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Chloé Chamard,1,2 Jerome J Maller,3,4 Nicolas Menjot,5 Eloi Debourdeau,1 Virginie Nael,6 Karen Ritchie,2,7 Isabelle Carriere,2,* Vincent Daien1,2,8,* 1Department of Ophthalmology, Gui de Chauliac Hospital, Montpellier, F-34000, France; 2Institute for Neurosciences of Montpellier INM, University Montpellier, INSERM, Montpellier, F-34091, France; 3General Electric Healthcare, Melbourne, VIC, Australia; 4Monash Alfred Psychiatry Research Centre, Melbourne, VIC, Australia; 5Department of Neuroradiology, Gui de Chauliac Hospital, Montpellier, F-34000, France; 6Bordeaux Population Health Research Center, UMR 1219, University Bordeaux, INSERM, Bordeaux, F-33000, France; 7Department of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; 8The Save Sight Institute, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia*These authors contributed equally to this workCorrespondence: Chloé Chamard, Department of Ophthalmology, Gui de Chauliac Hospital, 80 avenue Augustin Fliche, Montpellier, F-34000, France, Tel +33 6 33 55 65 06, Email chloe.chamard@gmail.comPurpose: Visual impairment is a major cause of disability and impairment of cognitive function in older people. Brain structural changes associated with visual function impairment are not well understood. The objective of this study was to assess the association between visual function and cortical thickness in older adults.Methods: Participants were selected from the French population-based ESPRIT cohort of 2259 community-dwelling adults ≥ 65 years old enrolled between 1999 and 2001. We considered visual function and brain MRI images at the 12-year follow-up in participants who were right-handed and free of dementia and/or stroke, randomly selected from the whole cohort. High-resolution structural T1-weighted brain scans acquired with a 3-Tesla scanner. Regional reconstruction and segmentation involved using the FreeSurfer image-analysis suite.Results: A total of 215 participants were included (mean [SD] age 81.8 [3.7] years; 53.0% women): 30 (14.0%) had central vision loss and 185 (86.0%) normal central vision. Vision loss was associated with thinner cortical thickness in the right insula (within the lateral sulcus of the brain) as compared with the control group (mean thickness 2.38 [0.04] vs 2.50 [0.03] mm, 4.8% thinning, pcorrected= 0.04) after adjustment for age, sex, lifetime depression and cardiovascular disease.Conclusion: The present study describes a significant thinning of the right insular cortex in older adults with vision loss. The insula subserves a wide variety of functions in humans ranging from sensory and affective processing to high-level cognitive processing. Reduced insula thickness associated with vision loss may increase cognitive burden in the ageing brain.Keywords: visual function, vision, cortical thickness, brain, morphometry, MRI

Background: Limited studies of multiple sclerosis (MS) exist whereby magnetic resonance imaging (MRI) of the brain with consistent imaging protocols occurs at the same time points as collection of healthy lifestyle measures. The aim of this study was to test the feasibility, acceptability and preliminary efficacy of acquiring MRI data as an objective, diagnostic and prognostic marker of MS, at the same time point as brain-healthy lifestyle measures including diet., Methods: Participants living with relapsing remitting MS partook in one structural MRI scanning session of the brain, completed two online 24-hour dietary recalls and demographic and self-reported lifestyle questionnaires (e.g. self-reported disability, comorbidities, physical activity, smoking status, body mass index (BMI), stress). Measures of central tenancy and level of dispersion were calculated for feasibility and acceptability of the research protocols. Lesion count was determined by one radiologist and volumetric analyses by a data analysis pipeline based on FreeSurfer software suite. Correlations between white matter lesion count, whole brain volume analyses and lifestyle measures were assessed using Spearman's rank-order correlation coefficient., Results: Thirteen female participants were included in the study: eligibility rate 90.6% (29/32), recruitment rate 46.9% (15/32) and compliance rate 87% (13/15). The mean time to complete all required tasks, including MRI acquisition was 115.86 minutes ( ± 23.04), over 4 days. Conversion to usual dietary intake was limited by the small sample. There was one strong, negative correlation between BMI and brain volume (r s  = -0.643, p = 0.018) and one strong, positive correlation between physical activity and brain volume (r s  = 0.670, p = 0.012) that were both statistically significant., Conclusions: Acquiring MRI brain scans at the same time point as lifestyle profiles in adults with MS is both feasible and accepted among adult females living with MS. Quantification of volumetric MRI data support further investigations using semi-automated pipelines among people living with MS, with pre-processing steps identified to increase automated feasibility. This protocol may be used to determine relationships between elements of a brain-healthy lifestyle, including dietary intake, and measures of disease burden and brain health, as assessed by T1-weighted and T2-weighted lesion count and whole brain volume, in an adequately powered sample., Trial Registration: The study protocol was retrospectively registered in the Australia New Zealand Clinical Trials Registry (ACTRN12624000296538)., (© 2024. The Author(s).)

Objective: Hippocampal volume (HV) is a key imaging marker to improve Alzheimer's disease risk prediction. However, longitudinal studies are rare, and hippocampus may also be implicated in the subtle aging-related cognitive decline observed in dementia-free individuals. Our aim was to determine whether HV, measured by manual or automatic segmentation, is associated with dementia risk and cognitive decline in participants with and without incident dementia., Methods: At baseline, 510 dementia-free participants from the French longitudinal ESPRIT cohort underwent magnetic resonance imaging. HV was measured by manual and by automatic segmentation (FreeSurfer 6.0). The presence of dementia and cognitive functions were investigated at each follow-up (2, 4, 7, 10, 12, and 15 years). Cox proportional hazards models and linear mixed models were used to assess the association of HV with dementia risk and with cognitive decline, respectively., Results: During the 15-years follow-up, 42 participants developed dementia. Reduced HV (regardless of the measurement method) was significantly associated with higher dementia risk and cognitive decline in the whole sample. However, only the automatically measured HV was associated with cognitive decline in dementia-free participants., Conclusion: These results suggest that HV can be used to predict the long-term risk of dementia but also cognitive decline in a dementia-free population. This raises the question of the relevance of HV measurement as an early marker of dementia in the general population., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Recent developments in neuroimaging techniques enable increasingly sensitive consideration of the cognitive impact of damage to white matter tract (WMT) microstructural organisation after mild traumatic brain injury (mTBI)., Objective: This study investigated the relationship between WMT microstructural properties and cognitive performance., Participants Setting and Design: Using an observational design, a group of 26 premorbidly healthy adults with mTBI and a group of 20 premorbidly healthy trauma control (TC) participants who were well-matched on age, sex, premorbid functioning and a range of physical, psychological and trauma-related variables, were recruited following hospital admission for traumatic injury., Main Measures: All participants underwent comprehensive unblinded neuropsychological examination and structural neuroimaging as outpatients 6-10 weeks after injury. Neuropsychological examination included measures of speed of processing, attention, memory, executive function, affective state, pain, fatigue and self-reported outcome. The WMT microstructural properties were estimated using both diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) modelling techniques. Tract properties were compared between the corpus callosum, inferior longitudinal fasciculus, uncinate fasciculus, anterior corona radiata and three segmented sections of the superior longitudinal fasciculus., Results: For the TC group, in all investigated tracts, with the exception of the uncinate fasciculus, two DTI metrics (fractional anisotropy and apparent diffusion coefficient) and one NODDI metric (intra-cellular volume fraction) revealed expected predictive linear relationships between extent of WMT microstructural organisation and processing speed, memory and executive function. The mTBI group showed a strikingly different pattern relative to the TC group, with no relationships evident between WMT microstructural organisation and cognition on most tracts., Conclusion: These findings indicate that the predictive relationship that normally exists in adults between WMT microstructural organisation and cognition, is significantly disrupted 6-10 weeks after mTBI and suggests that WMT microstructural organisation and cognitive function have disparate recovery trajectories., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Anderson, Oehr, Chen, Maller, Seal and Yang.)

Our study methodology is motivated from three disparate needs: one, imaging studies have existed in silo and study organs but not across organ systems; two, there are gaps in our understanding of paediatric structure and function; three, lack of representative data in New Zealand. Our research aims to address these issues in part, through the combination of magnetic resonance imaging, advanced image processing algorithms and computational modelling. Our study demonstrated the need to take an organ-system approach and scan multiple organs on the same child. We have pilot tested an imaging protocol to be minimally disruptive to the children and demonstrated state-of-the-art image processing and personalized computational models using the imaging data. Our imaging protocol spans brain, lungs, heart, muscle, bones, abdominal and vascular systems. Our initial set of results demonstrated child-specific measurements on one dataset. This work is novel and interesting as we have run multiple computational physiology workflows to generate personalized computational models. Our proposed work is the first step towards achieving the integration of imaging and modelling improving our understanding of the human body in paediatric health and disease., Competing Interests: Authors HK and JM were employed by the company GE Healthcare (Australia & New Zealand). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kumar, Green, Cornfeld, Condron, Emsden, Elsayed, Zhao, Gilbert, Nash, Clark, Tawhai, Burrowes, Murphy, Tayebi, McGeown, Kwon, Shim, Wang, Choisne, Carman, Besier, Handsfield, Babarenda Gamage, Shen, Maso Talou, Safaei, Maller, Taylor, Potter, Holdsworth and Wilson.)

Background: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer's disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated., Objective: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia., Methods: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm., Results: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes., Conclusion: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process., (Copyright © 2021. Published by Elsevier Inc.)

Using diffusion-weighted imaging (DWI), research has demonstrated changes suggestive of damage to white matter tracts (WMT) following mild traumatic brain injury (mTBI). Yet due to the predominant use of the diffusion tensor imaging (DTI) model, which has numerous well-established limitations, it has not yet been possible to clearly examine the nature of changes to WMT microstructure following mTBI. This study used a second DWI-based technique, neurite orientation dispersion and density imaging (NODDI), in combination with DTI to measure microstructural changes within the corpus callosum, three long association and one projection WMTs at 6-12 weeks following mTBI, compared with matched trauma controls (TC). Between-groups differences were identified across all WMT for the DTI metric fractional anisotropy (FA), and the NODDI metrics orientation dispersion index (ODI) and isotropic volume fraction (ISO). No statistically significant between-groups differences were found for other DTI and NODDI metrics. Our study revealed that reduced FA was accompanied by increased ODI, suggesting that mTBI results in reduced coherence of axonal fiber bundles within the studied WMTs. These between-groups differences in WMT microstructure were found at 6-12 weeks post-injury, which suggests that structural recovery is not yet complete towards end of the typical 3-month recovery period.

Objectives: Changes in brain connectivity have been observed within the default mode network (DMN) in chronic low back pain (CLBP), however the extent of these disruptions and how they may be related to CLBP requires further examination. While studies using seed-based analysis have found disrupted functional connectivity in the medial prefrontal cortex (mPFC), a major hub of the DMN, limited studies have investigated other equally important hubs, such as the posterior cingulate cortex (PCC) in CLBP., Methods: This preliminary study comprised 12 individuals with CLBP and 12 healthy controls who completed a resting-state functional magnetic resonance imaging (fMRI) scan. The mPFC and PCC were used as seeds to assess functional connectivity., Results: Both groups displayed similar patterns of DMN connectivity, however group comparisons showed that CLBP group had reduced connectivity between the PCC and angular gyrus compared to healthy controls. An exploratory analysis examined whether the alterations observed in mPFC and PCC connectivity were related to pain catastrophizing in CLBP, but no significant associations were observed., Conclusions: These results may suggest alterations in the PCC are apparent in CLBP, however, the impact and functional role of these disruptions require further investigation., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Adverse childhood events may have differential effects on the brain that persist into adulthood. Findings on structural brain alterations in older adults exposed to early-life adversity are inconsistent notably due to heterogeneity in imaging studies, population, psychiatric comorbidities, nature of adverse events, and genetic vulnerability. This study examines whether exposure related to physical or sexual maltreatment, emotional maltreatment, and global adverse environment during childhood are associated with specific alterations in grey matter volumes and if this varies according to sex and serotonin transporter-linked promoter region (5-HTTLPR) genotype., Method: Structural MRI was used to acquire anatomical scans from 398 community-dwelling older adults. Quantitative regional estimates of 23 subregional volumes were derived using FreeSurfer software. Retrospective reporting of childhood adversity was collected using structured self-reported questionnaire. Analyses adjusted for age, sex, brain volume, head injury, lifetime depression and anxiety disorder, psychiatric medication, and cardiovascular ischemic pathologies., Results: Exposure to adverse family environment was associated with smaller volumes of several frontal, cingulate, and parietal subregions and larger amygdala in the 5-HTTLPR SS genotype participants specifically but larger volumes of caudate, putamen, pallidum, and nucleus accumbens in the SL genotype participants. Highly significant differences were found with excessive sharing of parent problems with children, associated with larger grey-matter volumes in the thalamus and several frontal and parietal regions in 5-HTTLPR SL male participants specifically., Conclusions: Early-life adversity is associated with grey-matter volume alterations in older adults and this varies according to the type of adversity experienced, sex, and serotonergic genetic vulnerability; 5-HTTLPR SS participants appearing most vulnerable and SL individuals most resilient., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sports-related concussion (SRC) is a complex and heterogeneous injury with psychological, cognitive and functional consequences. Advances in diffusion magnetic resonance imaging (dMRI) allow sensitive measurement of white matter pathology post-SRC and may provide insight into injury and recovery. We systematically reviewed and meta-analyzed the literature examining dMRI alongside cognitive, emotional or motor assessments to determine relationships between these analyses. Sixteen studies examining young athletes (n = 6) or retired professionals (n = 10) met the inclusion criteria, with 12 emotional, 10 cognitive and four motor assessments. Studies had heterogeneous methodology, moderate quality and modest sample sizes. Fractional anisotropy (FA) was the most frequent dMRI metric, with SRC-induced changes described most commonly in the frontal lobe and least in the cerebellum and brainstem. There is an emerging complementary role for dMRI as part of a comprehensive assessment battery for SRC. However, larger-scale studies with broader subject populations (specifically, in females and in the 30-45 year age range) are needed to corroborate findings and determine the true diagnostic utility of dMRI post-SRC., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cynical hostility (CH), a specific dimension of hostility that consists of a mistrust of others, has been suggested as a high-risk trait for dementia. However, the influence of CH on the incidence of Alzheimer's disease (AD) remains poorly understood. This study investigated whether late-life CH is associated with AD risk and structural neuroimaging markers of AD., Methods: In community-dwelling older adults from the French ESPRIT cohort (n = 1388), incident dementia rate according to CH level was monitored during an 8-year follow-up and analyzed using Cox proportional hazards regression models. Brain magnetic resonance imaging volumes were measured at baseline (n = 508). Using automated segmentation procedures (Freesurfer 6.0), the authors assessed brain grey and white volumes on all magnetic resonance imaging scans. They also measured white matter hyperintensities volumes using semi-automated procedures. Mean volumes according to the level of CH were compared using ANOVA., Results: Eighty-four participants developed dementia (32 with AD). After controlling for potential confounders, high CH was predictive of AD (HR 2.74; 95% CI 1.10-6.85; p = 0.030) and all dementia types are taken together (HR 2.30; 95% CI 1.10-4.80; p = 0.027). High CH was associated with white matter alterations, particularly smaller anterior corpus callosum volume (p < 0.01) after False Discovery Rate correction, but not with grey matter volumes., Conclusions: High CH in late life is associated with cerebral white matter alterations, designated as early markers of dementia, and higher AD risk. Identifying lifestyle and biological determinants related to CH could provide clues on AD physiopathology and avenues for prevention strategies.

Objectives: Chronic pain patients often report higher levels of negative emotions, suggesting reduced ability to regulate emotions effectively, however, little is known of the underlying neural cognitive mechanisms. Therefore, the aim of this study was to explore brain activity and connectivity during cognitive reappraisal in chronic low back pain (CLBP)., Methods: This study recruited 24 female participants; 12 with CLBP and 12 healthy controls. Participants completed an emotion regulation task that involved cognitive reappraisal of negative images during functional magnetic resonance imaging. The negative affect following each image and perceived success of the task were reported. Region of interest and seed-to-voxel analyses were conducted using key regions involved in cognitive reappraisal (i.e., amygdalae and dorsomedial prefrontal cortex) as seed regions., Results: During the task, there were no group differences in the behavioural measures and blood oxygen level-dependent (BOLD) brain activation in the seed regions. Functional connectivity analysis showed reduced coupling between the amygdalae and dorsolateral prefrontal cortex, orbitofrontal cortex and inferior parietal cortex in the CLBP group compared to controls. Connectivity between the amygdala and inferior parietal cortex positively correlated with the percent of reduced negative affect during reappraisal in the CLBP group., Conclusions: These preliminary findings demonstrate that individuals with CLBP exhibit similar emotion regulation abilities to healthy controls at the behavioural and BOLD level. However, altered functional connectivity observed in the CLBP group may reduce effective cognitive reappraisal. These results provide evidence for the potential clinical impact of network changes in CLBP., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Correcting for eddy currents, movement-induced distortion and gradient inhomogeneities is imperative when processing diffusion MRI (dMRI) data, but is highly computing resource-intensive. Recently, Compute Unified Device Architecture (CUDA) was implemented for the widely-used eddy-correction software, 'eddy', which reduces processing time and allows more comprehensive correction. We investigated processing speed, performance and compatibility of CUDA-enabled eddy-current correction processing compared to commonly-used non-CUDA implementations. Four representative dMRI datasets from the Human Connectome Project, Alzheimer's Disease Neuroimaging Initiative and Chronic Diseases Connectome Project were processed on high-specification and regular workstations through three different configurations of 'eddy'. Processing times and graphics processing unit (GPU) resources used were monitored and compared. Using CUDA reduced the 'eddy' processing time by a factor of up to five. The CUDA slice-to-volume correction method was also faster than non-CUDA eddy except when datasets were large. We make a series of recommendations for eddy configuration and hardware. We suggest that users of eddy-correction software for dMRI processing utilise CUDA and take advantage of the slice-to-volume correction option. We recommend that users run eddy on computers with at least 32GB motherboard random access memory (RAM), and a graphics card with at least 4.5GB RAM and 3750 cores to optimise processing time.

Diffusion MRI (dMRI) is sensitive to anisotropic diffusion within bundles of nerve axons and can be used to make objective measurements of brain networks. Many brain disorders are now recognised as being caused by network dysfunction or are secondarily associated with changes in networks. There is therefore great potential in using dMRI measures that reflect network integrity as a future clinical tool to help manage these conditions. Here, we used dMRI to identify replicable, robust and objective markers that meaningfully reflect cognitive and emotional performance. Using diffusion kurtosis analysis and a battery of cognitive and emotional tests, we demonstrated strong relationships between white matter structure across networks of anatomically and functionally specific brain regions with both emotional bias and emotional memory performance in a large healthy cohort. When the connectivity of these regions was examined using diffusion tractography, the terminations of the identified tracts overlapped precisely with cortical loci relating to these domains, drawn from an independent spatial meta-analysis of available functional neuroimaging literature. The association with emotional bias was then replicated using an independently acquired healthy cohort drawn from the Human Connectome Project. These results demonstrate that, even in healthy individuals, white matter dMRI structural features underpin important cognitive and emotional functions. Our robust cross-correlation and replication supports the potential of structural brain biomarkers from diffusion kurtosis MRI to characterise early neurological changes and risk in individuals with a reduced threshold for cognitive dysfunction, with further testing required to demonstrate clinical utility., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Background : Findings on structural brain alterations following trauma are inconsistent due probably to heterogeneity in imaging studies and population, clinical presentations, genetic vulnerability, and selection of controls. This study examines whether trauma and re-experiencing symptoms are associated with specific alterations in grey matter volumes and if this varies according to 5-HTTLPR genotype. Methods : Structural MRI was used to acquire anatomical scans from 377 community-dwelling older adults. Quantitative regional estimates of 22 subregional volumes were derived using FreeSurfer software. Lifetime trauma was assessed using the validated Watson's PTSD inventory, which evaluates the most severe trauma experienced according to DSM criteria. Analyses adjusted for age, sex, total brain volume, head injury, and comorbidities. Results : Of the 212 participants reporting lifetime trauma, 35.4% reported re-experiencing symptoms and for 1.9%, this was severe enough to meet criteria for full threshold PTSD. In participants with the SS 5-HTTLPR genotype only, re-experiencing symptoms were associated with smaller volumes in middle and superior temporal, frontal (lateral orbital, rostral and caudal middle) and parietal (precuneus, inferior and superior) regions. The trauma-exposed participants without re-experiencing symptoms were not significantly different from the non-trauma-exposed participants except for smaller precuneus and superior parietal region in traumatized participants and a larger amygdala in traumatized women specifically. Conclusions : In the non-clinical sample, lifetime trauma and re-experiencing symptoms were associated with smaller volume in prefrontal, temporal and parietal cortex subregions, and this varied according to serotonergic genetic vulnerability, 5-HTTLPR SS individuals being most susceptible., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Bipolar disorder (BD) is a severe mood disorder that lacks established electrophysiological, neuroimaging or biological markers to assist with both diagnosis and monitoring disease severity. This study's aim is to describe the potential of new neurophysiological features assistive in BD diagnosis and severity measurement utilizing the recording of electrical activity from the outer ear canal called Electrovestibulography (EVestG). From EVestG data sensory vestibulo-acoustic features were extracted from a single supine-vertical translation stimulus to distinguish 50 depressed and partly remitted/remitted bipolar disorder patients [18 symptomatic (BD-S, MADRS > 19), 32 reduced symptomatic (BD-R, MADRS ≤ 19)] and 31 age and gender matched healthy individuals (controls). Six features were extracted from the measured firing pattern interval histogram and the extracted shape of the average field potential response. Five of the six features had low but significant correlations (p < 0.05) with the MADRS assessment. Using leave-one-out-cross-validation, unbiased parametric and non-parametric classification routines resulted in 75-79%, 84-86%, 76-85% and 79-82% accuracy for separation of control from BD, BD-S and BD-R as well as BD-S from BD-R groups, respectively. The main limitation of this study was the inability to fully disentangle the impact of prescribed medication from the responses recorded. A mix of stationary and movement evoked EVestG features produced good discrimination between control and BD patients whether BD-S or BD-R. Moreover, BD-S and BD-R appear to have measurably different pathophysiological manifestations. The firing pattern features used were dissimilar to those observed in a prior major depressive disorder study.

Reduced gray matter (GM) volume may represent a hallmark of major depressive disorder (MDD) neuropathology, typified by wide-ranging distribution of structural alteration. In the study, we aimed to replicate and extend our previous finding of profound and widespread GM loss in MDD, and evaluate the diagnostic accuracy of a structural biomarker derived from GM volume in an interconnected pattern across the brain. In a sub-study of the International Study to Predict Optimized Treatment in Depression (iSPOT-D), two cohorts of clinically defined MDD participants "Test" (n = 98) and "Replication" (n = 131) were assessed alongside healthy controls (n = 66). Using 3T MRI T1-weighted volumes, GM volume differences were evaluated using voxel-based morphometry. Sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate an MDD diagnostic biomarker based on a precise spatial pattern of GM loss constructed using principal component analysis. We demonstrated a highly conserved symmetric widespread pattern of reduced GM volume in MDD, replicating our previous findings. Three bilateral dominant clusters were observed: Cluster 1: midline/cingulate (GM reduction: Test: 6.4%, Replication: 5.3%), Cluster 2: medial temporal lobe (GM reduction: Test: 8.2%, Replication: 11.9%), Cluster 3: prefrontal cortex (GM reduction: Test: 12.1%, Replication: 23.2%). We developed a biomarker reflecting the global pattern of GM reduction, achieving good diagnostic classification performance (AUC: Test = 0.75, Replication = 0.84). This study establishes that a highly specific pattern of reduced GM volume is a feature of MDD, suggestive of a structural basis for this disease. We introduce and validate a novel diagnostic biomarker based on this pattern.

Depression following a traumatic brain injury (TBI) is common and difficult to treat using standard approaches. The current study investigated, for the first time, transcranial magnetic stimulation (TMS) for the treatment of post TBI depression. We specifically assessed the safety, tolerability, and efficacy of TMS in this patient population. We also explored cognitive outcomes. Twenty-one patients with a current episode of major depression subsequent to a TBI participated in a randomized double-blind placebo-controlled trial of repetitive TMS (rTMS). Sequential bilateral rTMS (to the left and right dorsolateral prefrontal cortex) was provided in 20 treatments over a period of 4 weeks. Patients were randomly allocated to receive either active or sham stimulation. There were no adverse effects and treatment was well tolerated. There was no significant effect of rTMS on post-TBI depression, with all patients showing a significant improvement in depressive symptoms irrespective of their treatment group ( p  = 0.002). There were significant improvements in cognition following active rTMS in the areas of working memory ( p  = 0.021) and executive function ( p  = 0.029). rTMS was shown to be safe and well tolerated in patients who had developed depression after a TBI. We did not find a therapeutic effect for post-TBI depression; however, this approach may have some utility in improving cognitive function. Future research should focus on alternative rTMS treatment approaches for post-TBI depression and the direct investigation of rTMS as a treatment for cognitive impairment in TBI.

Occipital bending (OB) describes asymmetry of the occipital lobes where one lobe wraps across the midline, and has been associated with the presence of mood disorders. We evaluated the relationship between OB and major depressive disorder (MDD) in a large population of subjects from the International Study to Predict Optimized Treatment in Depression. MDD patients (n = 231) and healthy controls (n = 68) underwent MRI and neuropsychiatric evaluation, including response or remission to antidepressant medication at baseline and at 8 weeks. Cortical thickness, ventricular volumes and regional grey matter volumes were measured. OB was visually assessed and OB angle measured using a semi-automated method. Correlations with MDD diagnosis, MRI measures and clinical features were tested. Results demonstrated a greater proportion of rightwards OB in MDD compared to control subjects (p = 0.02). There was no difference in the total prevalence of OB (combined left and rightward bending) between MDD and controls. MDD subjects with right OB had greater cortical thickness in three medial occipital regions (cuneus, lingual gyrus and calcarine sulcus) on the left. Lateral ventricular size was 20% lower bilaterally in right OB MDD subjects compared to non-OB MDD subjects. OB was not associated with severity (HDRS-17). Our data suggest the presence of a strong link between greater rightward occipital bending and MDD. Rightward-OB is associated with greater left medial occipital cortical thickness, and with reduced lateral ventricular size. The cause for greater rightward bending in MDD patients is unclear, however our data suggest a developmental aetiology., (Copyright © 2019. Published by Elsevier Ltd.)

The hippocampus is a key component of emotional and memory circuits and is broadly connected throughout the brain. We tracked the whole-brain connections of white matter fibres from the hippocampus using ultra-high angular resolution diffusion MRI in both a single 1150-direction dataset and a large normal cohort (n = 94; 391-directions). Using a connectomic approach, we identified six dominant pathways in terms of strength, length and anatomy, and characterised them by their age and gender variation. The strongest individual connection was to the ipsilateral thalamus. There was a strong age dependence of hippocampal connectivity to medial occipital regions. Overall, our results concur with preclinical and ex-vivo data, confirming that meaningful in vivo characterisation of hippocampal connections is possible in an individual. Our findings extend the collective knowledge of hippocampal anatomy, highlighting the importance of the spinal-limbic pathway and the striking lack of hippocampal connectivity with motor and sensory cortices.

Objective: To construct a clinical diagnostic biomarker using state-of-the-art microstructural MRI in the motor cortex of people with amyotrophic lateral sclerosis (ALS)., Methods: Clinical and MRI data were obtained from 21 ALS patients (aged 54 ± 14 years, 33% female) and 63 age- and gender-matched controls (aged 48 ± 18 years, 43% female). MRI was acquired at 3T and included T1-weighted scan (for volumetrics), arterial spin labelling (for cerebral blood flow), susceptibility-weighted angiography (for iron deposition) and multiband diffusion kurtosis imaging (for tissue microstructure). Group differences in imaging measures in the motor cortex were tested by general linear model and relationships to clinical variables by linear regression., Results: The ALS group had mild-to-moderate impairment (disease duration: 1.8 ± 0.8 years; ALS functional rating scale 40.2 ± 6.0; forced vital capacity 83% ± 22%). No age or gender differences were present between groups. We found significant group differences in diffusion kurtosis metrics (apparent, mean, radial and axial kurtosis: p < .01) and iron deposition in the motor cortex (p = .03). Within the ALS group, we found significant relationships between motor cortex volume, apparent diffusion and disease duration (adjusted R 2  = 0.27, p = .011); and between the apparent and radial kurtosis metrics and ALS functional rating scale (adjusted R 2  = 0.25, p = .033). A composite imaging biomarker comprising kurtosis and iron deposition measures yielded a maximal diagnostic accuracy of 83% (81% sensitivity, 85% specificity) and an area-under-the-curve of 0.86., Conclusion: Diffusion kurtosis is sensitive to early changes present in the motor region in ALS. We propose a composite imaging biomarker reflecting tissue microstructural changes in early ALS that may provide clinically valuable diagnostic information., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) is a chronic disease with a large global impact. There are currently no clinically useful predictors of treatment outcome, and the development of biomarkers to inform clinical treatment decisions is highly desirable., Methods: In this exploratory study we performed fixel-based analysis of diffusion MRI data from the International Study to Predict Optimized Treatment in Depression with the aim of identifying novel biomarkers at baseline that may relate to diagnosis and outcome to treatment with antidepressant medications. Analyses used MR data from individuals with MDD (n = 221) and healthy controls (n = 67)., Results: We show focal, gender-specific differences in the anterior limb of the internal capsule (males) and bilaterally in the genu of the corpus callosum (females) associated with diagnosis. Lower fibre cross-section in the tapetum, the conduit between the right and left hippocampi, were also associated with a decreased probability of remission. Analysis of conventional fractional anisotropy showed scattered abnormalities in the corona radiata, cerebral peduncles and mid-brain which were much lower in total volume compared to fixel-based analysis., Conclusions: Fixel-based analysis appeared to identify different underlying abnormalities than conventional tensor-based metrics, with almost no overlap between significant regions. We show that MDD is associated with gender specific abnormalities in the genu of the corpus callosum (females) and in the anterior limb of the internal capsule (males), as well as gender-independent differences in the tapetum that predict remission. Diffusion MRI may play a key role in future guidance of clinical decision-making for MDD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The impact of stressful life events (SLEs) on brain anatomy is poorly understood, particularly its long-term neural consequences. We tested the hypothesis that a serious SLE (repatriation of French citizens living in Algeria in 1962) is associated with changes in brain regions previously implicated in psychopathology (hippocampus, amygdala, corpus callosum, prefrontal cortex, anterior, posterior and isthmus cingulate cortex (ICC)) in a large elderly population., Methods: Structural magnetic resonance imaging was used to acquire anatomical scans from 82 subjects repatriated from Algeria and 339 subjects without this experience or any other trauma. We derived quantitative regional estimates of subcortical volume using FreeSurfer Software. The General Linear Model was used to test the association between repatriation and changes in brain volume adjusted for confounders (gender, age, education, total brain volume, traumatic brain injury, Mini Mental State Examination score at baseline, current and lifetime major depression and recent SLEs)., Results: Repatriation to France was associated with reduced volume in a number of areas; however, only left and right ICC survived to false discovery rate correction., Conclusions: In the elderly a previous (approximately 40 years before) serious SLE could be associated with long-term volume reduction in the ICC, independently of psychopathology.

Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD 17 ) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD 17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.

Background: Structural neuroimaging studies revealed a consistent pattern of volumetric reductions in both hippocampus (HC) and anterior cingulate cortex (ACC) of individuals with major depressive episode(s) (MDE). This study investigated HC and ACC volume differences in currently depressed individuals (n = 150), individuals with a past lifetime MDE history (n = 79) and healthy controls (n = 287)., Methods: Non-demented individuals were recruited from a cohort of community-dwelling older adults (ESPRIT study). T1-weighted magnetic resonance images and FreeSurfer Software (automated method) were used. Concerning HC, a manual method of measurement dividing HC into head, body, and tail was also used. General Linear Model was applied adjusting for covariates., Results: Current depression was associated with lower left posterior HC volume, using manual measurement, in comparison to healthy status. However, when we slightly changed sub-group inclusion criteria, results did not survive to correction for multiple comparisons., Conclusions: The finding of lower left posterior HC volume in currently depressed individuals but not in those with a past MDE compared to healthy controls could be related to brain neuroplasticity. Additionally, our results may suggest manual measures to be more sensitive than automated methods., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Diffusion MRI (dMRI) tractography is a uniquely powerful tool capable of demonstrating structural brain network abnormalities across a range of psychiatric disorders; however, it is not currently clinically useful. This is because limitations on sensitivity effectively restrict its application to scientific studies of cohorts, rather than individual patients. Recent improvements in dMRI hardware, acquisition, processing and analysis techniques may, however, overcome these measurement limitations. We therefore acquired the highest-ever angular resolution in vivo tractographic data set, and used these data to ask the question: 'is cutting-edge, optimised dMRI now sensitive enough to measure brain network abnormalities at a level that may enable personalised psychiatry?' The fibre tracking performance of this 'gold standard' data set of 1150 unique directions (11 shells) was compared to a conventional 64-direction protocol (single shell) and a clinically practical, highly optimised and accelerated 9-min protocol of 140 directions (3 shells). Three major tracts of relevance to psychiatry were evaluated: the cingulate bundle, the uncinate fasciculus and the corticospinal tract. We found up to a 34-fold improvement in tracking accuracy using the 1150-direction data set compared to the 64-direction data set, while 140-direction data offered a maximum 17-fold improvement. We also observed between 20 and 50% improvements in tracking efficiency for the 140-direction data set, a finding we then replicated in a normal cohort (n = 53). We found evidence that lower angular resolution data may introduce systematic anatomical biases. These data highlight the imminent potential of dMRI as a clinically meaningful technique at a personalised level, and should inform current practice in clinical studies.

Background: Concussion is regarded as a common injury in rugby league, however no studies have explored the long-term neurophysiological and cognitive effects of repeated concussion injuries in this sport., Methods: Former professional rugby athletes (n = 25) were compared to 25 age-matched participants with no history of a concussion. All participants completed standardised motor dexterity, reaction time, and cognitive tasks for working memory, associative learning and rule acquisition and reversal. Single-pulse transcranial magnetic stimulation (TMS) acquired motor evoked potentials and cortical silent period (cSP), as well as paired-pulse TMS for short latency intracortical inhibition and long intracortical inhibition (LICI)., Results: Compared to controls, dexterity and visuomotor reaction time was slower in the rugby group compared to controls (p = 0.02, p < 0.01, respectively). The rugby group also demonstrated poorer cognitive performance than controls (p range 0.02 to < 0.01). TMS revealed significantly reduced cSP at suprathreshold stimulation intensities (p range 0.02 to <0.01), and increased LICI (p = 0.03) in the rugby group., Discussion: These findings of motor and cognitive changes, along with neurophysiological alterations, particularly with intracortical inhibition, nearly two decades post-concussion provides evidence for long-term sequelae for athletes with a history of repeated head trauma in contact sports.

Cognitive dysfunction is a poorly understood but potentially devastating complication of cardiac surgery. Clinically meaningful assessment of cognitive changes after surgery is problematic because of the absence of a means to obtain reproducible, objective, and quantitative measures of the neural disturbances that cause altered brain function. By using both structural and functional connectivity magnetic resonance imaging data to construct a map of the inter-regional connections within the brain, connectomics has the potential to increase the specificity and sensitivity of perioperative neurological assessment, permitting rational individualized assessment and improvement of surgical techniques., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Concussion is common in the sporting arena and is often challenging to diagnose. The development of wearable head impact measurement systems has enabled measurement of head kinematics in contact sports., Objectives: The objective of this systematic review was to determine the characteristics of head kinematics measured by an accelerometer system among male athletes diagnosed with concussion., Methods: A systematic search was conducted in July 2015. Inclusion criteria were English-language studies published after 1990 with a study population of male athletes, in any sport, where objectively measured biomechanical forces were reported in the setting of a concussive event. The random effects meta-analysis model was used to combine estimates of biomechanical force measurements in concussed athletes., Results: Thirteen studies met the inclusion criteria, the majority of which were conducted with high school and college football teams in the US. Included studies measured a combination of linear and rotational acceleration. The meta-analysed mean peak linear head acceleration associated with a concussive episode was 98.68 g (95 % CI 82.36-115.00) and mean peak rotational head acceleration was 5776.60 rads/s 2 (95 % CI 4583.53-6969.67). The estimates of the biomechanical forces were consistent across studies, with I 2 values of 0 % for both meta-analyses., Conclusions: Head impact monitoring through accelerometery has been shown to be useful with regard to characterising the kinematic load to the head associated with concussion. Future research with improved clinical outcome measures and head kinematic data may improve accuracy when evaluating concussion, and may assist with both interpretation of biomechanical data and the development and utilisation of implementation strategies for the technology.

Recent neuroimaging studies in body dysmorphic disorder (BDD) have implicated abnormal structure and function of occipito-temporal and fronto-limbic regions in the potential pathophysiology of the disorder. To date, morphometric investigations have yielded inconsistent results, and have suggested that clinical symptoms may mediate structural brain abnormalities in BDD. We measured Grey Matter (GM) cortical thickness in 20 participants with BDD and 20 healthy control participants matched on age, gender, estimated IQ and handedness. We observed cortical thinning in BDD patients compared with healthy control participants within the left middle temporal and left inferior parietal gyrus. No significant relationships between cortical thickness and BDD symptom severity, insight, social anxiety and depression were observed within the BDD group. Thinning within left temporal and left inferior parietal regions supports the involvement of these regions in the pathophysiology of BDD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Primary Objective: Alterations to functional connectivity following a traumatic brain injury (TBI) may lead to impaired cognitive performance and major depressive disorder (MDD). In particular, functional gamma band connectivity is thought to reflect information binding important for working memory. The objective of this study was to determine whether altered functional gamma connectivity may be a factor in MDD following TBI (TBI-MDD)., Research Design: This study assessed individuals with TBI-MDD, as well as individuals with TBI alone and MDD alone using electroencephalographic recordings while participants performed a working memory task to assess differences in functional connectivity between these groups., Methods and Procedures: Functional connectivity was compared using the debiased weighted phase lag index (wPLI). wPLI was measured from a group of healthy controls (n = 31), participants with MDD (n = 17), participants with TBI (n = 20) and participants with TBI-MDD (n = 15)., Main Outcomes and Results: Contrary to the predictions, this study found both the groups with TBI and TBI-MDD showed higher gamma connectivity from posterior regions during WM retention., Conclusions: This may reflect dysfunctional functional connectivity in these groups, as a result of maladaptive neuroplastic reorganization.

Objective: To investigate the prevalence of occipital bending (an occipital lobe crossing or twisting across the midline) in subjects with schizophrenia and matched healthy controls., Method: Occipital bending prevalence was investigated in 37 patients with schizophrenia and 44 healthy controls., Results: Ratings showed that prevalence was nearly three times higher among schizophrenia patients (13/37 [35.1%]) than in control subjects (6/44 [13.6%]). Furthermore, those with schizophrenia had greater normalized gray matter volume but less white matter volume and had larger brain-to-cranial ratio., Conclusion: The results suggest that occipital bending is more prevalent among schizophrenia patients than healthy subjects and that schizophrenia patients have different gray matter-white matter proportions. Although the cause and clinical ramifications of occipital bending are unclear, the results infer that occipital bending may be a marker of psychiatric illness.

Ultrasound (US) at diagnostic frequency and power is known to alter nerve potentials; however, the precise mechanism of action is unknown. We investigated whether US alters resting nerve potential to lower the threshold for magnetic nerve stimulation. Seventeen healthy subjects were recruited. For each subject, a 1.5 MHz US imaging probe was placed onto the elbow with the beam directed at the ulnar nerve. The probe was coupled to the skin using standard acoustic coupling gel as would be done for a routine clinical US scan. Ulnar nerve stimulation was performed simultaneously with magnetic stimulation (MS). Successful magnetic stimulation of the ulnar nerve was confirmed with nerve potentials measured by electromyography. There was no significant change in electromyography signal when MS was performed during US exposure. US at the diagnostic frequency and power tested does not alter nerve thresholds with MS. Testing at other frequencies is required, however, before US is negated as a technique to modify MS thresholds., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Previous neuroimaging studies have demonstrated structural brain alterations in blind subjects, but most have focused on primary open angle glaucoma or retinopathy of prematurity, used low-field scanners, a limited number of receive channels, or have presented uncorrected results. We recruited 10 blind and 10 age and sex-matched controls to undergo high-resolution MRI using a 3T scanner and a 32-channel receive coil. We evaluated whole-brain morphological differences between the groups as well as manual segmentation of regional hippocampal volumes. There were no hippocampal volume differences between the groups. Whole-brain morphometry showed white matter volume differences between blind and sighted groups including localised larger regions in the visual cortex (occipital gyral volume and thickness) among those with blindness early in life compared to those with blindness later in life. Hence, in our patients, blindness resulted in brain volumetric differences that depend upon duration of blindness., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Episodic memory (EM) impairments in schizophrenia (SZ) are predictive of functional outcome and are a potential endophenotype of the disorder. The current study investigated the neuroanatomical correlates of EM encoding and retrieval in SZ with structural magnetic resonance and diffusion tensor imaging (DTI) measures in 22 patients with SZ and 22 age- and gender-matched healthy controls. Tract-based Spatial Statistics (TBSS) was used to investigate microstructural alterations in white matter (WM), while FreeSurfer surface-based analysis was used to determine abnormalities in grey matter (GM) and WM volumetrics and cortical thickness. Compared to controls, patients demonstrated GM deficits in temporal and parietal regions and lower fractional anisotropy (FA) of WM in diffuse brain regions. Patients also demonstrated reduced functioning in both encoding and retention of auditory-verbal EM. Among patients but not controls, EM encoding correlated with WM volume in the orbitofrontal cortex and increased radial diffusivity in the fornix, whereas EM retrieval correlated with WM volume in posterior parietal cortex. These findings suggest a differential role for frontal and parietal WM in EM encoding and retrieval processes, while myelin integrity of the fornix may play a specific role in mediating EM encoding processes in SZ., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation., Method: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed., Results: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow., Conclusions: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression.