Inc. All rights reserved.
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paper_title: Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study

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Abstract Background: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. Methods: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. Results: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. Conclusions: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.
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paper_title: Atlas-based hippocampus segmentation in Alzheimer’s disease and mild cognitive impairment

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This study assesses the performance of public-domain automated methodologies for MRI-based segmentation of the hippocampus in elderly subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Structural MR images of 54 age- and gender-matched healthy elderly individuals, subjects with probable AD, and subjects with MCI were collected at the University of Pittsburgh Alzheimer's Disease Research Center. Hippocampi in subject images were automatically segmented by using AIR, SPM, FLIRT, and the fully deformable method of Chen to align the images to the Harvard atlas, MNI atlas, and randomly selected, manually labeled subject images ( cohort atlases ). Mixed-effects statistical models analyzed the effects of side of the brain, disease state, registration method, choice of atlas, and manual tracing protocol on the spatial overlap between automated segmentations and expert manual segmentations. Registration methods that produced higher degrees of geometric deformation produced automated segmentations with higher agreement with manual segmentations. Side of the brain, presence of AD, choice of reference image, and manual tracing protocol were also significant factors contributing to automated segmentation performance. Fully automated techniques can be competitive with human raters on this difficult segmentation task, but a rigorous statistical analysis shows that a variety of methodological factors must be carefully considered to insure that automated methods perform well in practice. The use of fully deformable registration methods, cohort atlases, and user-defined manual tracings are recommended for highest performance in fully automated hippocampus segmentation.
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paper_title: High-Dimensional Mapping of the Hippocampus in Depression

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OBJECTIVE: Abnormalities of the hippocampus may play a role in the pathophysiology of depression, but efforts to identify a structural abnormality in this brain structure among depressed patients have produced mixed results. Previous research may have been limited by exclusive reliance on measures of hippocampal volume. High-dimensional brain mapping is a new analytic method that quantitatively characterizes the shape as well as volume of a brain structure. In this study, high-dimensional brain mapping was used to evaluate hippocampal shape and volume in patients with major depressive disorder and healthy comparison subjects. METHOD: By using magnetic resonance imaging, brain scans were obtained from 27 patients with major depressive disorder and 42 healthy comparison subjects. High-dimensional brain mapping generated a series of 10 variables (components) that represented hippocampal shape, and hippocampal volumes were also computed. Analysis of variance techniques were used to compare depressed patients ...
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paper_title: Expert knowledge-guided segmentation system for brain MRI.

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We describe an automated 3-D segmentation system for in vivo brain magnetic resonance images (MRI). Our segmentation method combines a variety of filtering, segmentation, and registration techniques and makes maximum use of the available a priori biomedical expertise, both in an implicit and an explicit form. We approach the issue of boundary finding as a process of fitting a group of deformable templates (simplex mesh surfaces) to the contours of the target structures. These templates evolve in parallel, supervised by a series of rules derived from analyzing the template's dynamics and from medical experience. The templates are also constrained by knowledge on the expected textural and shape properties of the target structures. We apply our system to segment four brain structures (corpus callosum, ventricles, hippocampus, and caudate nuclei) and discuss its robustness to imaging characteristics and acquisition noise.
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paper_title: Preservation of limbic and paralimbic structures in aging

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Patterns of gray matter (GM) loss were measured in 223 healthy subjects spanning eight decades. We observed significant clusters of accelerated loss in focal regions of the frontal and parietal cortices, including the dorsolateral frontal cortex, pre- and postcentral gyrus, and the inferior and superior parietal lobes. The rate of loss in these clusters was approximately twice that of the global average. By contrast, clusters of significant GM preservation were found in limbic and paralimbic structures, including the amygdala, hippocampus, thalamus, and the cingulate gyrus. In these clusters, GM loss was attenuated significantly relative to the global rate. The preservation of these structures is consistent with the functional importance of the thalamo-limbic circuits in sensory integration, arousal, emotion, and mem- ory, and lends credence to the idea that later-maturing cortical regions are more vulnerable to age-related morphologic changes. Moreover, the limbic findings act as a frame of reference to explore further the effects of stress and learning on these structures in an evidence-based manner across age. Hum Brain Mapp 25:391- 401, 2005. © 2005 Wiley-Liss, Inc.
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paper_title: Registration and Machine Learning Based Automated Segmentation of Subcortical and Cerebellar Brain Structures

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Abstract The large amount of imaging data collected in several ongoing multi-center studies requires automated methods to delineate brain structures of interest. We have previously reported on using artificial neural networks (ANN) to define subcortical brain structures. Here we present several automated segmentation methods using multidimensional registration. A direct comparison between template, probability, artificial neural network (ANN) and support vector machine (SVM)-based automated segmentation methods is presented. Three metrics for each segmentation method are reported in the delineation of subcortical and cerebellar brain regions. Results show that the machine learning methods outperform the template and probability-based methods. Utilization of these automated segmentation methods may be as reliable as manual raters and require no rater intervention.
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paper_title: Automatic anatomical brain MRI segmentation combining label propagation and decision fusion.

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Abstract Regions in three-dimensional magnetic resonance (MR) brain images can be classified using protocols for manually segmenting and labeling structures. For large cohorts, time and expertise requirements make this approach impractical. To achieve automation, an individual segmentation can be propagated to another individual using an anatomical correspondence estimate relating the atlas image to the target image. The accuracy of the resulting target labeling has been limited but can potentially be improved by combining multiple segmentations using decision fusion. We studied segmentation propagation and decision fusion on 30 normal brain MR images, which had been manually segmented into 67 structures. Correspondence estimates were established by nonrigid registration using free-form deformations. Both direct label propagation and an indirect approach were tested. Individual propagations showed an average similarity index (SI) of 0.754 ± 0.016 against manual segmentations. Decision fusion using 29 input segmentations increased SI to 0.836 ± 0.009. For indirect propagation of a single source via 27 intermediate images, SI was 0.779 ± 0.013. We also studied the effect of the decision fusion procedure using a numerical simulation with synthetic input data. The results helped to formulate a model that predicts the quality improvement of fused brain segmentations based on the number of individual propagated segmentations combined. We demonstrate a practicable procedure that exceeds the accuracy of previous automatic methods and can compete with manual delineations.
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paper_title: Hippocampal shape deformity analysis in obsessive–compulsive disorder

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Abnormalities of orbital prefrontal cortex and caudate nuclei have, thus far, been the main findings regarding the pathophysiology of obsessive–compulsive disorder (OCD). On the other hand, neuroimaging studies have failed to reach a consensus with regard to the issue of hippocampal abnormalities in OCD patients. Shape analysis may facilitate a resolution of the discordance among these former studies by detecting local structural changes, thus enhancing power to discriminate structural differences. It has been suggested that neural circuitry interconnecting brain areas may critically influence the shape of neuroanatomical structures, serving as a rationale for better sensitivity of shape analysis compared to volume analysis, especially in detecting abnormalities of neural circuitry. Shape analysis of the hippocampus was performed in 22 matched pairs of OCD patients and normal control subjects. As a result, we observed a bilateral hippocampal shape deformity including the most prominent characteristic of downward displacement of the head. The hippocampal structural alteration observed in this study indicates that this structure may play a role in the pathophysiology of OCD. Also, further considering the hippocampal neural connections specific to its surface topography, these surface deformities may reflect developmental alterations in these patients with regard to the neural circuitry involving hippocampus.
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paper_title: Hippocampal atrophy in recurrent major depression.

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Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders

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Magnetic resonance imaging (MRI) has opened a new window to the brain. Measuring hippocampal volume with MRI has provided important information about several neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. Smaller hippocampal volumes have been reported in epilepsy, Alzheimer's disease, dementia, mild cognitive impairment, the aged, traumatic brain injury, cardiac arrest, Parkinson's disease, Huntington's disease, Cushing's disease, herpes simplex encephalitis, Turner's syndrome, Down's syndrome, survivors of low birth weight, schizophrenia, major depression, posttraumatic stress disorder, chronic alcoholism, borderline personality disorder, obsessive–compulsive disorder, and antisocial personality disorder. Significantly larger hippocampal volumes have been correlated with autism and children with fragile X syndrome. Preservation of hippocampal volume has been reported in congenital hyperplasia, children with fetal alcohol syndrome, anorexia nervosa, attention-deficit and hyperactivity disorder, bipolar disorder, and panic disorder. Possible mechanisms of hippocampal volume loss in neuropsychiatric disorders are discussed.
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paper_title: Hippocampal volume in early onset depression

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BackgroundAbnormalities in limbic structures have been implicated in major depressive disorder (MDD). Although MDD is as common in adolescence as in adulthood, few studies have examined youth near illness onset in order to determine the possible influence of atypical development on the pathophysiology of this disorder.MethodsHippocampal volumes were measured in 17 MDD subjects (age = 16.67 ± 1.83 years [mean ± SD]; range = 13 – 18 years) and 17 age- and sex-matched healthy controls (16.23 ± 1.61 years [mean ± SD]; 13 – 18 years) using magnetic resonance imaging (MRI).ResultsAn analysis of covariance revealed a significant difference between MDD and control subjects (F = 8.66, df = 1, 29, P = 0.006). This was more strongly localized to the left hippocampus (P = 0.001) than the right hippocampus (P = 0.047).ConclusionsOur findings provide new evidence of abnormalities in the hippocampus in early onset depression. However, our results should be considered preliminary given the small sample size studied.
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paper_title: Hippocampus segmentation in MR images using atlas registration, voxel classification, and graph cuts

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Abstract Since hippocampal volume has been found to be an early biomarker for Alzheimer's disease, there is large interest in automated methods to accurately, robustly, and reproducibly extract the hippocampus from MRI data. In this work we present a segmentation method based on the minimization of an energy functional with intensity and prior terms, which are derived from manually labelled training images. The intensity energy is based on a statistical intensity model that is learned from the training images. The prior energy consists of a spatial and regularity term. The spatial prior is obtained from a probabilistic atlas created by registering the training images to the unlabelled target image, and deforming and averaging the training labels. The regularity prior energy encourages smooth segmentations. The resulting energy functional is globally minimized using graph cuts. The method was evaluated using image data from a population-based study on diseases among the elderly. Two set of images were used: a small set of 20 manually labelled MR images and a larger set of 498 images, for which manual volume measurements were available, but no segmentations. This data was previously used in a volumetry study that found significant associations between hippocampal volume and cognitive decline and incidence of dementia. Cross-validation experiments with the labelled set showed similarity indices of 0.852 and 0.864 and mean surface distances of 0.40 and 0.36 mm for the left and right hippocampus. 83% of the automated segmentations of the large set were rated as ‘good’ by a trained observer. Also, the proposed method was used to repeat the manual hippocampal volumetry study. The automatically obtained hippocampal volumes showed significant associations with cognitive decline and dementia, similar to the manually measured volumes. Finally, direct quantitative and qualitative comparisons showed that the proposed method outperforms a multi-atlas based segmentation method.
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paper_title: A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging.

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OBJECTIVE ::: To investigate the effect of age on global and regional brain volumes and rates of atrophy, and to compare directly results based on cross-sectional and longitudinal data. ::: ::: ::: METHODS ::: Thirty-nine healthy control subjects (age range, 31-84 years) underwent serial magnetic resonance imaging assessments. Measurements included the whole-brain, temporal lobe, hippocampal, and ventricular volumes at baseline and for repeat scans. ::: ::: ::: RESULTS ::: We found significant decreases in cross-sectional whole-brain (P<.001), temporal lobe (P<.001), and hippocampal (P =.003) volumes and a significant increase in ventricular volume (P<.001) with increasing age. Cross-sectional and longitudinal estimates of atrophy rates were similar. We also found directional evidence of acceleration in atrophy rates with increasing age in all analyses, with the most marked changes occurring after 70 years of age. This increase in rates after 70 years of age was particularly marked in the ventricles (P<.001) and the hippocampi (P =.01). ::: ::: ::: CONCLUSIONS ::: We found a significant age-associated decrease in global and regional brain volumes. Some evidence indicates that this decline in brain volumes may be due to a nonlinear acceleration in rates of atrophy with increasing age. A better understanding of this process may help to discriminate normal age-related changes from neurodegenerative diseases.
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paper_title: Measuring Size and Shape of the Hippocampus in MR Images Using a Deformable Shape Model

paper_content:

A method for segmentation and quantification of the shape and size of the hippocampus is proposed, based on an automated image analysis algorithm. The algorithm uses a deformable shape model to locate the hippocampus in magnetic resonance images and to determine a geometric representation of its boundary. The deformable model combines three types of information. First, it employs information about the geometric properties of the hippocampal boundary, from a local and relatively finer scale to a more global and relatively coarser scale. Second, the model includes a statistical characterization of normal shape variation across individuals, serving as prior knowledge to the algorithm. Third, the algorithm utilizes a number of manually defined boundary points, which can help guide the model deformation to the appropriate boundaries, wherever these boundaries are weak or not clearly defined in MR images. Excellent agreement is demonstrated between the algorithm and manual segmentations by well-trained raters, with a correlation coefficient equal to 0.97 and algorithm/rater differences statistically equivalent to interrater differences for manual definitions.
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paper_title: An update on regional brain volume differences associated with mood disorders.

paper_content:

Purpose of reviewStructural brain changes are apparent in some magnetic resonance imaging studies of patients with mood disorders, but results are inconsistent. The focus of this review is to examine whether there are demographic or clinical characteristics of people with mood disorders that are ass
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paper_title: Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder.

paper_content:

OBJECTIVE: Ventriculomegaly has been reported in bipolar disorder, although whether it occurs at illness onset or progresses during the course of the disorder is unknown. In addition, it is unknown whether ventriculomegaly in bipolar disorder reflects acquired volume loss or underdevelopment of periventricular structures. METHOD: Magnetic resonance imaging was used to measure the volumes of the lateral and third ventricles and periventricular structures (caudate, putamen, thalamus, hippocampus). Patients with DSM-IV bipolar disorder, 18 who were having a first episode and 17 with multiple episodes, were compared with 32 healthy subjects. RESULTS: The lateral ventricles were significantly larger in the patients with multiple-episode bipolar disorder than in the first-episode patients or the healthy subjects, even after periventricular and total cerebral volumes were taken into account. Having larger lateral ventricles was associated with a higher number of prior manic episodes. The multiple-episode patient...
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paper_title: Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory

paper_content:

We review lesion and neuroimaging evidence on the role of the hippocampus, and other structures, in retention and retrieval of recent and remote memories. We examine episodic, semantic and spatial memory, and show that important distinctions exist among different types of these memories and the structures that mediate them. We argue that retention and retrieval of detailed, vivid autobiographical memories depend on the hippocampal system no matter how long ago they were acquired. Semantic memories, on the other hand, benefit from hippocampal contribution for some time before they can be retrieved independently of the hippocampus. Even semantic memories, however, can have episodic elements associated with them that continue to depend on the hippocampus. Likewise, we distinguish between experientially detailed spatial memories (akin to episodic memory) and more schematic memories (akin to semantic memory) that are sufficient for navigation but not for re-experiencing the environment in which they were acquired. Like their episodic and semantic counterparts, the former type of spatial memory is dependent on the hippocampus no matter how long ago it was acquired, whereas the latter can survive independently of the hippocampus and is represented in extra-hippocampal structures. In short, the evidence reviewed suggests strongly that the function of the hippocampus (and possibly that of related limbic structures) is to help encode, retain, and retrieve experiences, no matter how long ago the events comprising the experience occurred, and no matter whether the memories are episodic or spatial. We conclude that the evidence favours a multiple trace theory (MTT) of memory over two other models: (1) traditional consolidation models which posit that the hippocampus is a time-limited memory structure for all forms of memory; and (2) versions of cognitive map theory which posit that the hippocampus is needed for representing all forms of allocentric space in memory.
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paper_title: Brain volume in first-episode schizophrenia: Systematic review and meta-analysis of magnetic resonance imaging studies

paper_content:

Background Studies of people with schizophrenia assessed using magnetic resonance imaging (MRI) usually include patients with first-episode and chronic disease, yet brain abnormalities may be limited to those with chronic schizophrenia. ::: ::: Aims To determine whether patients with a first episode of schizophrenia have characteristic brain abnormalities. ::: ::: Method Systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls. ::: ::: Results A total of 52 cross-sectional studies included 1424 patients with a first psychotic episode; 16 longitudinal studies included 465 such patients. Meta-analysis suggests that whole brain and hippocampal volume are reduced (both P <0.0001) and that ventricular volume is increased ( P <0.0001) in these patients relative to healthy controls. ::: ::: Conclusions Average volumetric changes are close to the limit of detection by MRI methods. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.
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paper_title: Computer-assisted enhanced volumetric segmentation magnetic resonance imaging data using a mixture of artificial neural networks.

paper_content:

An accurate computer-assisted method able to perform regional segmentation on 3D single modality images and measure its volume is designed using a mixture of unsupervised and supervised artificial neural networks. Firstly, an unsupervised artificial neural network is used to estimate representative textures that appear in the images. The region of interest of the resultant images is selected by means of a multi-layer perceptron after a training using a single sample slice, which contains a central portion of the 3D region of interest. The method was applied to magnetic resonance imaging data collected from an experimental acute inflammatory model (T(2) weighted) and from a clinical study of human Alzheimer's disease (T(1) weighted) to evaluate the proposed method. In the first case, a high correlation and parallelism was registered between the volumetric measurements, of the injured and healthy tissue, by the proposed method with respect to the manual measurements (r = 0.82 and p < 0.05) and to the histopathological studies (r = 0.87 and p < 0.05). The method was also applied to the clinical studies, and similar results were derived of the manual and semi-automatic volumetric measurement of both hippocampus and the corpus callosum (0.95 and 0.88).
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paper_title: Depression Duration But Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression

paper_content:

This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss.
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paper_title: Brain Anatomical Structure Segmentation by Hybrid Discriminative/Generative Models

paper_content:

In this paper, a hybrid discriminative/generative model for brain anatomical structure segmentation is proposed. The learning aspect of the approach is emphasized. In the discriminative appearance models, various cues such as intensity and curvatures are combined to locally capture the complex appearances of different anatomical structures. A probabilistic boosting tree (PBT) framework is adopted to learn multiclass discriminative models that combine hundreds of features across different scales. On the generative model side, both global and local shape models are used to capture the shape information about each anatomical structure. The parameters to combine the discriminative appearance and generative shape models are also automatically learned. Thus, low-level and high-level information is learned and integrated in a hybrid model. Segmentations are obtained by minimizing an energy function associated with the proposed hybrid model. Finally, a grid-face structure is designed to explicitly represent the 3-D region topology. This representation handles an arbitrary number of regions and facilitates fast surface evolution. Our system was trained and tested on a set of 3-D magnetic resonance imaging (MRI) volumes and the results obtained are encouraging.
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paper_title: Reduced hippocampal volume in drug-free depressed patients

paper_content:

A number of studies have used magnetic resonance imaging to examine the volumetric differences in temporal lobe structures especially the hippocampus in patients suffering from major depressive disorder (MDD). Although some studies reported lower hippocampal volume, others did not. It is proposed that the inconsistency among studies may be due to the heterogeneity of patients and antidepressant treatment during scanning. In this study, we aimed to evaluate the hippocampus in drug-free patients. Twenty-four patients (6 males and 18 females) diagnosed as having MDD according to the DSM-IV criteria and 24 healthy controls (6 males and 18 females) were included in the study. Eleven of the patients had their first mood episode and were drug-naive. Other patients were drug-free for at least 4 weeks. The Hamilton depression rating scale (HAM-D) assessed the severity of depression. Magnetic resonance imaging was performed on a 1.5-T MR unit. The Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal volume. The data were evaluated by a repeated measure of ANOVA and the intracranial volume was taken as a covariate. A significant hippocampal volume difference was observed between the patients and healthy controls (F=4.43, df=1.45, P 0.05). The left hippocampus of patients was significantly lower than those of controls (t=1.98, df=46, P<0.05). Correlation analysis showed a correlation between HAM-D scores and the right hippocampal volume. The results of this study indicate that hippocampus volume is reduced in depressed patients especially in the left side. This finding in the drug-free depressed outpatients without a history of alcohol dependence supports previous studies that have reported lower hippocampal volume.
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paper_title: MR-based automatic delineation of volumes of interest in human brain PET images using probability maps

paper_content:

The purpose of this study was to develop and validate an observer-independent approach for automatic generation of volume-of-interest (VOI) brain templates to be used in emission tomography studies of the brain. The method utilizes a VOI probability map created on the basis of a database of several subjects' MR-images, where VOI sets have been defined manually. High-resolution structural MR-images and 5-HT2A receptor binding PET-images (in terms of 18F-altanserin binding) from 10 healthy volunteers and 10 patients with mild cognitive impairment were included for the analysis. A template including 35 VOIs was manually delineated on the subjects' MR images. Through a warping algorithm template VOI sets defined from each individual were transferred to the other subjects MR-images and the voxel overlap was compared to the VOI set specifically drawn for that particular individual. Comparisons were also made for the VOI templates 5-HT2A receptor binding values. It was shown that when the generated VOI set is based on more than one template VOI set, delineation of VOIs is better reproduced and shows less variation as compared both to transfer of a single set of template VOIs as well as manual delineation of the VOI set. The approach was also shown to work equally well in individuals with pronounced cerebral atrophy. Probability-map-based automatic delineation of VOIs is a fast, objective, reproducible, and safe way to assess regional brain values from PET or SPECT scans. In addition, the method applies well in elderly subjects, even in the presence of pronounced cerebral atrophy.
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paper_title: Limbic system mechanisms of stress regulation: Hypothalamo-pituitary-adrenocortical axis

paper_content:

Limbic dysfunction and hypothalamo-pituitary-adrenocortical (HPA) axis dysregulation are key features of affective disorders. The following review summarizes our current understanding of the relationship between limbic structures and control of ACTH and glucocorticoid release, focusing on the hippocampus, medial prefrontal cortex and amygdala. In general, the hippocampus and anterior cingulate/prelimbic cortex inhibit stress-induced HPA activation, whereas the amygdala and perhaps the infralimbic cortex may enhance glucocorticoid secretion. Several characteristics of limbic–HPA interaction are notable: first, in all cases, the role of given limbic structures is both region- and stimulus-specific. Second, limbic sites have minimal direct projections to HPA effector neurons of the paraventricular nucleus (PVN); hippocampal, cortical and amygdalar efferents apparently relay with neurons in the bed nucleus of the stria terminalis, hypothalamus and brainstem to access corticotropin releasing hormone neurons. Third, hippocampal, cortical and amygdalar projection pathways show extensive overlap in regions such as the bed nucleus of the stria terminalis, hypothalamus and perhaps brainstem, implying that limbic information may be integrated at subcortical relay sites prior to accessing the PVN. Fourth, these limbic sites also show divergent projections, with the various structures having distinct subcortical targets. Finally, all regions express both glucocorticoid and mineralocorticoid receptors, allowing for glucocorticoid modulation of limbic signaling patterns. Overall, the influence of the limbic system on the HPA axis is likely the end result of the overall patterning of responses to given stimuli and glucocorticoids, with the magnitude of the secretory response determined with respect to the relative contributions of the various structures.
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paper_title: The hippocampus and depression1

paper_content:

Abstract The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies using 3-dimensional magnetic resonance imaging (MRI) volumetric measurement have reported decreases in hippocampal volume among depressed subjects compared with controls, whereas other studies have not found any volume loss. Differences among studies have been discussed. In some studies, the volume loss appears to have functional significance including an association with memory loss. Furthermore, we have found a trend towards loss of 5-HT 2A receptors in the hippocampus using positron emission tomography (PET) to detect regional changes in 〚 18 F〛altanserin binding. Functional imaging extends the sensitivity and specificity of structural imaging and will lead to a better understanding of affective disorders.
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paper_title: MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed

paper_content:

The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.
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paper_title: A Hierarchical Algorithm for MR Brain Image Parcellation

paper_content:

We introduce an algorithm for segmenting brain magnetic resonance (MR) images into anatomical compartments such as the major tissue classes and neuro-anatomical structures of the gray matter. The algorithm is guided by prior information represented within a tree structure. The tree mirrors the hierarchy of anatomical structures and the subtrees correspond to limited segmentation problems. The solution to each problem is estimated via a conventional classifier. Our algorithm can be adapted to a wide range of segmentation problems by modifying the tree structure or replacing the classifier. We evaluate the performance of our new segmentation approach by revisiting a previously published statistical group comparison between first-episode schizophrenia patients, first-episode affective psychosis patients, and comparison subjects. The original study is based on 50 MR volumes in which an expert identified the brain tissue classes as well as the superior temporal gyrus, amygdala, and hippocampus. We generate analogous segmentations using our new method and repeat the statistical group comparison. The results of our analysis are similar to the original findings, except for one structure (the left superior temporal gyrus) in which a trend-level statistical significance (p = 0.07) was observed instead of statistical significance.
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paper_title: Hippocampal Volume and Depression: A Meta-Analysis of MRI Studies

paper_content:

Objective: Several studies have found reduced hippocampal volume in patients with unipolar depression, but discrepancies exist. The authors performed a systematic review and meta-analysis of volumetric studies of the hippocampus in patients with mood disorders. Method: Studies of hippocampal volume in unipolar and bipolar patients were identified. A meta-analysis of the 12 studies of unipolar depression fulfilling specific criteria was performed. The sample comprised 351 patients and 279 healthy subjects. Results: The studies were highly heterogeneous regarding age and gender distribution, age at onset of the disorder, average number of episodes, and responsiveness to treatment, but the pooled effect size of depression was significant in both hemispheres for the unipolar patients. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side. The causes of the heterogeneity were analyzed, and a meta-regression showed that the total number of depressive episodes was significantly correlated to right but not left hippocampal volume reduction. Conclusions: Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder. Bipolar patients did not seem to show a reduction in hippocampal volume, but this has been much less investigated.
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paper_title: Detection and mapping of hippocampal abnormalities in autism

paper_content:

Abstract Brain imaging studies of the hippocampus in autism have yielded inconsistent results. In this study, a computational mapping strategy was used to examine the three-dimensional profile of hippocampal abnormalities in autism. Twenty-one males with autism (age: 9.5 ± 3.3 years) and 24 male controls (age: 10.3 ± 2.4 years) underwent a volumetric magnetic resonance imaging scan at 3 Tesla. The hippocampus was delineated, using an anatomical protocol, and hippocampal volumes were compared between the two groups. Hippocampal traces were also converted into three-dimensional parametric surface meshes, and statistical brain maps were created to visualize morphological differences in the shape and thickness of the hippocampus between groups. Parametric surface meshes and shape analysis revealed subtle differences between patients and controls, particularly in the right posterior hippocampus. These deficits were significant even though the groups did not differ significantly with traditional measures of hippocampal volume. These results suggest that autism may be associated with subtle regional reductions in the size of the hippocampus. The increased statistical and spatial power of computational mapping methods provided the ability to detect these differences, which were not found with traditional volumetric methods.
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paper_title: Hippocampus Shape Analysis and Late-Life Depression

paper_content:

Major depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F(1,103) = 5.26; p = 0.0240) but not right hippocampus volume (F(1,103) = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.
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paper_title: Deconstructing Psychosis With Human Brain Imaging

paper_content:

This review synthesizes our current knowledge on the neurobiology of psychosis from an array of in vivo brain-imaging studies. The evidence base consists of hundreds of studies of patients with schizophrenia and fewer on bipolar disorder but rarely providing direct comparisons between the disorders or integration across methods. Replicated findings in schizophrenia include reduced whole-brain and hippocampal volume as potential vulnerability markers, with further progression at onset; reduced N-acetyl aspartate concentrations in hippocampus and prefrontal cortex; striatal dopamine D2 receptors upregulation; and alteration in the relation between frontal and temporal activation. These findings are not attributable to medication effects but are of unclear specificity and may apply across the psychosis spectrum. There are consistently replicated associations of psychotic symptoms and cognitive impairment in both structural and functional imaging in schizophrenia but not, as yet, in bipolar disorder. Therefore, it would be premature to dispense with current diagnostic categories because direct comparisons among them are rare, insufficient studies have examined longitudinal changes, and long-term imaging outcome studies in first-episode psychosis have not yet been done. To address these issues and make neuroimaging “clinically relevant,” investigators will need to standardize their approaches to data acquisition and analysis, and construct the necessary range of “human brain maps,” to implement studies that are sufficiently powered to provide reliable data pertinent to deconstructing psychosis.
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paper_title: Differentiating hippocampal subregions by means of quantitative magnetization transfer and relaxometry: preliminary results

paper_content:

The hippocampal formation (HF) of healthy control subjects and schizophrenic patients was examined using an MRI experiment that implements sequences for relaxometry and magnetization transfer (MT) quantification. In addition to the semi-quantitative magnetization transfer ratio (MTR), all of the observable properties of the binary spin bath model were included. The study demonstrates that, in contrast to the MTR, quantitative MT parameters (especially the T2 relaxation time of restricted protons, T2b) are capable to differentiate functionally significant subregions within the HF. The MT methodology appears to be a promising new tool for the differential microstructural evaluation of the HF in neuropsychiatric disorders accompanied by memory disturbances.
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paper_title: Spatial representation and the architecture of the entorhinal cortex

paper_content:

It has recently been recognized that the entorhinal cortex has a crucial role in spatial representation and navigation. How the position of an animal is computed within the entorhinal circuitry remains to be determined, but the architectural organization of this brain area might provide some clues. Here, we review three organizational principles – recurrent connectivity, interlaminar connectivity and modular organization – and propose how each of them might contribute to the emergence and maintenance of positional representations in entorhinal neural networks.
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paper_title: The Human Hippocampus: Functional Anatomy, Vascularization and Serial Sections with MRI

paper_content:

Introduction.- Material and Methods.- Structure, Functions, and Connections: Preliminary Remarks.- Structure.- Cornu Ammonis (Hippocampus Proper).- Gyrus Dentatus (Fascia Dentata, Gyrus Involutus).- Structures Joined to the Hippocampus.- Functions and Connections.- Learning and Memory.- Emotional Behavior.-Motor Control.- Hypothalamus.- Comparative Studies.- Anatomy: Preliminary Remarks.- Hippocampal Body.- Intraventricular Part.- Extraventricular or Superficial Part.- Relations with Adjacent Structures.- Hippocampal Head.- Intraventricular Part.-Extraventricular or Uncal Part.- Relations of the Uncus with Adjacent Structures.- Hippocampal Tail.- Intraventricular Part.-Extraventricular Part.- Relations with Adjacent Structures.- General Features. Vascularization: Superficial (Leptomeningeal) Blood Vessels.- Superficial Hippocampal Arteries.- Superficial Hippocampal Veins.- Intrahippocampal (Deep) Blood Vessels.-Intrahippocampal Arteries.- Intrahippocampal Veins.- Hippocampal Head.- Vascular Network. Coronal, Sagittal and Axial Sections of the Hippocampus Showing its Relationships with the Surrounding Structures (after intravascular india ink injection).-Sectional Anatomy and Magnetic Resonance Imaging: Coronal Sections.- Sagittal Sections.- Axial Sections.- References.- Index.
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paper_title: The Parahippocampal Region: Corticocortical Connectivity

paper_content:

The parahippocampal region, as defined in this review, comprises the cortical regions that surround the rodent hippocampus including the perirhinal, postrhinal, and entorhinal cortices. The comparable regions in the primate brain are the perirhinal, parahippocampal, and entorhinal cortices. The perirhinal and postrhinal/parahippocampal cortices provide the major polysensory input to the hippocampus through their entorhinal connections and are the recipients of differing combinations of sensory information. The differences in the perirhinal and postrhinal cortical afferentation have important functional implications, in part, because these two regions project with different terminal patterns to the entorhinal cortex. The perirhinal cortex projects preferentially to the lateral entorhinal area (LEA), and the postrhinal cortex projects preferentially to the medial entorhinal area (MEA) and the caudal portion of LEA. Although the perirhinal and postrhinal cortices provide the major cortical input to the entorhinal cortex, the entorhinal cortex itself receives some direct cortical input. An examination of the cortical afferentation of the entorhinal cortex reveals an interesting principle of connectivity among these regions; the composition of the direct neocortical input to the LEA is more similar to that of the perirhinal cortex, and the composition of the direct neocortical input to the MEA is more similar to that of the postrhinal cortex. Thus, polymodal associational input to the LEA and the MEA exhibits some segregation and is organized in parallel. The organization of intrinsic connections for each of the parahippocampal regions also contributes to the segregation of information into parallel pathways.
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paper_title: Brodmann's localisation in the cerebral cortex

paper_content:

Part 1 The principles of comparative cortical cytoarchitectonics: the basic laminar pattern of the cerebral cortex - homogenetic and heterogenetic cortical formations regional variations in cell structure of the cerebral cortex particularities of the cytoarchitecture in different animals. Part 2 The principles of comparative field organisation in the cerebral cortex: description of individual brain maps common features in cortical architectonics variations in cortical architectonics. Part 3 Synthesis - hypothesis of the cortex as a morphological, physiological and pathological organ - histological cortical: localization in relation to morphology localization and histopathology physiology of the cortex as an organ.
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paper_title: Where are the perirhinal and parahippocampal cortices? a historical overview of the nomenclature and boundaries applied to the primate medial temporal lobe

paper_content:

Strong evidence has emerged over the last 15 years showing that the perirhinal and parahippocampal cortices play an important role in normal memory function. Despite our progress in understanding the mnemonic functions of these areas, controversy still exists concerning the precise location of the boundaries of these areas in the primate brain. To provide a context for understanding the current discrepancies in the literature, we present a historical overview of the different boundary schemes and nomenclatures that have been applied to the medial temporal lobe cortices in both humans and nonhuman primates. We describe how the boundaries and the names applied to these regions have evolved over time, starting with the classic cytoarchitectonisists working in the early 1900s, and ending with the various schemes being used in the contemporary literature. We show that the current controversies concerning the boundaries of the perirhinal and parahippocampal cortices can be traced directly to the classic cytoarchitectonic literature.
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paper_title: Co-Planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System: An Approach to Cerebral Imaging

paper_content:

Direct and Indirect Radiologic Localization Reference System: Basal Brain Line CA-CP Cerebral Structures in Three-Dimensional Space Practical Examples for the Use of the Atlas in Neuroradiologic Examinations Three-Dimensional Atlas of a Human Brain Nomenclature-Abbreviations Anatomic Index Conclusions.
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paper_title: Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps

paper_content:

Probabilistic maps of neocortical areas and subcortical fiber tracts, warped to a common reference brain, have been published using microscopic architectonic parcellations in ten human postmortem brains. The maps have been successfully applied as topographical references for the anatomical localization of activations observed in functional imaging studies. Here, for the first time, we present stereotaxic, probabilistic maps of the hippocampus, the amygdala and the entorhinal cortex and some of their subdivisions. Cytoarchitectonic mapping was performed in serial, cell-body stained histological sections. The positions and the extent of cytoarchitectonically defined structures were traced in digitized histological sections, 3-D reconstructed and warped to the reference space of the MNI single subject brain using both linear and non-linear elastic tools of alignment. The probability maps and volumes of all structures were calculated. The precise localization of the borders of the mapped regions cannot be predicted consistently by macroanatomical landmarks. Many borders, e.g. between the subiculum and entorhinal cortex, subiculum and Cornu ammonis, and amygdala and hippocampus, do not match sulcal landmarks such as the bottom of a sulcus. Only microscopic observation enables the precise localization of the borders of these brain regions. The superposition of the cytoarchitectonic maps in the common spatial reference system shows a considerably lower degree of intersubject variability in size and position of the allocortical structures and nuclei than the previously delineated neocortical areas. For the first time, the present observations provide cytoarchitectonically verified maps of the human amygdala, hippocampus and entorhinal cortex, which take into account the stereotaxic position of the brain structures as well as intersubject variability. We believe that these maps are efficient tools for the precise microstructural localization of fMRI, PET and anatomical MR data, both in healthy and pathologically altered brains.
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paper_title: Course of illness, hippocampal function, and hippocampal volume in major depression.

paper_content:

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.
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paper_title: An update on regional brain volume differences associated with mood disorders.

paper_content:

Purpose of reviewStructural brain changes are apparent in some magnetic resonance imaging studies of patients with mood disorders, but results are inconsistent. The focus of this review is to examine whether there are demographic or clinical characteristics of people with mood disorders that are ass
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paper_title: Volumetric brain imaging findings in mood disorders

paper_content:

Volumetric neuroimaging is increasingly being used by researchers of affective disorders to assess potential involvement of different brain structures in mood regulation and to test neuroanatomic models of mood disorders. In unipolar depression, findings suggest abnormalities in the frontal lobe (particularly the subgenual prefrontal cortex), basal ganglia (particularly the caudate and putamen), cerebellum, and hippocampus/amygdala complex. In bipolar disorder, abnormalities in the third ventricle, frontal lobe, cerebellum, and possibly the temporal lobe are noted. We review the findings for the various regions of the brain, and discuss the implications on the understanding of mood disorders. Directions for future research in volumetric imaging is then discussed.
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paper_title: MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed

paper_content:

The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.
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paper_title: Protocol for volumetric segmentation of medial temporal structures using high-resolution 3-D magnetic resonance imaging

paper_content:

Quantitative analysis of brain structures in normal subjects and in different neurological conditions can be carried out in vivo through magnetic resonance imaging (MRI) volumetric studies. The use of high-resolution MRI combined with image post-processing that allows simultaneous multiplanar view may facilitate volumetric segmentation of temporal lobe structures. We define a protocol for volumetric studies of medial temporal lobe structures using high-resolution MR images and we studied 30 healthy subjects (19 women; mean age, 33 years; age range, 21–55 years). Images underwent field non-homogeneity correction and linear stereotaxic transformation into a standard space. Structures of interest comprised temporopolar, entorhinal, perirhinal, parahippocampal cortices, hippocampus, and the amygdala. Segmentation was carried out with multiplanar assessment. There was no statistically significant left/right-sided asymmetry concerning any structure analyzed. Neither gender nor age influenced the volumes obtained. The coefficient of repeatability showed no significant difference of intra- and interobserver measurements. Imaging post-processing and simultaneous multiplanar view of high-resolution MRI facilitates volumetric assessment of the medial portion of the temporal lobe with strict adherence to anatomic landmarks. This protocol shows no significant inter- and intraobserver variations and thus is reliable for longitudinal studies. Hum. Brain Mapp. 22:145–154, 2004. © 2004 Wiley-Liss, Inc.
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paper_title: Article Hippocampal Deformities in Schizophrenia Characterized by High Dimensional Brain Mapping

paper_content:

OBJECTIVE: Abnormalities of hippocampal structure have been reported in schizophrenia subjects. However, such abnormalities have been difficult to discriminate from normal neuroanatomical variation. High dimensional brain mapping, which utilizes probabilistic deformations of a neuroanatomical template, was used to characterize disease-related patterns of changes in hippocampal volume, shape, and asymmetry. METHOD: T1-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects who were similar in age, gender, and parental socioeconomic status. The schizophrenia subjects were clinically stable at the time of assessment. RESULTS: Significant abnormalities of hippocampal shape and asymmetry (but not volume after total cerebral volume was included as a covariate) were found in the schizophrenia subjects. The pattern of shape abnormality suggested a neuroanatomical deformity of the head of the hippocampus, which contains neurons that project to the frontal cortex. The pattern...
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paper_title: Course of illness, hippocampal function, and hippocampal volume in major depression.

paper_content:

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.
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paper_title: Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study

paper_content:

Rationale ::: The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients.
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paper_title: A Volumetric Study of Hippocampus and Amygdala in Depressed Patients With Subjective Memory Problems

paper_content:

MRI was used to measure amygdalar and hippocampal volumes in 14 nondemented depressed patients who persistently complained of “memory” difficulties and in 14 control subjects. Mild neuropsychological impairment had been detected in 5 patients before the study but had later improved. The volume of the left amygdala was smaller in depressed subjects, and there was a trend for smaller left hippocampus in the 5 patients who had exhibited mild cognitive impairment. The authors conclude that subjective memory complaints in depressed patients do not translate into a clinical picture of dementia, but that abnormalities in the amygdala and hippocampus may be relevant in explaining affective and cognitive symptoms.
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paper_title: Hippocampal volume and subjective memory impairment in depressed patients

paper_content:

The relationship between severity of subjective memory impairment and volume of the hippocampus/amygdala complex was investigated in non-demented depressed patients and it was found to correlate with decreasing volume in the right hippocampus.
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paper_title: High-Dimensional Mapping of the Hippocampus in Depression

paper_content:

OBJECTIVE: Abnormalities of the hippocampus may play a role in the pathophysiology of depression, but efforts to identify a structural abnormality in this brain structure among depressed patients have produced mixed results. Previous research may have been limited by exclusive reliance on measures of hippocampal volume. High-dimensional brain mapping is a new analytic method that quantitatively characterizes the shape as well as volume of a brain structure. In this study, high-dimensional brain mapping was used to evaluate hippocampal shape and volume in patients with major depressive disorder and healthy comparison subjects. METHOD: By using magnetic resonance imaging, brain scans were obtained from 27 patients with major depressive disorder and 42 healthy comparison subjects. High-dimensional brain mapping generated a series of 10 variables (components) that represented hippocampal shape, and hippocampal volumes were also computed. Analysis of variance techniques were used to compare depressed patients ...
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paper_title: Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas.

paper_content:

PURPOSE ::: To test automated three-dimensional magnetic resonance (MR) imaging morphometry of the human hippocampus, to determine the potential gain in precision compared with conventional manual morphometry. ::: ::: ::: MATERIAL AND METHODS ::: A canonical three-dimensional MR image atlas was used as a deformable template and automatically matched to three-dimensional MR images of 10 individuals (five healthy and five schizophrenic subjects). A subvolume containing the hippocampus was defined by using 16 landmarks that constrained the automated search for hippocampal boundaries. Transformation of the hippocampus template was automatically performed by using global pattern matching through a sequence of low-then high-dimensional translations, rotations, and scalings. ::: ::: ::: RESULTS ::: The average test-retest volume difference measured with the automatic method was 3.1%, compared with the manual test-retest difference of 7.1%. Correlation between automated and manually determined volumes demonstrated the validity of the automated technique (intraclass correlation coefficient = .86). ::: ::: ::: CONCLUSION ::: The automated method estimates hippocampal volumes with less variability (ie, lower variance) than that of manual out-lining.
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paper_title: Volumetric Analysis of the Prefrontal Cortex, Amygdala, and Hippocampus in Major Depression

paper_content:

Volumetric Analysis of the Prefrontal Cortex, Amygdala, and Hippocampus in Major Depression
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paper_title: Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms

paper_content:

Abstract Background: Although it has been hypothesized that glucocorticoid hypersecretion in depressed patients leads to neuronal atrophy in the hippocampus, magnetic resonance imaging (MRI) –based morphometry studies of the hippocampus to date have produced mixed results. Methods: In our MRI study, hippocampal volumes were measured in 25 depressed patients (13 with melancholia and 12 without melancholia) and 15 control subjects. Results: No significant differences in hippocampus volumes were found between any of the subject groups, although within subjects right hippocampal volumes were found to be significantly larger than left hippocampal volumes. Additionally, right and total (left + right) hippocampal volumes in control and depressed subjects were found to be positively correlated with trait anxiety as measured by the state/trait anxiety inventory. Conclusions: Because our subject group is younger than those in studies reporting hippocampal atrophy, we conclude that longitudinal studies will be necessary for investigation of the lifelong course of hippocampal volumetry.
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paper_title: Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age‐associated memory impairment: Correlation to visual and verbal memory

paper_content:

Age-associated memory impairment (AAMI) is a common but disputed entity. It is unclear whether AAMI is a phenomenon of normal aging or an early sign of Alzheimer9s disease. The present study aimed to identify possible structural abnormalities in the medial temporal lobe of AAMI subjects. We measured volumes of the hippocampus and amygdala by MRI in 16 AAMI subjects and in 16 age- and sex-matched controls and correlated the volumes with subjects9 performance on two visual memory tasks (the Benton and the Heaton visual retention tests) and on a verbal memory task (the Buschke-Fuld Selective Reminding Test). The mean hippocampal and amygdaloid volumes normalized for brain size per se did not differ between the two study groups. In controls, but not in AAMI subjects, the right hippocampus was larger than the left. Accordingly, the volumetric asymmetry between the right and left hippocampi was smaller in AAMI subjects than in controls (Student9s t test, p p p p
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paper_title: Volumetry of Hippocampus and Amygdala with High-resolution MRI and Three-dimensional Analysis Software: Minimizing the Discrepancies between Laboratories

paper_content:

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm 3 ), while no interhemispheric differences for the amygdala (1154 versus 1160 mm 3 )c ould be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.
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paper_title: Regional specificity of hippocampal volume reductions in first-episode schizophrenia

paper_content:

Abstract Hippocampal volume reductions are widely observed in schizophrenia. Some studies suggest anterior hippocampal regions are more susceptible and associated with frontal lobe dysfunctions, while others implicate posterior regions. Using high-resolution MR images and novel computational image analysis methods, we identified the hippocampal subregions most vulnerable to disease processes in 62 (45 m/17 f) first-episode schizophrenia patients compared to 60 (30 m/30 f) healthy controls, similar in age. The hippocampi were traced on coronal brain slices and hemispheric volumes were compared between diagnostic groups. Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups in 3D. CSF concentrations were also compared statistically at homologous hippocampal surface points to localize corresponding gray matter reductions. Significant bilateral hippocampal volume reductions were observed in schizophrenia irrespective of brain size corrections. Statistical mapping results, confirmed by permutation testing, showed pronounced left hemisphere shape differences in anterior and midbody CA1 and CA2 regions in patients. Significant CSF increases surrounding the hippocampus were observed in a similar spatial pattern in schizophrenia. Results confirm that hippocampal volume reductions are a robust neuroanatomical correlate of schizophrenia and are present by first episode. Mid- to antero-lateral hippocampal regions show pronounced volume changes and complementary increases in peri-hippocampal CSF, suggesting that these hippocampal regions are more susceptible to disease processes in schizophrenia. Targeting regional hippocampal abnormalities may help dissociate schizophrenia patients from other groups exhibiting global hippocampal volume changes, and better focus systems-level pathophysiological hypotheses.
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paper_title: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging

paper_content:

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer9s disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.
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paper_title: Hippocampal atrophy in recurrent major depression.

paper_content:

Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms

paper_content:

Abstract Background: Although it has been hypothesized that glucocorticoid hypersecretion in depressed patients leads to neuronal atrophy in the hippocampus, magnetic resonance imaging (MRI) –based morphometry studies of the hippocampus to date have produced mixed results. Methods: In our MRI study, hippocampal volumes were measured in 25 depressed patients (13 with melancholia and 12 without melancholia) and 15 control subjects. Results: No significant differences in hippocampus volumes were found between any of the subject groups, although within subjects right hippocampal volumes were found to be significantly larger than left hippocampal volumes. Additionally, right and total (left + right) hippocampal volumes in control and depressed subjects were found to be positively correlated with trait anxiety as measured by the state/trait anxiety inventory. Conclusions: Because our subject group is younger than those in studies reporting hippocampal atrophy, we conclude that longitudinal studies will be necessary for investigation of the lifelong course of hippocampal volumetry.
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paper_title: Reliability of medial temporal lobe volume measurements using reformatted 3D images

paper_content:

Abstract The study assessed whether standardizing the angle of image display and controlling for head position in three planes affects the scan–rescan reliability of medial temporal lobe volume measures when very thin (1.5 mm) slices are used. Five volunteers were scanned two times on consecutive days. A three-dimensional MRI sequence acquired whole brain data in 1.4 mm thick coronal slices. The data were displayed as 1.5 mm thick images and were rated both in the originally acquired coronal plane, and after reformatting to correct for head tilt and display the brain in the coronal plane perpendicular to the long axis of the left anterior hippocampus. One rater measured five brain regions (temporal lobe, anterior and posterior hippocampus, amygdala, and temporal horn) on the left and right sides of the two non-reformatted and two reformatted scans to obtain inter-scan variance. Furthermore, most scans were remeasured, to obtain `reread' variances. All data were log-transformed in order to produce comparable variability across brain regions of different sizes. For all the regions, except the temporal horn, the non-reformatted scans showed significantly larger scan–rescan variability than the reformatted scans. A typical standard deviation for a non-reformatted pair of scans was 0.10, corresponding to 26% error, while a typical value for a reformatted pair of scans was 0.04, corresponding to 10% error. For all the regions, the reread data (intra-rater reliability) gave similar results for both reformatted and non-reformatted images with similar standard deviations (typical value for reread standard deviation was 0.020, corresponding to 5% error). The data suggest that, even when very thin slices are acquired, volume measurement accuracy of gray matter structures in the temporal lobe is considerably improved by controlling for image orientation in three planes. For these structures, the sample size needed to detect a small (5%) within-subject volume change would be halved if reformatted images were used. Image contrast is an additional important factor since the reformatted T 1 weighted images used in this study, which have suboptimal CSF/brain contrast, worsened measurement accuracy in the temporal horn.
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paper_title: Hippocampal volume reduction and HPA-system activity in major depression

paper_content:

Structural imaging studies investigating hippocampal volumes in patients suffering from major depression have yielded mixed results. Here, 24 unipolar depressed in-patients and 14 healthy controls carefully matched for age, gender, and years of education underwent quantitative magnetic resonance imaging (MRI). Saliva cortisol was measured at 0800 and 1600 h in patients during a one-week wash-out and the following 4 weeks. Hippocampal volumes were significantly reduced in the patient group even after adjusting for intracranial brain volume (ICV) and age. Across groups, age was significantly negatively correlated with uncorrected hippocampal volumes. In patients, severity of disease (baseline HAMD scores) and baseline cortisol levels were not related to hippocampal volumes. However, there was a negative association between duration of the index episode before hospitalization and hippocampal volumes. Additionally, hippocampal volumes were significantly negatively correlated with duration of illness. Finally, we observed a trend for higher hippocampal volumes in those patients who showed a subsequent decrease in cortisol levels under pharmacotherapy. 2006 Elsevier Ltd. All rights reserved.
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paper_title: MRI-based hippocampal volume measurements in epilepsy.

paper_content:

In the study of brain morphometry, it is accepted that a relationship exists between brain structure and function, both normal and abnormal. One descriptor of morphometric structure is volume. Abnormalities in hippocampal morphology, including unilateral or bilateral volume loss, are known to occur in epilepsy, Alzheimer's disease, and in certain amnestic syndromes. Precise quantitation should improve understanding of the role of any biologic system in normal function and in disease. The objectives of magnetic resonance (MR)-based hippocampal volume measurements are precise quantitation, identification of a normal range, and identification of the association between biologic variables and aberrations in this volumetric parameter. Volumetric measures introduce a level of precision in the estimation of hippocampal size that is not available simply by visually inspecting a set of MR images, thus enabling statistically based hypothesis testing. To produce accurate hippocampal volume measurements with magnetic resonance imaging (MRI), attention must be directed to the two major components of the operation as a whole, MR image acquisition and image processing.
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paper_title: Regional specificity of hippocampal volume reductions in first-episode schizophrenia

paper_content:

Abstract Hippocampal volume reductions are widely observed in schizophrenia. Some studies suggest anterior hippocampal regions are more susceptible and associated with frontal lobe dysfunctions, while others implicate posterior regions. Using high-resolution MR images and novel computational image analysis methods, we identified the hippocampal subregions most vulnerable to disease processes in 62 (45 m/17 f) first-episode schizophrenia patients compared to 60 (30 m/30 f) healthy controls, similar in age. The hippocampi were traced on coronal brain slices and hemispheric volumes were compared between diagnostic groups. Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups in 3D. CSF concentrations were also compared statistically at homologous hippocampal surface points to localize corresponding gray matter reductions. Significant bilateral hippocampal volume reductions were observed in schizophrenia irrespective of brain size corrections. Statistical mapping results, confirmed by permutation testing, showed pronounced left hemisphere shape differences in anterior and midbody CA1 and CA2 regions in patients. Significant CSF increases surrounding the hippocampus were observed in a similar spatial pattern in schizophrenia. Results confirm that hippocampal volume reductions are a robust neuroanatomical correlate of schizophrenia and are present by first episode. Mid- to antero-lateral hippocampal regions show pronounced volume changes and complementary increases in peri-hippocampal CSF, suggesting that these hippocampal regions are more susceptible to disease processes in schizophrenia. Targeting regional hippocampal abnormalities may help dissociate schizophrenia patients from other groups exhibiting global hippocampal volume changes, and better focus systems-level pathophysiological hypotheses.
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paper_title: Hippocampal volumetric and morphometric studies in frontal and temporal lobe epilepsy.

paper_content:

The most common temporal lobe pathology is Ammons Horn sclerosis (AHS), and several different imaging techniques have been utilized to detect this with varying success. We describe the clinical application of magnetic resonance imaging (MRI) using a three-dimensional volume technique which allows total hippocampal volume to be measured and symmetry evaluated. Hippocampal surface area was calculated in sequential 1.5 mm thick contiguous images, using a GE IC workstation. Total volumes and surface areas were calculated. The cross-sectional surface area at 1.5 mm intervals was displayed graphically, permitting morphometric analysis of the hippocampus throughout its length. Focal atrophy within any part of the hippocampal formation (HF) and its extent could thus be assessed. Patients with well-lateralized temporal lobe epilepsy (TLE) (n = 20) and well-defined frontal lobe epilepsy (FLE) (n = 20) were studied, and volumes compared with normal values derived from 10 neurologically normal controls. Asymmetric hippocampal volume loss was demonstrated in all 20 patients with clinically typed TLE, but not in normal controls or patients with FLE. Volume loss distribution was anterior in 12 patients, posterior in one patient and widespread in seven patients. Secondarily generalized seizures were strongly associated with widespread loss. This method of surface area and volumetric analysis of the hippocampus in TLE can demonstrate asymmetry and focal involvement, and help distinguish between hippocampal and frontal pathologies.
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paper_title: Hippocampal Changes in Patients With a First Episode of Major Depression

paper_content:

OBJECTIVE: Previous work suggests that patients with unipolar depression may have structural as well as functional abnormalities in limbic-thalamic-cortical networks, which are hypothesized to modulate human mood states. A core area in these networks is the hippocampus. In the present study, differences in volumes of hippocampal gray and white matter between patients with a first episode of major depression and healthy comparison subjects were examined. METHOD: Thirty patients with a first episode of major depression and 30 healthy comparison subjects who were matched for age, gender, handedness, and education were examined with high-resolution magnetic resonance imaging. RESULTS: Male patients with a first episode of major depression had significantly smaller hippocampal total and gray matter volumes than healthy male comparison subjects. Both male and female patients showed significant alterations of left-right asymmetry and significant reductions of left and right hippocampal white matter fibers in rel...
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paper_title: Course of illness, hippocampal function, and hippocampal volume in major depression.

paper_content:

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.
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paper_title: MRI investigation of temporal lobe structures in bipolar patients

paper_content:

Previous anatomical MRI studies have suggested abnormalities in amygdala volumes in bipolar disorder, whereas hippocampus, temporal lobe (TL), and superior temporal gyri (STG) measures have been reported to be normal. This study further investigated the existence of anatomical abnormalities in these brain structures in bipolar subjects, to attempt to replicate previously reported findings. Twenty-four DSM-IV bipolar patients (mean ageS.D.=35 10 years) and 36 healthy controls (mean age S.D.=3710 years) were studied. 3D SPGR images were obtained with a 1.5T-GE Signa magnet (TR=25 ms, TE=5 ms, FOV=24 cm, slice-thickness=1.5 mm, matrix-size=256192). Volumetric measurements of TL, hippocampus, amygdala, and STG were performed blindly, with a semi-automated software. Bipolar patients had significantly larger left amygdala volumes compared with controls (mean volumes S.D.=2.57 0.69 vs. 2.17 0.58 ml, respectively; ANCOVA, age, gender, ICV as covariates; F=4.42, df=1/55, P=0.04). The volumes of the other temporal lobe structures did not differ significantly between the two groups (ANCOVA, age, gender, and ICV as covariates, P >0.05). Our findings of enlarged left amygdala in bipolar patients are in agreement with prior MRI studies, suggesting that abnormalities in this brain structure may be implicated in pathophysiology of the illness. Longitudinal studies in high-risk offspring and first-episode patients will be needed to examine whether such abnormalities precede the appearance of symptoms, or whether they may appear subsequently as a result of illness course. # 2003 Elsevier Science Ltd. All rights reserved.
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paper_title: Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects

paper_content:

Abstract Findings from cerebral magnetic resonance imaging (MRI) studies in schizophrenia indicating temporal lobe involvement have been inconsistent and controversial. In a prospective study, we quantified the volumes of temporal lobe structures in 20 male patients with first episode schizophrenia (FES; mean±S.D.=27.4±4.8 years) and 20 healthy age-matched male control subjects (27.7±3.1 years). Measurements were performed on contiguous 2.2-mm coronal MRI slices, which included, as well as the temporal lobe, the amygdala, the hippocampal formation, and the temporal horn of the lateral ventricle. The definition of the borders of the structures relied on measurement guidelines derived from mutual comparisons of MRI and histological data. The definition of the hippocampus–amygdala interface was also validated in a correlated triplanar display. We did not detect any significant volume reductions of the measured structures in the FES group, as compared with healthy control subjects, on either side. Comparisons within groups, however, revealed that in both the patients and the healthy volunteers the hippocampal formations showed a significant right-sided bias (+9%, P =0.004, in the FES group; +12%, P =0.0003 in the control subjects). A significant volume difference in favor of the right hemisphere was also observed in the temporal horns of the lateral ventricles (+17%, P =0.02 in the patients with FES; +34%, P =0.003, in the control group). There was only a nonsignificant trend for a larger temporal horn on the left side in patients with schizophrenia as compared with the control subjects. Our findings do not indicate a loss or reversal of the normal volume asymmetry pattern in the FES group.
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paper_title: Anatomical MRI study of hippocampus and amygdala in patients with current and remitted major depression

paper_content:

Morphometric MRI studies suggest decreased hippocampal volumes in currently depressed patients, with conflicting findings for the amygdala. We studied these temporal lobe structures and superior temporal gyrus (STG) in patients with current and remitted major depression. We scanned 31 unmedicated depressed patients (21 currently depressed, 10 remitted) and 31 matched healthy controls with a 3D SPGR sequence in a 1.5 Tesla GE Signa Imaging System. There was a trend towards smaller left amygdala volumes in all depressed patients compared with healthy controls. We found significantly smaller hippocampal volumes bilaterally in currently depressed patients than in remitted patients. Furthermore, we found a statistically significant inverse correlation between length of illness and left hippocampus volumes and right superior temporal gyrus volumes. Our finding of smaller hippocampi in currently depressed patients is consistent with the hypothesis that hypercortisolism could result in hippocampal neurotoxicity in major depression. A smaller hippocampal size may be more characteristic of the depressive state and not be present in remitted patients.
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paper_title: Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression

paper_content:

Objective: Smaller hippocampal volume has been reported only in some but not all studies of unipolar major depressive disorder. Severe stress early in life has also been associated with smaller hippocampal volume and with persistent changes in the hypothalamic-pituitary-adrenal axis. However, prior hippocampal morphometric studies in depressed patients have neither reported nor controlled for a history of early childhood trauma. In this study, the volumes of the hippocampus and of control brain regions were measured in depressed women with and without childhood abuse and in healthy nonabused comparison subjects. Method: Study participants were 32 women with current unipolar major depressive disorder—21 with a history of prepubertal physical and/or sexual abuse and 11 without a history of prepubertal abuse—and 14 healthy nonabused female volunteers. The volumes of the whole hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans by a single rater who was blind to the subjects’ diagnoses. Results: The depressed subjects with childhood abuse had an 18% smaller mean left hippocampal volume than the nonabused depressed subjects and a 15% smaller mean left hippocampal volume than the healthy subjects. Right hippocampal volume was similar across the three groups. The right and left hippocampal volumes in the depressed women without abuse were similar to those in the healthy subjects. Conclusions: A smaller hippocampal volume in adult women with major depressive disorder was observed exclusively in those who had a history of severe and prolonged physical and/or sexual abuse in childhood. An unreported history of childhood abuse in depressed subjects could in part explain the inconsistencies in hippocampal volume findings in prior studies in major depressive disorder.
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paper_title: Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder

paper_content:

Background In vivo imaging studies in adult bipolar patients have suggested enlargement of the amygdala. It is not known whether this abnormality is already present early in the illness course or whether it develops later in life. We conducted a morphometric MRI study to examine the size of specific temporal lobe structures in adolescents and young adults with bipolar disorder and healthy control subjects, as well as their relationship with age, to examine possible neurodevelopmental abnormalities. Methods Subjects included 16 DSM-IV bipolar patients (16 ± 3 years) and 21 healthy controls (mean age ± SD = 17 ± 4 years). Measures of amygdala, hippocampus, temporal gray matter, temporal lobe, and intracranial volumes (ICV) were obtained. Results There was a trend to smaller left amygdala volumes in patients (mean volumes ± SD = 1.58 ± .42 mL) versus control subjects (1.83 ± .4 mL; F = 3.87, df = 1,32, p = .06). Bipolar patients did not show significant differences in right or left hippocampus, temporal lobe gray matter, temporal lobe, or right amygdala volumes (analysis of covariance, age, gender, and ICV as covariates, p > .05) compared with healthy control subjects. Furthermore, there was a direct correlation between left amygdala volumes and age (r = .50, p = .047) in patients, whereas in healthy controls there was an inverse correlation (r = −.48, p = .03). Conclusions The direct correlation between left amygdala volumes and age in bipolar patients, not present in healthy control subjects, may reflect abnormal developmental mechanisms in bipolar disorder.
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paper_title: Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study

paper_content:

Abstract Background: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. Methods: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. Results: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. Conclusions: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.
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paper_title: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging

paper_content:

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer9s disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.
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paper_title: Hippocampal atrophy in recurrent major depression.

paper_content:

Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: MRI-based measurement of hippocampal volume in patients with combat- related posttraumatic stress disorder

paper_content:

Patients with combat-related posttraumatic stress disorder (PTSD) clinically demonstrate alterations in memory, including nightmares, flashbacks, intrusive memories, and amnesia for war experiences. In addition, descriptions from all wars of this century document alterations in memory occurring in combat veterans during or after the stress of battle. These include forgetting one's name or identity and forgetting events that had just taken place during the previous battle (1, 2), as well as gaps in memory that continue to recur for many years after the war (3). Servicemen who had been prisoners of war during the Korean conflict were found to have an impairment in short-term verbal memory, as measured by the logical memory component of the Wechsler Memory Scale, in comparison with veterans of the Korean war who did not have a history of imprisonment (4). We also found deficits in short-term verbal memory, as measured by the logical memory component of the Wechsler Memory Scale, in Vietnam combat veterans with combat-related PTSD in comparison with healthy subjects who were matched for age, years of education, and alcohol abuse (5). ::: ::: Several lines of evidence suggest a relation between stress and damage to the hippocampus (6). The hippocampus and the adjacent perirhinal, parahippocampal, and entorhinal cortex play an important role in short-term memory (7). Studies in humans have shown that reductions in hippocampal volume secondary to either neurosurgery (8) or the pathophysiological effects of epilepsy (9) are associated with deficits in short-term memory as measured by the Wechsler Memory Scale. Monkeys exposed to the extreme stress of improper caging have shown increased glucocorticoid release as well as damage to the CA2 and CA3 subfields of the hippocampus (10). Studies in a variety of animal species suggest that direct glucocorticoid exposure results in a loss of neurons and a decrease in dendritic branching in the hippocampus (11, 12) with associated deficits in memory function (13). The mechanism of action of glucocorticoid toxicity is probably through an increase in the vulnerability of neurons to the toxicity of excitatory amino acids (14–16). Studies using computed tomography in human subjects who are exposed to high levels of glucocorticoids secondary to glucocorticoid steroid therapy (17, 18) or who have affective disorders (also felt to be related to stress) (19) have shown changes in brain structure, including ventricular enlargement and widening of the cortical sulci. Magnetic resonance imaging (MRI) studies in patients with affective disorders have shown a smaller right hippocampal volume (20) and temporal lobe volume (21) in bipolar disorder and abnormalities of the hippocampus, including alterations in T1 (22), but no change in hippocampal volume (23) in major depression. One MRI study (24) found a relation between deficits in short-term memory and smaller hippocampal volume, as well as higher plasma cortisol levels and smaller hippocampal volume, in patients with Cushing's disease. Stress in both healthy human subjects (25) and soldiers undergoing random artillery bombardment (26) results in an increase in urinary cortisol, suggesting the possibility that exposure to the extreme stress of combat may be associated with damage to the hippocampus. ::: ::: The purpose of this study was to use MRI to measure the volume of the hippocampus and comparison brain structures in patients with PTSD and in matched comparison subjects. We hypothesized that PTSD would be associated with smaller hippocampal volume in relation to that of the comparison subjects. We also hypothesized that smaller hippocampal volume would be associated with deficits in short-term verbal memory in patients with PTSD.
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paper_title: Hippocampal volume in early onset depression

paper_content:

BackgroundAbnormalities in limbic structures have been implicated in major depressive disorder (MDD). Although MDD is as common in adolescence as in adulthood, few studies have examined youth near illness onset in order to determine the possible influence of atypical development on the pathophysiology of this disorder.MethodsHippocampal volumes were measured in 17 MDD subjects (age = 16.67 ± 1.83 years [mean ± SD]; range = 13 – 18 years) and 17 age- and sex-matched healthy controls (16.23 ± 1.61 years [mean ± SD]; 13 – 18 years) using magnetic resonance imaging (MRI).ResultsAn analysis of covariance revealed a significant difference between MDD and control subjects (F = 8.66, df = 1, 29, P = 0.006). This was more strongly localized to the left hippocampus (P = 0.001) than the right hippocampus (P = 0.047).ConclusionsOur findings provide new evidence of abnormalities in the hippocampus in early onset depression. However, our results should be considered preliminary given the small sample size studied.
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paper_title: B.: Hippocampal volume in normal aging and traumatic brain injury

paper_content:

PURPOSE ::: To present a normative database of hippocampal and temporal horn volume and to clarify the relationship between these measures and cognitive outcome in patients with traumatic brain injury. ::: ::: ::: METHODS ::: Ninety-six healthy volunteers and 94 patients with traumatic brain injury were examined with coronal intermediate and T2-weighted MR imaging. Multispectral segmentation and volume analyses were performed. The volumetry of the hippocampus and temporal horn was characterized in the control subjects. Volumetric measures in a group of patients with traumatic brain injury who had received MR imaging 3 months or less after injury were compared with measurements in other patients in the chronic phase of recovery. The relationship between neuropsychological testing and volumetric measures was analyzed with particular emphasis on the correlation between cognitive outcome and hippocampal and temporal horn volumes. ::: ::: ::: RESULTS ::: No significant age group differences were found in the normative group from age 16 to 65. Left and right hippocampal volumes were interrelated and did not differ from each other. This was also true for the temporal horns. Hippocampal and temporal horn volumes were not significantly related. Women had larger hippocampi relative to cranial volume. Comparisons between patients with traumatic brain injury and control subjects showed significant yet modest bilateral atrophic changes in hippocampal and temporal horn enlargement in the patients with brain injury. Hippocampal and temporal horn volumes correlated significantly with each other in the group with traumatic brain injury. Cognitive outcome was modestly related to hippocampal and temporal horn volumes. However, in a specific subgroup whose images were acquired between 71 and 210 days after injury, strong correlations were noted in which temporal horn volume correlated highly with IQ and hippocampal volume correlated with verbal memory function. ::: ::: ::: CONCLUSION ::: Hippocampal and temporal horn volumes appear to be independent variables in healthy control subjects. Traumatic brain injury results in significant hippocampal atrophy and temporal horn enlargement. The hippocampus and temporal horn volumes were inversely correlated in the group with traumatic brain injury, suggesting a differential relationship of these structures in patients with brain injury as compared with control subjects. In the subacute phase, the volume of the temporal horn may be indicative of intellectual outcome and that of the hippocampus appears to be indicative of verbal memory function.
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paper_title: Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age‐associated memory impairment: Correlation to visual and verbal memory

paper_content:

Age-associated memory impairment (AAMI) is a common but disputed entity. It is unclear whether AAMI is a phenomenon of normal aging or an early sign of Alzheimer9s disease. The present study aimed to identify possible structural abnormalities in the medial temporal lobe of AAMI subjects. We measured volumes of the hippocampus and amygdala by MRI in 16 AAMI subjects and in 16 age- and sex-matched controls and correlated the volumes with subjects9 performance on two visual memory tasks (the Benton and the Heaton visual retention tests) and on a verbal memory task (the Buschke-Fuld Selective Reminding Test). The mean hippocampal and amygdaloid volumes normalized for brain size per se did not differ between the two study groups. In controls, but not in AAMI subjects, the right hippocampus was larger than the left. Accordingly, the volumetric asymmetry between the right and left hippocampi was smaller in AAMI subjects than in controls (Student9s t test, p p p p
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paper_title: Reliability of medial temporal lobe volume measurements using reformatted 3D images

paper_content:

Abstract The study assessed whether standardizing the angle of image display and controlling for head position in three planes affects the scan–rescan reliability of medial temporal lobe volume measures when very thin (1.5 mm) slices are used. Five volunteers were scanned two times on consecutive days. A three-dimensional MRI sequence acquired whole brain data in 1.4 mm thick coronal slices. The data were displayed as 1.5 mm thick images and were rated both in the originally acquired coronal plane, and after reformatting to correct for head tilt and display the brain in the coronal plane perpendicular to the long axis of the left anterior hippocampus. One rater measured five brain regions (temporal lobe, anterior and posterior hippocampus, amygdala, and temporal horn) on the left and right sides of the two non-reformatted and two reformatted scans to obtain inter-scan variance. Furthermore, most scans were remeasured, to obtain `reread' variances. All data were log-transformed in order to produce comparable variability across brain regions of different sizes. For all the regions, except the temporal horn, the non-reformatted scans showed significantly larger scan–rescan variability than the reformatted scans. A typical standard deviation for a non-reformatted pair of scans was 0.10, corresponding to 26% error, while a typical value for a reformatted pair of scans was 0.04, corresponding to 10% error. For all the regions, the reread data (intra-rater reliability) gave similar results for both reformatted and non-reformatted images with similar standard deviations (typical value for reread standard deviation was 0.020, corresponding to 5% error). The data suggest that, even when very thin slices are acquired, volume measurement accuracy of gray matter structures in the temporal lobe is considerably improved by controlling for image orientation in three planes. For these structures, the sample size needed to detect a small (5%) within-subject volume change would be halved if reformatted images were used. Image contrast is an additional important factor since the reformatted T 1 weighted images used in this study, which have suboptimal CSF/brain contrast, worsened measurement accuracy in the temporal horn.
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paper_title: Volumetry of Hippocampus and Amygdala with High-resolution MRI and Three-dimensional Analysis Software: Minimizing the Discrepancies between Laboratories

paper_content:

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm 3 ), while no interhemispheric differences for the amygdala (1154 versus 1160 mm 3 )c ould be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.
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paper_title: MRI-based hippocampal volume measurements in epilepsy.

paper_content:

In the study of brain morphometry, it is accepted that a relationship exists between brain structure and function, both normal and abnormal. One descriptor of morphometric structure is volume. Abnormalities in hippocampal morphology, including unilateral or bilateral volume loss, are known to occur in epilepsy, Alzheimer's disease, and in certain amnestic syndromes. Precise quantitation should improve understanding of the role of any biologic system in normal function and in disease. The objectives of magnetic resonance (MR)-based hippocampal volume measurements are precise quantitation, identification of a normal range, and identification of the association between biologic variables and aberrations in this volumetric parameter. Volumetric measures introduce a level of precision in the estimation of hippocampal size that is not available simply by visually inspecting a set of MR images, thus enabling statistically based hypothesis testing. To produce accurate hippocampal volume measurements with magnetic resonance imaging (MRI), attention must be directed to the two major components of the operation as a whole, MR image acquisition and image processing.
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paper_title: Regional specificity of hippocampal volume reductions in first-episode schizophrenia

paper_content:

Abstract Hippocampal volume reductions are widely observed in schizophrenia. Some studies suggest anterior hippocampal regions are more susceptible and associated with frontal lobe dysfunctions, while others implicate posterior regions. Using high-resolution MR images and novel computational image analysis methods, we identified the hippocampal subregions most vulnerable to disease processes in 62 (45 m/17 f) first-episode schizophrenia patients compared to 60 (30 m/30 f) healthy controls, similar in age. The hippocampi were traced on coronal brain slices and hemispheric volumes were compared between diagnostic groups. Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups in 3D. CSF concentrations were also compared statistically at homologous hippocampal surface points to localize corresponding gray matter reductions. Significant bilateral hippocampal volume reductions were observed in schizophrenia irrespective of brain size corrections. Statistical mapping results, confirmed by permutation testing, showed pronounced left hemisphere shape differences in anterior and midbody CA1 and CA2 regions in patients. Significant CSF increases surrounding the hippocampus were observed in a similar spatial pattern in schizophrenia. Results confirm that hippocampal volume reductions are a robust neuroanatomical correlate of schizophrenia and are present by first episode. Mid- to antero-lateral hippocampal regions show pronounced volume changes and complementary increases in peri-hippocampal CSF, suggesting that these hippocampal regions are more susceptible to disease processes in schizophrenia. Targeting regional hippocampal abnormalities may help dissociate schizophrenia patients from other groups exhibiting global hippocampal volume changes, and better focus systems-level pathophysiological hypotheses.
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paper_title: MRI investigation of temporal lobe structures in bipolar patients

paper_content:

Previous anatomical MRI studies have suggested abnormalities in amygdala volumes in bipolar disorder, whereas hippocampus, temporal lobe (TL), and superior temporal gyri (STG) measures have been reported to be normal. This study further investigated the existence of anatomical abnormalities in these brain structures in bipolar subjects, to attempt to replicate previously reported findings. Twenty-four DSM-IV bipolar patients (mean ageS.D.=35 10 years) and 36 healthy controls (mean age S.D.=3710 years) were studied. 3D SPGR images were obtained with a 1.5T-GE Signa magnet (TR=25 ms, TE=5 ms, FOV=24 cm, slice-thickness=1.5 mm, matrix-size=256192). Volumetric measurements of TL, hippocampus, amygdala, and STG were performed blindly, with a semi-automated software. Bipolar patients had significantly larger left amygdala volumes compared with controls (mean volumes S.D.=2.57 0.69 vs. 2.17 0.58 ml, respectively; ANCOVA, age, gender, ICV as covariates; F=4.42, df=1/55, P=0.04). The volumes of the other temporal lobe structures did not differ significantly between the two groups (ANCOVA, age, gender, and ICV as covariates, P >0.05). Our findings of enlarged left amygdala in bipolar patients are in agreement with prior MRI studies, suggesting that abnormalities in this brain structure may be implicated in pathophysiology of the illness. Longitudinal studies in high-risk offspring and first-episode patients will be needed to examine whether such abnormalities precede the appearance of symptoms, or whether they may appear subsequently as a result of illness course. # 2003 Elsevier Science Ltd. All rights reserved.
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paper_title: A Volumetric Study of Hippocampus and Amygdala in Depressed Patients With Subjective Memory Problems

paper_content:

MRI was used to measure amygdalar and hippocampal volumes in 14 nondemented depressed patients who persistently complained of “memory” difficulties and in 14 control subjects. Mild neuropsychological impairment had been detected in 5 patients before the study but had later improved. The volume of the left amygdala was smaller in depressed subjects, and there was a trend for smaller left hippocampus in the 5 patients who had exhibited mild cognitive impairment. The authors conclude that subjective memory complaints in depressed patients do not translate into a clinical picture of dementia, but that abnormalities in the amygdala and hippocampus may be relevant in explaining affective and cognitive symptoms.
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paper_title: Anatomical MRI study of hippocampus and amygdala in patients with current and remitted major depression

paper_content:

Morphometric MRI studies suggest decreased hippocampal volumes in currently depressed patients, with conflicting findings for the amygdala. We studied these temporal lobe structures and superior temporal gyrus (STG) in patients with current and remitted major depression. We scanned 31 unmedicated depressed patients (21 currently depressed, 10 remitted) and 31 matched healthy controls with a 3D SPGR sequence in a 1.5 Tesla GE Signa Imaging System. There was a trend towards smaller left amygdala volumes in all depressed patients compared with healthy controls. We found significantly smaller hippocampal volumes bilaterally in currently depressed patients than in remitted patients. Furthermore, we found a statistically significant inverse correlation between length of illness and left hippocampus volumes and right superior temporal gyrus volumes. Our finding of smaller hippocampi in currently depressed patients is consistent with the hypothesis that hypercortisolism could result in hippocampal neurotoxicity in major depression. A smaller hippocampal size may be more characteristic of the depressive state and not be present in remitted patients.
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paper_title: Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder

paper_content:

Background In vivo imaging studies in adult bipolar patients have suggested enlargement of the amygdala. It is not known whether this abnormality is already present early in the illness course or whether it develops later in life. We conducted a morphometric MRI study to examine the size of specific temporal lobe structures in adolescents and young adults with bipolar disorder and healthy control subjects, as well as their relationship with age, to examine possible neurodevelopmental abnormalities. Methods Subjects included 16 DSM-IV bipolar patients (16 ± 3 years) and 21 healthy controls (mean age ± SD = 17 ± 4 years). Measures of amygdala, hippocampus, temporal gray matter, temporal lobe, and intracranial volumes (ICV) were obtained. Results There was a trend to smaller left amygdala volumes in patients (mean volumes ± SD = 1.58 ± .42 mL) versus control subjects (1.83 ± .4 mL; F = 3.87, df = 1,32, p = .06). Bipolar patients did not show significant differences in right or left hippocampus, temporal lobe gray matter, temporal lobe, or right amygdala volumes (analysis of covariance, age, gender, and ICV as covariates, p > .05) compared with healthy control subjects. Furthermore, there was a direct correlation between left amygdala volumes and age (r = .50, p = .047) in patients, whereas in healthy controls there was an inverse correlation (r = −.48, p = .03). Conclusions The direct correlation between left amygdala volumes and age in bipolar patients, not present in healthy control subjects, may reflect abnormal developmental mechanisms in bipolar disorder.
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paper_title: Hippocampal atrophy in recurrent major depression.

paper_content:

Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: Reliability of medial temporal lobe volume measurements using reformatted 3D images

paper_content:

Abstract The study assessed whether standardizing the angle of image display and controlling for head position in three planes affects the scan–rescan reliability of medial temporal lobe volume measures when very thin (1.5 mm) slices are used. Five volunteers were scanned two times on consecutive days. A three-dimensional MRI sequence acquired whole brain data in 1.4 mm thick coronal slices. The data were displayed as 1.5 mm thick images and were rated both in the originally acquired coronal plane, and after reformatting to correct for head tilt and display the brain in the coronal plane perpendicular to the long axis of the left anterior hippocampus. One rater measured five brain regions (temporal lobe, anterior and posterior hippocampus, amygdala, and temporal horn) on the left and right sides of the two non-reformatted and two reformatted scans to obtain inter-scan variance. Furthermore, most scans were remeasured, to obtain `reread' variances. All data were log-transformed in order to produce comparable variability across brain regions of different sizes. For all the regions, except the temporal horn, the non-reformatted scans showed significantly larger scan–rescan variability than the reformatted scans. A typical standard deviation for a non-reformatted pair of scans was 0.10, corresponding to 26% error, while a typical value for a reformatted pair of scans was 0.04, corresponding to 10% error. For all the regions, the reread data (intra-rater reliability) gave similar results for both reformatted and non-reformatted images with similar standard deviations (typical value for reread standard deviation was 0.020, corresponding to 5% error). The data suggest that, even when very thin slices are acquired, volume measurement accuracy of gray matter structures in the temporal lobe is considerably improved by controlling for image orientation in three planes. For these structures, the sample size needed to detect a small (5%) within-subject volume change would be halved if reformatted images were used. Image contrast is an additional important factor since the reformatted T 1 weighted images used in this study, which have suboptimal CSF/brain contrast, worsened measurement accuracy in the temporal horn.
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paper_title: Volumetry of Hippocampus and Amygdala with High-resolution MRI and Three-dimensional Analysis Software: Minimizing the Discrepancies between Laboratories

paper_content:

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm 3 ), while no interhemispheric differences for the amygdala (1154 versus 1160 mm 3 )c ould be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.
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paper_title: Hippocampal volume reduction and HPA-system activity in major depression

paper_content:

Structural imaging studies investigating hippocampal volumes in patients suffering from major depression have yielded mixed results. Here, 24 unipolar depressed in-patients and 14 healthy controls carefully matched for age, gender, and years of education underwent quantitative magnetic resonance imaging (MRI). Saliva cortisol was measured at 0800 and 1600 h in patients during a one-week wash-out and the following 4 weeks. Hippocampal volumes were significantly reduced in the patient group even after adjusting for intracranial brain volume (ICV) and age. Across groups, age was significantly negatively correlated with uncorrected hippocampal volumes. In patients, severity of disease (baseline HAMD scores) and baseline cortisol levels were not related to hippocampal volumes. However, there was a negative association between duration of the index episode before hospitalization and hippocampal volumes. Additionally, hippocampal volumes were significantly negatively correlated with duration of illness. Finally, we observed a trend for higher hippocampal volumes in those patients who showed a subsequent decrease in cortisol levels under pharmacotherapy. 2006 Elsevier Ltd. All rights reserved.
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paper_title: Hippocampal Changes in Patients With a First Episode of Major Depression

paper_content:

OBJECTIVE: Previous work suggests that patients with unipolar depression may have structural as well as functional abnormalities in limbic-thalamic-cortical networks, which are hypothesized to modulate human mood states. A core area in these networks is the hippocampus. In the present study, differences in volumes of hippocampal gray and white matter between patients with a first episode of major depression and healthy comparison subjects were examined. METHOD: Thirty patients with a first episode of major depression and 30 healthy comparison subjects who were matched for age, gender, handedness, and education were examined with high-resolution magnetic resonance imaging. RESULTS: Male patients with a first episode of major depression had significantly smaller hippocampal total and gray matter volumes than healthy male comparison subjects. Both male and female patients showed significant alterations of left-right asymmetry and significant reductions of left and right hippocampal white matter fibers in rel...
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paper_title: Article Hippocampal Deformities in Schizophrenia Characterized by High Dimensional Brain Mapping

paper_content:

OBJECTIVE: Abnormalities of hippocampal structure have been reported in schizophrenia subjects. However, such abnormalities have been difficult to discriminate from normal neuroanatomical variation. High dimensional brain mapping, which utilizes probabilistic deformations of a neuroanatomical template, was used to characterize disease-related patterns of changes in hippocampal volume, shape, and asymmetry. METHOD: T1-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects who were similar in age, gender, and parental socioeconomic status. The schizophrenia subjects were clinically stable at the time of assessment. RESULTS: Significant abnormalities of hippocampal shape and asymmetry (but not volume after total cerebral volume was included as a covariate) were found in the schizophrenia subjects. The pattern of shape abnormality suggested a neuroanatomical deformity of the head of the hippocampus, which contains neurons that project to the frontal cortex. The pattern...
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paper_title: Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects

paper_content:

Abstract Findings from cerebral magnetic resonance imaging (MRI) studies in schizophrenia indicating temporal lobe involvement have been inconsistent and controversial. In a prospective study, we quantified the volumes of temporal lobe structures in 20 male patients with first episode schizophrenia (FES; mean±S.D.=27.4±4.8 years) and 20 healthy age-matched male control subjects (27.7±3.1 years). Measurements were performed on contiguous 2.2-mm coronal MRI slices, which included, as well as the temporal lobe, the amygdala, the hippocampal formation, and the temporal horn of the lateral ventricle. The definition of the borders of the structures relied on measurement guidelines derived from mutual comparisons of MRI and histological data. The definition of the hippocampus–amygdala interface was also validated in a correlated triplanar display. We did not detect any significant volume reductions of the measured structures in the FES group, as compared with healthy control subjects, on either side. Comparisons within groups, however, revealed that in both the patients and the healthy volunteers the hippocampal formations showed a significant right-sided bias (+9%, P =0.004, in the FES group; +12%, P =0.0003 in the control subjects). A significant volume difference in favor of the right hemisphere was also observed in the temporal horns of the lateral ventricles (+17%, P =0.02 in the patients with FES; +34%, P =0.003, in the control group). There was only a nonsignificant trend for a larger temporal horn on the left side in patients with schizophrenia as compared with the control subjects. Our findings do not indicate a loss or reversal of the normal volume asymmetry pattern in the FES group.
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paper_title: Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study

paper_content:

Abstract Background: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. Methods: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. Results: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. Conclusions: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.
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paper_title: High-Dimensional Mapping of the Hippocampus in Depression

paper_content:

OBJECTIVE: Abnormalities of the hippocampus may play a role in the pathophysiology of depression, but efforts to identify a structural abnormality in this brain structure among depressed patients have produced mixed results. Previous research may have been limited by exclusive reliance on measures of hippocampal volume. High-dimensional brain mapping is a new analytic method that quantitatively characterizes the shape as well as volume of a brain structure. In this study, high-dimensional brain mapping was used to evaluate hippocampal shape and volume in patients with major depressive disorder and healthy comparison subjects. METHOD: By using magnetic resonance imaging, brain scans were obtained from 27 patients with major depressive disorder and 42 healthy comparison subjects. High-dimensional brain mapping generated a series of 10 variables (components) that represented hippocampal shape, and hippocampal volumes were also computed. Analysis of variance techniques were used to compare depressed patients ...
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paper_title: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging

paper_content:

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer9s disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.
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paper_title: Mesial temporal lobe measurements on magnetic resonance imaging scans

paper_content:

Abstract Changes in the mesial temporal lobe, particularly in the hippocampus, amygdala, and entorhinal cortex, are reported to occur in several neuropsychiatric conditions. Neuroimaging provides a non-invasive means of studying these changes. We present a method for reliably measuring the hippocampus, amygdala, and entorhinal cortex on MRI. The advantages of our method include high reliability, the use of orthogonal views in delineating boundaries and circumscription of measurement such that no tissue of any one anatomic structure is included in the measurement of another structure.
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paper_title: Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects

paper_content:

Background Hippocampal volumes obtained from a group of medication-free, remitted subjects with recurrent major depressive disorder (MDD) were compared against corresponding measures from healthy controls. Methods Thirty-one subjects with recurrent MDD in full remission, and 57 healthy controls underwent high resolution magnetic resonance imaging (MRI) on a GE 3T scanner. Eight patients with MDD were medication-naive, and twenty-three MDD patients were off antidepressant medications for a mean of 30 months at the time of the MRI study. Results Patients showed smaller total and posterior hippocampal volume relative to controls. Anterior hippocampal volume did not differ between patients and controls. Conclusions Recurrent depression is associated with smaller hippocampal volume which is most prominent in the posterior hippocampus. Smaller hippocampal volume appears to be a trait characteristic for MDD.
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paper_title: Hippocampal atrophy in recurrent major depression.

paper_content:

Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas.

paper_content:

PURPOSE ::: To test automated three-dimensional magnetic resonance (MR) imaging morphometry of the human hippocampus, to determine the potential gain in precision compared with conventional manual morphometry. ::: ::: ::: MATERIAL AND METHODS ::: A canonical three-dimensional MR image atlas was used as a deformable template and automatically matched to three-dimensional MR images of 10 individuals (five healthy and five schizophrenic subjects). A subvolume containing the hippocampus was defined by using 16 landmarks that constrained the automated search for hippocampal boundaries. Transformation of the hippocampus template was automatically performed by using global pattern matching through a sequence of low-then high-dimensional translations, rotations, and scalings. ::: ::: ::: RESULTS ::: The average test-retest volume difference measured with the automatic method was 3.1%, compared with the manual test-retest difference of 7.1%. Correlation between automated and manually determined volumes demonstrated the validity of the automated technique (intraclass correlation coefficient = .86). ::: ::: ::: CONCLUSION ::: The automated method estimates hippocampal volumes with less variability (ie, lower variance) than that of manual out-lining.
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paper_title: Enlarged amygdala volume and reduced hippocampal volume in young women with major depression.

paper_content:

Background. Evidence is increasing that amygdala and hippocampus show significant structural abnormalities in affective disorders. Two previous studies found enlarged amygdala size in subjects with recent-onset major depression. Method. Amygdala and hippocampal volumes were assessed in 17 young women with major depressive disorder and 17 healthy matched control subjects by use of three-dimensional structural magnetic resonance imaging. The severity of depressive symptoms was assessed using the Hamilton Depression Scale and the Beck Depression Inventory. Results. Compared with control subjects, depressive subjects had significantly larger (+13%) amygdala volumes and significantly smaller (−12%) hippocampal volumes. Amygdala and hippocampal volumes were not significantly correlated with disorder-related variables. Conclusions. Our results are consistent with previous findings of structural abnormalities of amygdala and hippocampus in subjects with recent-onset major depression. It may be suggested that the size of the amygdala is enlarged in the first years of the disorder, and may decrease with prolonged disorder duration.
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paper_title: Untreated Depression and Hippocampal Volume Loss

paper_content:

OBJECTIVE: The purpose of this study was to investigate the effect of antidepressant treatment on hippocampal volumes in patients with major depression. METHOD: For 38 female outpatients, the total time each had been in a depressive episode was divided into days during which the patient was receiving antidepressant medication and days during which no antidepressant treatment was received. Hippocampal gray matter volumes were determined by high resolution magnetic resonance imaging and unbiased stereological measurement. RESULTS: Longer durations during which depressive episodes went untreated with antidepressant medication were associated with reductions in hippocampal volume. There was no significant relationship between hippocampal volume loss and time depressed while taking antidepressant medication or with lifetime exposure to antidepressants. CONCLUSIONS: Antidepressants may have a neuroprotective effect during depression.
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paper_title: Depression Duration But Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression

paper_content:

This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss.
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paper_title: Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: A pilot study

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Background Previous reports of ventricular and hippocampal volumes in patients with bipolar disorder (BP) have been inconsistent in their findings. One possibility is that volumetric abnormalities are determined by disease subtype. Prior evidence suggests that psychotic (PBP) and nonpsychotic (NPBP) forms of BP are two subtypes that might differ in pathophysiology. Methods We investigated ventricular and hippocampal volumes in 38 adults with clearly defined PBP (n = 23) and NPBP subtypes, compared with 33 persons with schizophrenia (SZ) and 44 healthy community control subjects (HC). Ventricular and hippocampal volumes were reliably measured on high-resolution anatomic magnetic resonance imaging scans. We used a multivariate analysis of covariance to compare volumes across groups, covarying for total brain volume. Potential effects of BP illness features were explored, contrasting PBP and NPBP. Results For ventricular but not hippocampal regions, we found significant volume difference in PBP but not NPBP compared with HC (p Conclusions These results suggest that PBP but not NPBP is associated with increased ventricle volumes and a trend toward smaller left hippocampal volumes, as observed in SZ.
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paper_title: Hippocampal/amygdala volumes in geriatric depression

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Background. The hippocampus, amygdala and related functional circuits have been implicated in the regulation of emotional expression and memory processes, which are affected in major depression. Several recent investigations have reported abnormalities in these structures in adult and elderly depressives. Methods. Elderly DSM-III-R unipolar depressives ( N =40) and normal controls ( N =46) participated in a magnetic resonance imaging study (1.0T). Brain images were obtained in the coronal plane. Using established anatomical guidelines for structure delineation, volumetric measurements of left and right hippocampus and anterior hippocampus/amygdala complex were completed under blinded conditions using a semi-automated computer mensuration system, with patients and controls in random order. Results. Medial temporal volumes did not significantly distinguish either elderly depressed and age-similar normal control subjects, or late onset and early onset depressed patients (ANCOVA). Major overlap of measured volumes existed between patient and control groups. In depressives, hippocampal volumes significantly correlated with age, and cognitive and depression ratings, but not with number of prior depressive episodes or age-at-onset of first depression. Conclusions. Hippocampal volumes do not discriminate a typical clinical population of elderly depressed patients from age-similar normal control subjects. If hippocampal dysfunction contributes to a diagnosis of syndromal depression in the elderly, such dysfunction does not appear to be regularly reflected in structural abnormalities captured by volumetric measurement as conducted. On the other hand, relationships between hippocampal volumes and clinical phenomena in depressives, but not controls, suggest potentially meaningful interactions between hippocampal structure and the expression of major depression in the elderly.
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paper_title: Hippocampal Changes in Patients With a First Episode of Major Depression

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OBJECTIVE: Previous work suggests that patients with unipolar depression may have structural as well as functional abnormalities in limbic-thalamic-cortical networks, which are hypothesized to modulate human mood states. A core area in these networks is the hippocampus. In the present study, differences in volumes of hippocampal gray and white matter between patients with a first episode of major depression and healthy comparison subjects were examined. METHOD: Thirty patients with a first episode of major depression and 30 healthy comparison subjects who were matched for age, gender, handedness, and education were examined with high-resolution magnetic resonance imaging. RESULTS: Male patients with a first episode of major depression had significantly smaller hippocampal total and gray matter volumes than healthy male comparison subjects. Both male and female patients showed significant alterations of left-right asymmetry and significant reductions of left and right hippocampal white matter fibers in rel...
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paper_title: The Human Hippocampus: Functional Anatomy, Vascularization and Serial Sections with MRI

paper_content:

Introduction.- Material and Methods.- Structure, Functions, and Connections: Preliminary Remarks.- Structure.- Cornu Ammonis (Hippocampus Proper).- Gyrus Dentatus (Fascia Dentata, Gyrus Involutus).- Structures Joined to the Hippocampus.- Functions and Connections.- Learning and Memory.- Emotional Behavior.-Motor Control.- Hypothalamus.- Comparative Studies.- Anatomy: Preliminary Remarks.- Hippocampal Body.- Intraventricular Part.- Extraventricular or Superficial Part.- Relations with Adjacent Structures.- Hippocampal Head.- Intraventricular Part.-Extraventricular or Uncal Part.- Relations of the Uncus with Adjacent Structures.- Hippocampal Tail.- Intraventricular Part.-Extraventricular Part.- Relations with Adjacent Structures.- General Features. Vascularization: Superficial (Leptomeningeal) Blood Vessels.- Superficial Hippocampal Arteries.- Superficial Hippocampal Veins.- Intrahippocampal (Deep) Blood Vessels.-Intrahippocampal Arteries.- Intrahippocampal Veins.- Hippocampal Head.- Vascular Network. Coronal, Sagittal and Axial Sections of the Hippocampus Showing its Relationships with the Surrounding Structures (after intravascular india ink injection).-Sectional Anatomy and Magnetic Resonance Imaging: Coronal Sections.- Sagittal Sections.- Axial Sections.- References.- Index.
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paper_title: Segmented Hippocampal Volume in Children and Adolescents with Posttraumatic Stress Disorder

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Background Although many studies of adults with posttraumatic stress disorder (PTSD) have reported smaller hippocampal volume compared with control subjects, comparable studies of children and adolescents have failed to replicate these findings or have noted opposite trends suggesting a larger hippocampus. We therefore performed a secondary analysis combining data from prior studies to examine the hypothesis that hippocampus would be larger in pediatric subjects with PTSD compared with non-maltreated control subjects. We also hypothesized that differences in PTSD subjects would be observed between boys and girls. Methods Sixty-one subjects (31 boys, 30 girls) with maltreatment-related PTSD and 122 control subjects matched on age and gender underwent magnetic resonance imaging. Results As hypothesized, we observed a significantly larger hippocampus controlling for cerebral volume in PTSD subjects compared with control subjects. Segmented hippocampal white-matter volume was greater in PTSD subjects but not gray-matter volume. Hippocampal volume was positively related to age of trauma onset and level of psychopathology, particularly externalizing behavior. No interactions with group were observed for age or gender. Conclusions Future longitudinal studies with trauma control subjects and neuropsychological measures are indicated to further elucidate the relationship between hippocampus and behavioral abnormalities in young PTSD subjects.
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paper_title: MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed

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The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.
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paper_title: MRI investigation of temporal lobe structures in bipolar patients

paper_content:

Previous anatomical MRI studies have suggested abnormalities in amygdala volumes in bipolar disorder, whereas hippocampus, temporal lobe (TL), and superior temporal gyri (STG) measures have been reported to be normal. This study further investigated the existence of anatomical abnormalities in these brain structures in bipolar subjects, to attempt to replicate previously reported findings. Twenty-four DSM-IV bipolar patients (mean ageS.D.=35 10 years) and 36 healthy controls (mean age S.D.=3710 years) were studied. 3D SPGR images were obtained with a 1.5T-GE Signa magnet (TR=25 ms, TE=5 ms, FOV=24 cm, slice-thickness=1.5 mm, matrix-size=256192). Volumetric measurements of TL, hippocampus, amygdala, and STG were performed blindly, with a semi-automated software. Bipolar patients had significantly larger left amygdala volumes compared with controls (mean volumes S.D.=2.57 0.69 vs. 2.17 0.58 ml, respectively; ANCOVA, age, gender, ICV as covariates; F=4.42, df=1/55, P=0.04). The volumes of the other temporal lobe structures did not differ significantly between the two groups (ANCOVA, age, gender, and ICV as covariates, P >0.05). Our findings of enlarged left amygdala in bipolar patients are in agreement with prior MRI studies, suggesting that abnormalities in this brain structure may be implicated in pathophysiology of the illness. Longitudinal studies in high-risk offspring and first-episode patients will be needed to examine whether such abnormalities precede the appearance of symptoms, or whether they may appear subsequently as a result of illness course. # 2003 Elsevier Science Ltd. All rights reserved.
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paper_title: Anatomical MRI study of hippocampus and amygdala in patients with current and remitted major depression

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Morphometric MRI studies suggest decreased hippocampal volumes in currently depressed patients, with conflicting findings for the amygdala. We studied these temporal lobe structures and superior temporal gyrus (STG) in patients with current and remitted major depression. We scanned 31 unmedicated depressed patients (21 currently depressed, 10 remitted) and 31 matched healthy controls with a 3D SPGR sequence in a 1.5 Tesla GE Signa Imaging System. There was a trend towards smaller left amygdala volumes in all depressed patients compared with healthy controls. We found significantly smaller hippocampal volumes bilaterally in currently depressed patients than in remitted patients. Furthermore, we found a statistically significant inverse correlation between length of illness and left hippocampus volumes and right superior temporal gyrus volumes. Our finding of smaller hippocampi in currently depressed patients is consistent with the hypothesis that hypercortisolism could result in hippocampal neurotoxicity in major depression. A smaller hippocampal size may be more characteristic of the depressive state and not be present in remitted patients.
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paper_title: MRI-based measurement of hippocampal volume in patients with combat- related posttraumatic stress disorder

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Patients with combat-related posttraumatic stress disorder (PTSD) clinically demonstrate alterations in memory, including nightmares, flashbacks, intrusive memories, and amnesia for war experiences. In addition, descriptions from all wars of this century document alterations in memory occurring in combat veterans during or after the stress of battle. These include forgetting one's name or identity and forgetting events that had just taken place during the previous battle (1, 2), as well as gaps in memory that continue to recur for many years after the war (3). Servicemen who had been prisoners of war during the Korean conflict were found to have an impairment in short-term verbal memory, as measured by the logical memory component of the Wechsler Memory Scale, in comparison with veterans of the Korean war who did not have a history of imprisonment (4). We also found deficits in short-term verbal memory, as measured by the logical memory component of the Wechsler Memory Scale, in Vietnam combat veterans with combat-related PTSD in comparison with healthy subjects who were matched for age, years of education, and alcohol abuse (5). ::: ::: Several lines of evidence suggest a relation between stress and damage to the hippocampus (6). The hippocampus and the adjacent perirhinal, parahippocampal, and entorhinal cortex play an important role in short-term memory (7). Studies in humans have shown that reductions in hippocampal volume secondary to either neurosurgery (8) or the pathophysiological effects of epilepsy (9) are associated with deficits in short-term memory as measured by the Wechsler Memory Scale. Monkeys exposed to the extreme stress of improper caging have shown increased glucocorticoid release as well as damage to the CA2 and CA3 subfields of the hippocampus (10). Studies in a variety of animal species suggest that direct glucocorticoid exposure results in a loss of neurons and a decrease in dendritic branching in the hippocampus (11, 12) with associated deficits in memory function (13). The mechanism of action of glucocorticoid toxicity is probably through an increase in the vulnerability of neurons to the toxicity of excitatory amino acids (14–16). Studies using computed tomography in human subjects who are exposed to high levels of glucocorticoids secondary to glucocorticoid steroid therapy (17, 18) or who have affective disorders (also felt to be related to stress) (19) have shown changes in brain structure, including ventricular enlargement and widening of the cortical sulci. Magnetic resonance imaging (MRI) studies in patients with affective disorders have shown a smaller right hippocampal volume (20) and temporal lobe volume (21) in bipolar disorder and abnormalities of the hippocampus, including alterations in T1 (22), but no change in hippocampal volume (23) in major depression. One MRI study (24) found a relation between deficits in short-term memory and smaller hippocampal volume, as well as higher plasma cortisol levels and smaller hippocampal volume, in patients with Cushing's disease. Stress in both healthy human subjects (25) and soldiers undergoing random artillery bombardment (26) results in an increase in urinary cortisol, suggesting the possibility that exposure to the extreme stress of combat may be associated with damage to the hippocampus. ::: ::: The purpose of this study was to use MRI to measure the volume of the hippocampus and comparison brain structures in patients with PTSD and in matched comparison subjects. We hypothesized that PTSD would be associated with smaller hippocampal volume in relation to that of the comparison subjects. We also hypothesized that smaller hippocampal volume would be associated with deficits in short-term verbal memory in patients with PTSD.
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paper_title: Volumetry of Hippocampus and Amygdala with High-resolution MRI and Three-dimensional Analysis Software: Minimizing the Discrepancies between Laboratories

paper_content:

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm 3 ), while no interhemispheric differences for the amygdala (1154 versus 1160 mm 3 )c ould be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.
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paper_title: Regional specificity of hippocampal volume reductions in first-episode schizophrenia

paper_content:

Abstract Hippocampal volume reductions are widely observed in schizophrenia. Some studies suggest anterior hippocampal regions are more susceptible and associated with frontal lobe dysfunctions, while others implicate posterior regions. Using high-resolution MR images and novel computational image analysis methods, we identified the hippocampal subregions most vulnerable to disease processes in 62 (45 m/17 f) first-episode schizophrenia patients compared to 60 (30 m/30 f) healthy controls, similar in age. The hippocampi were traced on coronal brain slices and hemispheric volumes were compared between diagnostic groups. Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups in 3D. CSF concentrations were also compared statistically at homologous hippocampal surface points to localize corresponding gray matter reductions. Significant bilateral hippocampal volume reductions were observed in schizophrenia irrespective of brain size corrections. Statistical mapping results, confirmed by permutation testing, showed pronounced left hemisphere shape differences in anterior and midbody CA1 and CA2 regions in patients. Significant CSF increases surrounding the hippocampus were observed in a similar spatial pattern in schizophrenia. Results confirm that hippocampal volume reductions are a robust neuroanatomical correlate of schizophrenia and are present by first episode. Mid- to antero-lateral hippocampal regions show pronounced volume changes and complementary increases in peri-hippocampal CSF, suggesting that these hippocampal regions are more susceptible to disease processes in schizophrenia. Targeting regional hippocampal abnormalities may help dissociate schizophrenia patients from other groups exhibiting global hippocampal volume changes, and better focus systems-level pathophysiological hypotheses.
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paper_title: Sex and symmetry differences in hippocampal volumetrics: Before and beyond the opening of the crus of the fornix

paper_content:

Published normative volumetrics of the hippocampus (HC) vary substantially. While the protocol suggested by Watson et al. (Neurology 42 (1992) 1743-1750; Arch Neurology 54 (1997) 1521- 1531) is the most frequently adhered to, this leaves the posterior section of the HC tail unmeasured, which has been estimated to be in the order of 2-4 mm, representing 5-10% of total HC volume. The objective of the current study was to compare HC volumes according to the method of Watson et al. (Neurology 42 (1992) 1743-1750; Arch Neurology 54 (1997) 1521-1531) against those measured to include the posterior tail section. From a random community sample of 60-64 yr old individuals, 478 subjects underwent magnetic resonance imaging brain scans. Of these, 452 scans (238 males and 214 females) were adequate for hippo- campal measurement. The scans comprised whole brain T1- weighted and T2-weighted FLAIR images. One hundred and fifty scans were ran- domly selected for the measurement of HC volumes beyond the opening of the crus of the fornix by manual tracings on T1-weighted images by a trained operator. Intracranial volume (ICV) and total brain volume (TBV) were measured using an automated program. We found that the posterior HC tail extended for a mean of just over 5 mm and comprised 11% of total HC volume. Males had significantly larger raw HC vol- umes, and while normalization with ICV or TBV reversed this pattern, it was significant only when the posterior HC tail was included in the measurement. In conclusion, this study showed that including the poste- rior part of the tail can influence the results of HC measurement. An argument is presented that accurate HC volumes should include the entire HC and not exclude the tail. V C 2005 Wiley-Liss, Inc.
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paper_title: Hippocampal atrophy in recurrent major depression.

paper_content:

Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: Reliability of medial temporal lobe volume measurements using reformatted 3D images

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Abstract The study assessed whether standardizing the angle of image display and controlling for head position in three planes affects the scan–rescan reliability of medial temporal lobe volume measures when very thin (1.5 mm) slices are used. Five volunteers were scanned two times on consecutive days. A three-dimensional MRI sequence acquired whole brain data in 1.4 mm thick coronal slices. The data were displayed as 1.5 mm thick images and were rated both in the originally acquired coronal plane, and after reformatting to correct for head tilt and display the brain in the coronal plane perpendicular to the long axis of the left anterior hippocampus. One rater measured five brain regions (temporal lobe, anterior and posterior hippocampus, amygdala, and temporal horn) on the left and right sides of the two non-reformatted and two reformatted scans to obtain inter-scan variance. Furthermore, most scans were remeasured, to obtain `reread' variances. All data were log-transformed in order to produce comparable variability across brain regions of different sizes. For all the regions, except the temporal horn, the non-reformatted scans showed significantly larger scan–rescan variability than the reformatted scans. A typical standard deviation for a non-reformatted pair of scans was 0.10, corresponding to 26% error, while a typical value for a reformatted pair of scans was 0.04, corresponding to 10% error. For all the regions, the reread data (intra-rater reliability) gave similar results for both reformatted and non-reformatted images with similar standard deviations (typical value for reread standard deviation was 0.020, corresponding to 5% error). The data suggest that, even when very thin slices are acquired, volume measurement accuracy of gray matter structures in the temporal lobe is considerably improved by controlling for image orientation in three planes. For these structures, the sample size needed to detect a small (5%) within-subject volume change would be halved if reformatted images were used. Image contrast is an additional important factor since the reformatted T 1 weighted images used in this study, which have suboptimal CSF/brain contrast, worsened measurement accuracy in the temporal horn.
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paper_title: Article Hippocampal Deformities in Schizophrenia Characterized by High Dimensional Brain Mapping

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OBJECTIVE: Abnormalities of hippocampal structure have been reported in schizophrenia subjects. However, such abnormalities have been difficult to discriminate from normal neuroanatomical variation. High dimensional brain mapping, which utilizes probabilistic deformations of a neuroanatomical template, was used to characterize disease-related patterns of changes in hippocampal volume, shape, and asymmetry. METHOD: T1-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects who were similar in age, gender, and parental socioeconomic status. The schizophrenia subjects were clinically stable at the time of assessment. RESULTS: Significant abnormalities of hippocampal shape and asymmetry (but not volume after total cerebral volume was included as a covariate) were found in the schizophrenia subjects. The pattern of shape abnormality suggested a neuroanatomical deformity of the head of the hippocampus, which contains neurons that project to the frontal cortex. The pattern...
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paper_title: Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects

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Abstract Findings from cerebral magnetic resonance imaging (MRI) studies in schizophrenia indicating temporal lobe involvement have been inconsistent and controversial. In a prospective study, we quantified the volumes of temporal lobe structures in 20 male patients with first episode schizophrenia (FES; mean±S.D.=27.4±4.8 years) and 20 healthy age-matched male control subjects (27.7±3.1 years). Measurements were performed on contiguous 2.2-mm coronal MRI slices, which included, as well as the temporal lobe, the amygdala, the hippocampal formation, and the temporal horn of the lateral ventricle. The definition of the borders of the structures relied on measurement guidelines derived from mutual comparisons of MRI and histological data. The definition of the hippocampus–amygdala interface was also validated in a correlated triplanar display. We did not detect any significant volume reductions of the measured structures in the FES group, as compared with healthy control subjects, on either side. Comparisons within groups, however, revealed that in both the patients and the healthy volunteers the hippocampal formations showed a significant right-sided bias (+9%, P =0.004, in the FES group; +12%, P =0.0003 in the control subjects). A significant volume difference in favor of the right hemisphere was also observed in the temporal horns of the lateral ventricles (+17%, P =0.02 in the patients with FES; +34%, P =0.003, in the control group). There was only a nonsignificant trend for a larger temporal horn on the left side in patients with schizophrenia as compared with the control subjects. Our findings do not indicate a loss or reversal of the normal volume asymmetry pattern in the FES group.
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paper_title: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging

paper_content:

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer9s disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.
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paper_title: Mesial temporal lobe measurements on magnetic resonance imaging scans

paper_content:

Abstract Changes in the mesial temporal lobe, particularly in the hippocampus, amygdala, and entorhinal cortex, are reported to occur in several neuropsychiatric conditions. Neuroimaging provides a non-invasive means of studying these changes. We present a method for reliably measuring the hippocampus, amygdala, and entorhinal cortex on MRI. The advantages of our method include high reliability, the use of orthogonal views in delineating boundaries and circumscription of measurement such that no tissue of any one anatomic structure is included in the measurement of another structure.
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paper_title: Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas.

paper_content:

PURPOSE ::: To test automated three-dimensional magnetic resonance (MR) imaging morphometry of the human hippocampus, to determine the potential gain in precision compared with conventional manual morphometry. ::: ::: ::: MATERIAL AND METHODS ::: A canonical three-dimensional MR image atlas was used as a deformable template and automatically matched to three-dimensional MR images of 10 individuals (five healthy and five schizophrenic subjects). A subvolume containing the hippocampus was defined by using 16 landmarks that constrained the automated search for hippocampal boundaries. Transformation of the hippocampus template was automatically performed by using global pattern matching through a sequence of low-then high-dimensional translations, rotations, and scalings. ::: ::: ::: RESULTS ::: The average test-retest volume difference measured with the automatic method was 3.1%, compared with the manual test-retest difference of 7.1%. Correlation between automated and manually determined volumes demonstrated the validity of the automated technique (intraclass correlation coefficient = .86). ::: ::: ::: CONCLUSION ::: The automated method estimates hippocampal volumes with less variability (ie, lower variance) than that of manual out-lining.
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paper_title: Untreated Depression and Hippocampal Volume Loss

paper_content:

OBJECTIVE: The purpose of this study was to investigate the effect of antidepressant treatment on hippocampal volumes in patients with major depression. METHOD: For 38 female outpatients, the total time each had been in a depressive episode was divided into days during which the patient was receiving antidepressant medication and days during which no antidepressant treatment was received. Hippocampal gray matter volumes were determined by high resolution magnetic resonance imaging and unbiased stereological measurement. RESULTS: Longer durations during which depressive episodes went untreated with antidepressant medication were associated with reductions in hippocampal volume. There was no significant relationship between hippocampal volume loss and time depressed while taking antidepressant medication or with lifetime exposure to antidepressants. CONCLUSIONS: Antidepressants may have a neuroprotective effect during depression.
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paper_title: Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps

paper_content:

Probabilistic maps of neocortical areas and subcortical fiber tracts, warped to a common reference brain, have been published using microscopic architectonic parcellations in ten human postmortem brains. The maps have been successfully applied as topographical references for the anatomical localization of activations observed in functional imaging studies. Here, for the first time, we present stereotaxic, probabilistic maps of the hippocampus, the amygdala and the entorhinal cortex and some of their subdivisions. Cytoarchitectonic mapping was performed in serial, cell-body stained histological sections. The positions and the extent of cytoarchitectonically defined structures were traced in digitized histological sections, 3-D reconstructed and warped to the reference space of the MNI single subject brain using both linear and non-linear elastic tools of alignment. The probability maps and volumes of all structures were calculated. The precise localization of the borders of the mapped regions cannot be predicted consistently by macroanatomical landmarks. Many borders, e.g. between the subiculum and entorhinal cortex, subiculum and Cornu ammonis, and amygdala and hippocampus, do not match sulcal landmarks such as the bottom of a sulcus. Only microscopic observation enables the precise localization of the borders of these brain regions. The superposition of the cytoarchitectonic maps in the common spatial reference system shows a considerably lower degree of intersubject variability in size and position of the allocortical structures and nuclei than the previously delineated neocortical areas. For the first time, the present observations provide cytoarchitectonically verified maps of the human amygdala, hippocampus and entorhinal cortex, which take into account the stereotaxic position of the brain structures as well as intersubject variability. We believe that these maps are efficient tools for the precise microstructural localization of fMRI, PET and anatomical MR data, both in healthy and pathologically altered brains.
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paper_title: Increased Amygdala: Hippocampal Volume Ratios Associated with Severity of Anxiety in Pediatric Major Depression

paper_content:

Background: Neurobiologic abnormalities in the temporal lobe, particularly medial temporolimbic circuits, have been implicated in the pathogenesis of major depressive disorder (MDD). Although MDD commonly emerges during childhood and adolescence, to our knowledge, no prior study has examined temporal lobe anatomy in pediatric patients with MDD near the onset of illness before treatment. Methods: Volumetric magnetic resonance imaging scans were conducted in 23 psychotropic drug-naive pediatric patients with MDD, aged 8–17 years, and 23 case-matched healthy comparison subjects. Results: Pediatric patients with MDD had significantly larger left (14%) and right (11%) amygdala:hippocampal volume ratios than controls. Increased left and right amygdala:hippocampal volume ratios were associated with increased severity of anxiety but not increased severity of depression or duration of illness. Conclusion: These results suggest that alterations in amygdala:hippocampal volume ratios in pediatric MDD may more reflect...
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paper_title: Multitracer: a Java-based tool for anatomic delineation of grayscale volumetric images

paper_content:

Abstract A Java-based tool for delineating anatomic boundaries in 8- and 16- bit grayscale volumetric images is described. Modern features implemented by the tool include the ability to simultaneously view the current cursor position and the previously delineated boundaries on three orthogonal planes, the ability to magnify images during delineation using high-quality interpolation, the ability to encode and save boundaries with subvoxel resolution, and the ability to utilize coregistered images interchangeably during delineation. Additional features facilitate use of the tool in a multiuser, multiplatform environment and provide support for the documentation of anatomic delineation protocols. In addition to providing direct estimates of structure volumes, areas, and lengths, the tool allows contoured boundaries to be exported for more sophisticated analyses. The tool also provides support for manual editing of image volumes to remove confounding structures and for manual correction of image volumes that have been inaccurately edited. In addition to its research utility, the tool also has potential value in education, allowing students to interact with volumetric data and structural boundaries in three dimensions.
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paper_title: Protocol for volumetric segmentation of medial temporal structures using high-resolution 3-D magnetic resonance imaging

paper_content:

Quantitative analysis of brain structures in normal subjects and in different neurological conditions can be carried out in vivo through magnetic resonance imaging (MRI) volumetric studies. The use of high-resolution MRI combined with image post-processing that allows simultaneous multiplanar view may facilitate volumetric segmentation of temporal lobe structures. We define a protocol for volumetric studies of medial temporal lobe structures using high-resolution MR images and we studied 30 healthy subjects (19 women; mean age, 33 years; age range, 21–55 years). Images underwent field non-homogeneity correction and linear stereotaxic transformation into a standard space. Structures of interest comprised temporopolar, entorhinal, perirhinal, parahippocampal cortices, hippocampus, and the amygdala. Segmentation was carried out with multiplanar assessment. There was no statistically significant left/right-sided asymmetry concerning any structure analyzed. Neither gender nor age influenced the volumes obtained. The coefficient of repeatability showed no significant difference of intra- and interobserver measurements. Imaging post-processing and simultaneous multiplanar view of high-resolution MRI facilitates volumetric assessment of the medial portion of the temporal lobe with strict adherence to anatomic landmarks. This protocol shows no significant inter- and intraobserver variations and thus is reliable for longitudinal studies. Hum. Brain Mapp. 22:145–154, 2004. © 2004 Wiley-Liss, Inc.
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paper_title: Volumetry of Hippocampus and Amygdala with High-resolution MRI and Three-dimensional Analysis Software: Minimizing the Discrepancies between Laboratories

paper_content:

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm 3 ), while no interhemispheric differences for the amygdala (1154 versus 1160 mm 3 )c ould be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.
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paper_title: MRI-based hippocampal volume measurements in epilepsy.

paper_content:

In the study of brain morphometry, it is accepted that a relationship exists between brain structure and function, both normal and abnormal. One descriptor of morphometric structure is volume. Abnormalities in hippocampal morphology, including unilateral or bilateral volume loss, are known to occur in epilepsy, Alzheimer's disease, and in certain amnestic syndromes. Precise quantitation should improve understanding of the role of any biologic system in normal function and in disease. The objectives of magnetic resonance (MR)-based hippocampal volume measurements are precise quantitation, identification of a normal range, and identification of the association between biologic variables and aberrations in this volumetric parameter. Volumetric measures introduce a level of precision in the estimation of hippocampal size that is not available simply by visually inspecting a set of MR images, thus enabling statistically based hypothesis testing. To produce accurate hippocampal volume measurements with magnetic resonance imaging (MRI), attention must be directed to the two major components of the operation as a whole, MR image acquisition and image processing.
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paper_title: Temporal Lobe Anatomy and Psychiatric Symptoms in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)

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ABSTRACT Objective To investigate the association between mesial temporal lobe morphology, ratios of prefrontal cortex to amygdala and hippocampus volumes, and psychiatric symptomatology in children and adolescents with velocardiofacial syndrome (VCFS). Method Scores on behavioral rating scales and volumetric measures of the amygdala, hippocampus, and prefrontal cortex based on high-resolution magnetic resonance imaging were compared among 47 children with VCFS, 15 of their siblings, and 18 community controls. Results After covarying for whole brain volume, children with VCFS exhibited 11% greater volume of the left amygdala ( p =.002) and 8% greater volume of the right amygdala ( p =.01). Children with VCFS exhibited smaller volumes of the hippocampus, but not disproportionately to reductions in whole brain volume. Children with VCFS exhibited smaller volumetric ratios of prefrontal and orbitofrontal cortex to amygdala, but not prefrontal cortex to hippocampus. For children with VCFS, but not for the comparison sample, larger volumes of the amygdala and smaller ratios of prefrontal cortex to amygdala were associated with higher scores on the Internalizing, Externalizing, Anxiety, and Aggression scales of the Child Behavior Checklist and on the parent version of the Young Mania Rating Scale. Conclusions These findings suggest that the prefrontal cortex-amygdala circuit that underlies emotional processing is disrupted in children with VCFS and may be an important neurobiological substrate of psychiatric disorder in these children. J. Am. Acad. Child Adolesc. Psychiatry , 2006;45(5):000-000.
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paper_title: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging

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Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer9s disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.
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paper_title: Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects

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Background Hippocampal volumes obtained from a group of medication-free, remitted subjects with recurrent major depressive disorder (MDD) were compared against corresponding measures from healthy controls. Methods Thirty-one subjects with recurrent MDD in full remission, and 57 healthy controls underwent high resolution magnetic resonance imaging (MRI) on a GE 3T scanner. Eight patients with MDD were medication-naive, and twenty-three MDD patients were off antidepressant medications for a mean of 30 months at the time of the MRI study. Results Patients showed smaller total and posterior hippocampal volume relative to controls. Anterior hippocampal volume did not differ between patients and controls. Conclusions Recurrent depression is associated with smaller hippocampal volume which is most prominent in the posterior hippocampus. Smaller hippocampal volume appears to be a trait characteristic for MDD.
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paper_title: Hippocampal atrophy in recurrent major depression.

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Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
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paper_title: Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome

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Evidence from numerous structural magnetic resonance imaging (MRI) studies has converged to implicate mesial temporal lobe structures in the pathophysiology of several developmental and psychiatric disorders. Efforts to integrate the results of these studies are challenged, however, by the lack of consistency, detail and precision in published protocols for the manual measurement of the amygdala and hippocampus. In this study, we describe a highly detailed, standardized protocol for measuring the amygdala and the hippocampus. Within the context of this protocol, we tested the inter- and intra-rater reliability of two frequently cited methods for normalizing the anatomical position of the amygdala and hippocampus prior to measurement. One method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the long axis of the hippocampus. The second method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the axis connecting the anterior and posterior commissures. Inter- and intra-rater reliability coefficients (using the intraclass correlation) ranged from 0.80 to 0.98, indicating that both methods for positional normalization are highly reliable. In addition, we tested the validity of each method by comparing the temporal lobe anatomy of children with fragile X syndrome to a group of unaffected children matched by age and gender. We found that hippocampal volumes in children with fragile X were significantly increased when either rotational method was used. These results replicated previous findings, suggesting that either method can be validly applied to neuroanatomic studies of pediatric populations.
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paper_title: Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps

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Probabilistic maps of neocortical areas and subcortical fiber tracts, warped to a common reference brain, have been published using microscopic architectonic parcellations in ten human postmortem brains. The maps have been successfully applied as topographical references for the anatomical localization of activations observed in functional imaging studies. Here, for the first time, we present stereotaxic, probabilistic maps of the hippocampus, the amygdala and the entorhinal cortex and some of their subdivisions. Cytoarchitectonic mapping was performed in serial, cell-body stained histological sections. The positions and the extent of cytoarchitectonically defined structures were traced in digitized histological sections, 3-D reconstructed and warped to the reference space of the MNI single subject brain using both linear and non-linear elastic tools of alignment. The probability maps and volumes of all structures were calculated. The precise localization of the borders of the mapped regions cannot be predicted consistently by macroanatomical landmarks. Many borders, e.g. between the subiculum and entorhinal cortex, subiculum and Cornu ammonis, and amygdala and hippocampus, do not match sulcal landmarks such as the bottom of a sulcus. Only microscopic observation enables the precise localization of the borders of these brain regions. The superposition of the cytoarchitectonic maps in the common spatial reference system shows a considerably lower degree of intersubject variability in size and position of the allocortical structures and nuclei than the previously delineated neocortical areas. For the first time, the present observations provide cytoarchitectonically verified maps of the human amygdala, hippocampus and entorhinal cortex, which take into account the stereotaxic position of the brain structures as well as intersubject variability. We believe that these maps are efficient tools for the precise microstructural localization of fMRI, PET and anatomical MR data, both in healthy and pathologically altered brains.
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paper_title: Hippocampal and Amygdalar Volumes in Dissociative Identity Disorder

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Objective: Smaller hippocampal volume has been reported in several stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD), borderline personality disorder with early abuse, and depression with early abuse. Patients with borderline personality disorder and early abuse have also been found to have smaller amygdalar volume. The authors examined hippocampal and amygdalar volumes in patients with dissociative identity disorder, a disorder that has been associated with a history of severe childhood trauma. Method: The authors used magnetic resonance imaging to measure the volumes of the hippocampus and amygdala in 15 female patients with dissociative identity disorder and 23 female subjects without dissociative identity disorder or any other psychiatric disorder. The volumetric measurements for the two groups were compared. Results: Hippocampal volume was 19.2% smaller and amygdalar volume was 31.6% smaller in the patients with dissociative identity disorder, compared to the healthy subjects. The ratio of hippocampal volume to amygdalar volume was significantly different between groups. Conclusions: The findings are consistent with the presence of smaller hippocampal and amygdalar volumes in patients with dissociative identity disorder, compared with healthy subjects.
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paper_title: Reduced hippocampal volume in drug-free depressed patients

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A number of studies have used magnetic resonance imaging to examine the volumetric differences in temporal lobe structures especially the hippocampus in patients suffering from major depressive disorder (MDD). Although some studies reported lower hippocampal volume, others did not. It is proposed that the inconsistency among studies may be due to the heterogeneity of patients and antidepressant treatment during scanning. In this study, we aimed to evaluate the hippocampus in drug-free patients. Twenty-four patients (6 males and 18 females) diagnosed as having MDD according to the DSM-IV criteria and 24 healthy controls (6 males and 18 females) were included in the study. Eleven of the patients had their first mood episode and were drug-naive. Other patients were drug-free for at least 4 weeks. The Hamilton depression rating scale (HAM-D) assessed the severity of depression. Magnetic resonance imaging was performed on a 1.5-T MR unit. The Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal volume. The data were evaluated by a repeated measure of ANOVA and the intracranial volume was taken as a covariate. A significant hippocampal volume difference was observed between the patients and healthy controls (F=4.43, df=1.45, P 0.05). The left hippocampus of patients was significantly lower than those of controls (t=1.98, df=46, P<0.05). Correlation analysis showed a correlation between HAM-D scores and the right hippocampal volume. The results of this study indicate that hippocampus volume is reduced in depressed patients especially in the left side. This finding in the drug-free depressed outpatients without a history of alcohol dependence supports previous studies that have reported lower hippocampal volume.
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paper_title: MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed

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The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.
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Title: Defining the human hippocampus in cerebral magnetic resonance images — An overview of current segmentation protocols

Section 1: Introduction
Description 1: Provide an overview of why the human hippocampus is significant in neuropsychiatric research and the challenges in measuring its volume and shape, along with physiological and pathological implications.

Section 2: Definition and anatomy of the hippocampus
Description 2: Discuss the anatomical complexity and terminological inconsistencies in defining the hippocampal borders in MR images, referencing historical and current anatomical evidence.

Section 3: Methods
Description 3: Describe the methods used to identify relevant segmentation protocols for delineation of the hippocampus in MR images, including details of the literature search and inclusion criteria.

Section 4: MRI acquisition parameters
Description 4: Summarize the MRI acquisition parameters such as acquisition planes, voxel size, and head coverage used in the studies reviewed.

Section 5: Tracing planes
Description 5: Discuss the preferred tracing planes for manual hippocampal segmentation and the use of orthogonal viewing planes for guiding anatomical decisions.

Section 6: Gray and white matter
Description 6: Highlight the segmentation protocols concerning the inclusion of hippocampal gray and white matter.

Section 7: Anterior border
Description 7: Describe the criteria and landmarks used for defining the anterior border of the hippocampus in various segmentation protocols.

Section 8: Posterior border
Description 8: Summarize the different methods and landmarks used to define the posterior border of the hippocampus.

Section 9: Superior border
Description 9: Define the methods used for delineating the superior border of the hippocampus.

Section 10: Inferior border
Description 10: Explain the criteria used to identify the inferior border of the hippocampus.

Section 11: Lateral border
Description 11: Discuss the methods used to delineate the lateral border of the hippocampus.

Section 12: Superior medial border of the hippocampus
Description 12: Define the common methods used for identifying the superior medial border of the hippocampus.

Section 13: Inferior medial border of the hippocampus
Description 13: Detail the various approaches to defining the inferior medial border of the hippocampus in segmentation protocols.

Section 14: Discussion
Description 14: Evaluate the variance in anatomical protocols, the technical and anatomical sources of discrepancies in hippocampal measurements, and general guidelines to enhance the quality and reliability of segmentation protocols.

Section 15: Conclusion
Description 15: Provide a summary of the major areas of discrepancy in hippocampal segmentation protocols and suggest recommendations for improving consensus and replication in hippocampal morphometry studies using MRI.