Dorsal bed nucleus of stria terminalis in depressed and nondepressed temporal lobe epilepsy patients.

OBJECTIVE: Temporal lobe epilepsy (TLE) and depression are common comorbid disorders whose underlying shared neural network has yet to be determined. Although animal studies demonstrate a role for the dorsal bed nucleus of the stria terminalis (dBNST) in both seizures and depression, and human clinical studies demonstrate a therapeutic effect of stimulating this region on treatment-resistant depression, the role of the dBNST in depressed and nondepressed TLE patients is still unclear. Here, we tested the hypothesis that this structure is morphologically abnormal in these epilepsy patients, with an increased abnormality in TLE patients with comorbid depression. METHODS: In this case-controlled study, 3-T structural magnetic resonance imaging scans were obtained from TLE patients with no depression (TLEonly), TLE patients with depression (TLEdep), and healthy control (HC) subjects. TLE subjects were recruited from the Yale University Comprehensive Epilepsy Center, diagnosed with the International League Against Epilepsy 2014 Diagnostic Guidelines, and confirmed by video-electroencephalography. Diagnosis of major depressive disorder was confirmed by a trained neuropsychologist through a Mini International Neuropsychiatric Interview based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The dBNST was delineated manually by reliable raters using Bioimage Suite software. RESULTS: The number of patients and subjects included 35 TLEonly patients, 20 TLEdep patients, and 102 HC subjects. Both TLEonly and TLEdep patients had higher dBNST volumes compared to HC subjects, unilaterally in the left hemisphere in the TLEonly patients (p = .003) and bilaterally in the TLEdep patients (p < .0001). Furthermore, the TLEdep patients had a higher dBNST volume than the TLEonly patients in the right hemisphere (p = .02). SIGNIFICANCE: Here, we demonstrate an abnormality of the dBNST in TLE patients, both without depression (left enlargement) and with depression (bilateral enlargement). Our results demonstrate this region to underlie TLE both with and without depression, implicating it as a target in treating the comorbidity between these two disorders.

Presurgical language fMRI: Technical practices in epilepsy surgical planning.

Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, image acquisition, analysis and interpretation, and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4, or 5 tasks with a modal run duration of 5 min. Variants of over 15 protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols was used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, and brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.

Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning.

The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance.

Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Child Neurology: Functional Reorganization Mediating Supplementary Motor Area Syndrome Recovery in Agenesis of the Corpus Callosum.

Supplementary motor area (SMA) syndrome is a typically transient condition resulting from damage to the medial premotor cortex. The exact mechanism of recovery remains unknown but is traditionally described as a process involving functional compensation by the contralateral SMA through corpus callosal fibers. The purpose of this case study is to highlight a distinct extra-callosal mechanism of functional recovery from SMA syndrome in a patient with agenesis of the corpus callosum (ACC). We present the clinical presentation and perioperative functional neuroimaging features of a 16-year-old patient with complete ACC who exhibited recovery from an SMA syndrome resulting from surgical resection of a right-sided low-grade glioma. Preoperative functional MRI (fMRI) revealed anatomically concordant activation areas during finger and toe tapping tasks bilaterally. Three months following surgery, the patient had fully recovered, and a repeat fMRI revealed shift of the majority of the left toe tapping area from the expected contralateral hemisphere to the ipsilateral left paracentral lobule and SMA. The fMRI signal remodeling observed in this acallosal patient suggests that within-hemisphere plasticity of the healthy hemisphere may constitute an alternative critical process in SMA syndrome resolution and challenges the traditional view that transcallosal fibers are necessary for functional recovery.

Management of patients with medically intractable epilepsy and anterior temporal lobe encephaloceles.

OBJECTIVE: Temporal lobe encephaloceles (TLENs) are a significant cause of medically refractory epilepsy, but there is little consensus regarding their workup and treatment. This study characterizes these lesions and their role in seizures and aims to standardize preoperative evaluation and surgical management. METHODS: Patients with TLEN who had undergone resective epilepsy surgery from December 2015 to August 2020 at a single institution were included in the study. Medical records were reviewed for each patient to collect relevant seizure workup information including demographics, radiological findings, surgical data, and neuropsychological evaluation. RESULTS: For patients who presented to the authors' program with suspected medically intractable temporal lobe epilepsy (219 patients), TLEN was considered to be the epileptogenic focus in 5.5%. Ten patients with TLEN had undergone resection and were included in this study. Concordance between ictal scalp electroencephalography (EEG) lateralization and TLEN was found in 9/10 patients (90%), and 4/10 patients (40%) had signs suggestive of idiopathic intracranial hypertension (IIH). Surgical outcome was reported in patients with at least 12 months of follow-up (9/10). Patients with scalp EEG findings concordant with the TLEN side had a good outcome (Engel class I: 7 patients, class II: 1 patient). One patient with discordant EEG findings had a bad outcome (Engel class III). No significant neuropsychological deficits were observed after the surgery. CONCLUSIONS: TLENs are epileptogenic lesions that should be screened for in patients with medically refractory epilepsy who have signs of IIH and no other lesions on MRI. Restricted resection is safe and effective in patients with scalp EEG findings concordant with TLEN.

The changing landscape in epilepsy imaging: Unmasking subtle and unique entities.

Dramatic changes have occurred recently in the field of epilepsy, including a fundamental shift in the etiology of epileptogenic substrates found at surgery. Hippocampal sclerosis is no longer the most common etiology found at epilepsy surgery and this decrease has been associated with an increase in the incidence of focal cortical dysplasia and encephaloceles. Significant advances have been made in molecular biology and genetics underlying the basis of malformations of cortical development, and our ability to detect epileptogenic abnormalities with MR imaging has markedly improved. This article begins with a discussion of these trends and reviews imaging techniques essential for detecting of subtle epilepsy findings. Representative examples of subtle imaging findings are presented, which are often overlooked but should not be missed. These include temporal lobe encephaloceles, malformations of cortical development (and especially focal cortical dysplasia), hippocampal sclerosis, hippocampal malformation (also known as HIMAL), ulegyria, autoimmune encephalitis, and Rasmussen's encephalitis. Recent findings on the pathophysiology and genetic underpinnings of several causes of localization-related epilepsy are incorporated. For instance, it has been recently found that focal cortical dysplasia IIb, tuberous sclerosis, hemimegalencephaly, and gangliogliomas are all the result of mutations of the mTOR pathway for cell growth.

Frequency, prognosis and surgical treatment of structural abnormalities seen with magnetic resonance imaging in childhood epilepsy.

The epidemiology of lesions identified by magnetic resonance imaging (MRI), along with the use of pre-surgical evaluations and surgery in childhood-onset epilepsy patients has not previously been described. In a prospectively identified community-based cohort of children enrolled from 1993 to 1997, we examined (i) the frequency of lesions identified by MRI; (ii) clinical factors associated with 'positive' MRI scans; and (iii) the utilization of comprehensive epilepsy evaluations and neurosurgery. Of the original cohort of 613 children, 518 (85%) had usable MRI scans. Eighty-two (16%) had MRI abnormalities potentially relevant to epilepsy ('positive' scans). Idiopathic epilepsy syndromes were identified in 162 (31%) of whom 3% had positive scans. The remainder had non-idiopathic epilepsy syndromes of which 22% had positive MRI findings. Multiple logistic regression analysis identified non-idiopathic epilepsy and abnormal motor-sensory (neurological) examinations as predictors of a positive MRI scan. Of the non-idiopathic patients with normal neurological exams and who were not pharmacoresistant, 10% had positive MRI scans, including four patients with gliomas. Evaluations at comprehensive epilepsy centres occurred in 54 pharmacoresistant cases. To date 5% of the imaged cohort or 8% of non-idiopathic epilepsy patients have undergone surgical procedures (including vagal nerve stimulator implantation) to treat their epilepsy (n = 22) or for tumours (n = 6) without being drug resistant. Applying our findings to the general population of children in the USA, we estimate that there will be 127/1 000 000 new cases per year of pharmacoresistant epilepsy, and 52/1 000 000 childhood-onset epilepsy patients undergoing epilepsy evaluations. In addition, approximately 27/1 000 000 will have an epilepsy-related surgical procedure. These findings support recommendations for the use of MRI in evaluating newly diagnosed paediatric epilepsy patients, especially with non-idiopathic syndromes, and provide estimates on the utilization of comprehensive evaluations and surgery.

Diagnosis and Management of pituitary disease with focus on the role of Magnetic Resonance Imaging.

Magnetic resonance (MR) imaging is an essential tool in the diagnosis and management of pituitary diseases, indispensable for making correct treatment decisions. Successful management and follow-up of pituitary pathology requires an understanding of the MR appearance of normal and abnormal structures in the sellar region. This review will describe the MR appearance of the normal and abnormal pituitary gland and proposes an algorithm for the management strategy of some of the most common abnormalities in or around the sella.

Transitioning from Radiology Training to Academic Faculty: Defining Your Role and Interests.

Transitioning from radiology training to academic faculty presents many challenges. In this review, we discuss strategies to navigate this process and to facilitate success through appropriate selection of career tracks. Various modern avenues include roles as a Clinician-Educator, Clinician-Investigator, and Clinician-Administrator. Selection of the appropriate career track based on personal interests and institutional culture is critical for early and long-term career satisfaction.

Transitioning From Radiology Training to Academic Faculty: The Importance of Mentorship.

Transitioning from radiology residency to academic faculty presents many challenges. In this review, we discuss the importance of introspection and mentorship to successfully navigate this process. Key points include alignment of goals with those of the institution, formation of a mentorship program, and periodic reassessment of career goals. These tips and tools can help make the transition from residency to academic faculty more seamless.

Superior Pituitary Border Analysis in Immunotherapy-Induced Hypophysitis.

Immunotherapy-induced hypophysitis presents with headache, fatigue, and visual disturbances. The diagnosis is supported by imaging findings of pituitary swelling, enhancement, and hypermetabolism and established by low levels of pituitary hormones. A 64-year-old man with metastatic melanoma on nivolumab presented with a severe headache, initially attributed to sinus disease. Contrast CT was interpreted as minor sinus disease and no pituitary abnormality. Hypophysitis was eventually diagnosed and successfully treated based on PET and laboratory findings. Our retrospective analysis demonstrated abnormal convex superior pituitary border visible on contrast and noncontrast CT and PET. This feature may aid diagnosis in the challenging cases.

Long-term outcomes of tissue-based ACTH-antibody assay-guided transsphenoidal resection of pituitary adenomas in Cushing disease.

OBJECTIVE Cushing disease is caused by a pituitary micro- or macroadenoma that hypersecretes adrenocorticotropic hormone (ACTH), resulting in hypercortisolemia. For decades, transsphenoidal resection (TSR) has been an efficacious treatment but with certain limitations, namely precise tumor localization and complete excision. The authors evaluated the novel use of a double-antibody sandwich assay for the real-time quantitation of ACTH in resected pituitary specimens with the goals of augmenting pathological diagnosis and ultimately improving long-term patient outcome. METHODS This study involved a retrospective review of records and an analysis of assay values, pathology slides, and MRI studies of patients with Cushing disease who had undergone TSR in the period from 2009 to 2014 and had at least 1 year of follow-up in coordination with an endocrinologist. In the operating room, biopsy specimens from the patients had been analyzed for tissue ACTH concentration. Additional samples were simultaneously sent for frozen-section pathological analysis. The ACTH assay performance was compared against pathology assessments of surgical tumor samples using receiver operating characteristic (ROC) analysis and against pre- and postoperative MRI studies. RESULTS Fourteen patients underwent TSR with guidance by ACTH-antibody assay and pathological assessment of 127 biopsy samples and were followed up for an average of 3 years. The ACTH threshold for discriminating adenomatous from normal tissue was 290,000 pg/mg of tissue, based on jointly maximized sensitivity (95.0%) and specificity (71.3%). Lateralization discordance between preoperative MRI studies and surgical visualization was noted in 3 patients, confirming the impression that MRI alone may not achieve optimal localization. A majority of the patients (85.7%) attained long-term disease remission based on urinary free cortisol levels, plasma cortisol levels, and long-term corticosteroid therapy. Comparisons of patient-months of remission and treatment failure showed that the remission rate in the study sample statistically exceeds the rate in historical controls (71.9%; p = 0.0007, Fisher's exact test). Long-term unexpected hormonal deficiencies were statistically similar between study patients (29%) and those in a meta-analysis (25%; p = 0.7596, Fisher's exact test). CONCLUSIONS These preliminary findings reflect the promising potential of tissue-based ACTH-antibody-guided assay for improving the cure rates of Cushing disease patients undergoing TSR. Further studies with larger sample sizes, further refinements of assay interpretation, and longer-term follow-ups are needed.

A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly. Laboratory investigation.

OBJECT: Greig cephalopolysyndactyly syndrome (GCPS) is one of a spectrum of overlapping clinical syndromes resulting from mutations in the gene GLI3 on chromosome 7p. Cerebral cavernous malformation (CCM) is caused by mutations in three distinct genes, including Malcavernin (CCM2), which also maps to chromosome 7p and is located 2.8 Mbp from GLI3. The authors describe a new syndrome that combines the vascular lesions characteristic of CCM with the hallmarks of GCPS, including polydactyly, hypertelorism, and developmental delay. METHODS: The authors used high-resolution array-based comparative genome hybridization (CGH) analysis to characterize the 3 million-bp deletion on chromosome 7 that accounts for this novel clinical presentation. A 4-year-old girl presented with polydactyly, hypertelorism, and developmental delay and was also found to have multiple CCMs after suffering a seizure. RESULTS. Genetic analysis using array-based CGH revealed a deletion affecting multiple genes in the 7p14-13 locus, the interval that includes both CCM2 and GLI3. Quantitative real-time polymerase chain reaction (RT-PCR) on genomic DNA confirmed this genomic lesion. CONCLUSIONS: A novel syndrome, combining features of CCM and GCPS, can be added to the group of entities that result from deleterious genetic variants involving GLI3, including GCPS, acrocallosal syndrome, Pallister-Hall syndrome, and contiguous gene syndrome. The deletion responsible for this new entity can be easily detected using either array-based chromosomal analysis or quantitative RT-PCR.

Increased number of subcortical hyperintensities on MRI in children and adolescents with Tourette's syndrome, obsessive-compulsive disorder, and attention deficit hyperactivity disorder.

OBJECTIVE: To investigate whether cerebral hyperintensities on T2-weighted magnetic resonance images (MRI) are associated with childhood neuropsychiatric disorders. METHOD: The authors compared the frequency of cortical and subcortical cerebral hyperintensities in 100 children and adolescents with Tourette's syndrome, obsessive-compulsive disorder (OCD), or attention deficit hyperactivity disorder (ADHD) and 32 healthy comparison subjects. RESULTS: The frequency of cerebral hyperintensities was significantly higher in subjects with Tourette's syndrome, OCD, or ADHD than in healthy comparison subjects; each diagnostic group seemed to contribute to this effect. Among the patient groups, the likelihood of detecting cerebral hyperintensities in the subcortex (primarily the basal ganglia and thalamus) was significantly greater than in the cortex. CONCLUSIONS: A childhood diagnosis of Tourette's syndrome, OCD, or ADHD significantly increased the likelihood of detecting cerebral hyperintensities, particularly in the subcortex, supporting the notion that subcortical injury may play a role in the pathophysiology of these conditions.

Volumetry of amygdala and hippocampus and memory performance in Alzheimer's disease.

Magnetic resonance imaging (MRI) is showing increased utility in examining medial temporal lobe atrophy and its relationship to memory performance in Alzheimer's disease (AD). We studied 56 AD patients and 42 older healthy subjects with neuropsychological assessment and MRI. Hippocampal and amygdaloid volumes (normalized to intracranial volume) were contrasted between AD patients and healthy controls and correlated with neuropsychological performance. Comparisons between AD patients and healthy controls revealed highly significant differences in the normalized volume of hippocampus and amygdala by analysis of covariance. Group differences tended to be at least as large for amygdaloid as hippocampal volume, including when the subset of AD patients with the mildest symptoms was considered separately. Within the AD group, performance on the Memory-Orientation subscale of the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) was significantly correlated with normalized amygdaloid volume but not with normalized hippocampal volume. Other ADAS-Cog subscales (Language, Praxis) were uncorrelated with either volume. In the healthy control sample, neither hippocampal nor amygdaloid volumes were significant predictors of any neuropsychological measure. While a substantial literature continues to justify the focus on the hippocampus in MRI studies of AD, these results suggest that the amygdala should receive similar attention, including in studies of the prodromal stages of AD.

MR imaging of epilepsy: strategies for successful interpretation.

MR imaging plays a pivotal role in the evaluation of patients with epilepsy. With its high spatial resolution, excellent inherent soft tissue contrast, multiplanar imaging capability, and lack of ionizing radiation, MR imaging has emerged as a versatile diagnostic tool in the evaluation of patients with epilepsy. MR imaging not only identifies specific epileptogenic substrates but also determines specific treatment and predicts prognosis. Employing appropriate imaging protocols and reviewing the images in a systematic manner helps in the identification of subtle epileptogenic structural abnormalities. With future improvements in software, hardware, and post-processing methods, MR imaging should be able to throw more light on epileptogenesis and help physicians to better understand its structural basis.

Basal Ganglia volumes in patients with Gilles de la Tourette syndrome.

BACKGROUND: Despite strong circumstantial evidence that the pathophysiology of Gilles de la Tourette syndrome (TS) involves structural and functional disturbances of the basal ganglia, inconsistent findings from relatively small in vivo TS imaging studies have supported contradictory conclusions concerning the role of abnormal anatomical characteristics of the basal ganglia in the pathophysiology of TS. METHODS: Basal ganglia volumes were measured on high-resolution magnetic resonance images acquired for 154 children and adults with TS and 130 healthy control subjects. Repeated-measures analyses tested hypotheses concerning regional specificity, age effects, and abnormal asymmetries in the basal ganglia of subjects with TS. Subjects with prior neuroleptic exposure had larger basal ganglia volumes and were excluded from further statistical analyses. RESULTS: Caudate nucleus volumes were significantly (P =.008) smaller in children and adults with TS. Lenticular nucleus volumes also were smaller in adults with TS and in children with TS who were diagnosed as having comorbid obsessive-compulsive disorder. Regional anatomical asymmetries did not differ across groups. Regional volumes did not correlate significantly with the severity of tic, obsessive-compulsive disorder, or attention-deficit/hyperactivity disorder symptoms. CONCLUSIONS: Reduced caudate nucleus volumes may be a good candidate marker for a trait abnormality in the structure of the basal ganglia in persons with TS. Smaller lenticular nucleus volumes may be an additional marker for the presence of comorbid obsessive-compulsive disorder and for the persistence of tic symptoms into adulthood. Brain regions other than the basal ganglia may have greater clinical relevance in determining the severity of tic symptoms.

Imaging of lumbar spinal surgery complications.

UNLABELLED: Lumbar spine surgery for spinal stenosis is a frequently performed procedure and was the fastest growing type of surgery in the US from 1980 to 2000. With increasing surgical invasiveness, postoperative complications also tend to be higher. Cross-sectional imaging techniques (CT and MRI) are more sensitive than radiographs and play an increasingly important role in evaluation of patients with lumbar spine surgery. Their use in patients with metallic implants is somewhat limited by artefacts, which can obscure pathology and decrease accuracy and reader confidence. Metal artefact reduction techniques have been developed, which can significantly improve image quality and enable early detection of postoperative complications. Complications can occur throughout postoperative course. Early complications include hardware displacement, incidental durotomy, postoperative collections-most commonly seroma, and less likely haematoma and/or infection. Incidental durotomy with CSF leak causing intracranial hypotension has characteristic MR brain findings and diagnosis of occult leak sites have been improved with use of dynamic CT myelography. Haematomas, even when compressing the thecal sac, are usually asymptomatic. Early infection, with nonspecific MR findings, can be diagnosed accurately using dual radiotracer studies. Delayed complications include loosening, hardware failure, symptomatic new or recurrent disc herniation, peri-/epidural fibrosis, arachnoiditis, and radiculitis. TEACHING POINTS: • CT and MRI play an increasingly important role in evaluation of patients with lumbar spine surgery • Complications can occur throughout the postoperative course and early detection is critical • Artefact reduction techniques can improve image quality for early and improved detection of complications.

Childhood trauma associated with smaller hippocampal volume in women with major depression.

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.