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Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain., Competing Interests: Competing interests statement:D.H.W. served as Site PI for studies by Biogen, Merck, and Eli Lilly/Avid. He has received consulting fees from GE Healthcare and Neuronix. He is on the DSMB for a trial sponsored by Functional Neuromodulation. A.J.S. receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, and U01 AG072177). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions, Inc. (Dementia Advisory Board); and Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging, and Behavior). O.C. reports having received consulting fees from AskBio (2020) and Therapanacea (2022), having received payments for writing a lay audience short paper from Expression Santé (2019), and that his laboratory has received grants (paid to the institution) from Qynapse (2017 to present). Members of his laboratory have co-supervised a Ph.D. thesis with myBrainTechnologies (2016 to 2019) and with Qynapse (2017 to present). O.C.’s spouse is an employee and holds stock options of myBrainTechnologies (2015 to present). O.C. has a patent registered at the International Bureau of the World Intellectual Property Organization (PCT/IB2016/0526993, J.-B. Schiratti, S. Allassonniere, O.C., S. Durrleman, A method for determining the temporal progression of a biological phenomenon and associated methods and devices) (2017). M.E. receives support from multiple NIH grants, the Alzheimer’s Association, and the Alzheimer’s Therapeutic Research Institute. M.V.Z. serves as a consultant and/or speaker for the following pharmaceutical companies: Eurofarma, Lundbeck, Abbott, Greencare, Myralis, and Elleven Healthcare.

Background: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level., Methods: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up., Results: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BAC slow-5  = 73.2%, BAC slow-4  = 72.9%, BAC slow-3  = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%., Conclusions: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Adult gyrification provides a window into coordinated early neurodevelopment when disruptions predispose individuals to psychiatric illness. We hypothesized that the echoes of such disruptions should be observed within structural gyrification networks in early psychiatric illness that would demonstrate associations with developmentally relevant variables rather than specific psychiatric symptoms. We employed a new data-driven method (Orthogonal Projective Non-Negative Matrix Factorization) to delineate novel gyrification-based networks of structural covariance in 308 healthy controls. Gyrification within the networks was then compared to 713 patients with recent onset psychosis or depression, and at clinical high-risk. Associations with diagnosis, symptoms, cognition, and functioning were investigated using linear models. Results demonstrated 18 novel gyrification networks in controls as verified by internal and external validation. Gyrification was reduced in patients in temporal-insular, lateral occipital, and lateral fronto-parietal networks (pFDR < 0.01) and was not moderated by illness group. Higher gyrification was associated with better cognitive performance and lifetime role functioning, but not with symptoms. The findings demonstrated that gyrification can be parsed into novel brain networks that highlight generalized illness effects linked to developmental vulnerability. When combined, our study widens the window into the etiology of psychiatric risk and its expression in adulthood., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning)., Competing Interests: Declaration of competing interest AB has consulting fees from Biogen and lecture fees from Lundbeck, Otsuka and Janssen. AP has served as a consultant for Boehringer Ingelheim. AS: Advisory board (DSP), Research grants (CynK, DSP, MTPC, and Ono). CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. CH is faculty member, Lundbeck Psychiatric Institute. CP is on an advisory board for Lundbeck, Australia Pty Ltd and also received honoraria for talks presented at educational meetings organized by Lundbeck. CSW is on an advisory board for Lundbeck, Australia Pty Ltd and in collaboration with Astellas Pharma Inc., Japan. DJS has received research grants or consultancy honoraria from Lundbeck and Sun. EV has received grants and served as a consultant, advisor or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. IN has no conflicts of interest to declare. RTS has received consulting fees from Genentech and Roche. SL has received consulting fees and speaking honoraria from Roche, Novartis, Biogen and Merck., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution., Competing Interests: Declaration of Competing Interest Christos Pantelis has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck and Shire., (Copyright © 2020. Published by Elsevier B.V.)

Gray matter reduction of the orbitofrontal cortex (OFC) has been reported in borderline personality disorder (BPD), but it remains unknown whether the BPD patients exhibit morphologic changes of the olfactory sulcus, a potential marker of forebrain development located on the OFC. We used magnetic resonance imaging to investigate the length and depth of the olfactory sulcus in 20 teenagers (15 females and 5 males) with first-presentation BPD and 20 healthy controls (15 females and 5 males). While there was no group difference in the length of the sulcus, the BPD patients (especially those with a history of trauma) had a significantly shallower right olfactory sulcus compared with controls. In addition, sulcus depth was negatively correlated with the severity of impulsivity and affective instability in the BPD patients. These preliminary findings may suggest a significant role of environmental risk factors (i.e., trauma exposure) during childhood to adolescence in the neurobiology of BPD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Complex human behavior emerges from dynamic patterns of neural activity that transiently synchronize between distributed brain networks. This study aims to model the dynamics of neural activity in individuals with schizophrenia and to investigate whether the attributes of these dynamics associate with the disorder's behavioral and cognitive deficits. A hidden Markov model (HMM) was inferred from resting-state functional magnetic resonance imaging (fMRI) data that was temporally concatenated across individuals with schizophrenia (n = 41) and healthy comparison individuals (n = 41). Under the HMM, fluctuations in fMRI activity within 14 canonical resting-state networks were described using a repertoire of 12 brain states. The proportion of time spent in each state and the mean length of visits to each state were compared between groups, and canonical correlation analysis was used to test for associations between these state descriptors and symptom severity. Individuals with schizophrenia activated default mode and executive networks for a significantly shorter proportion of the 8-min acquisition than healthy comparison individuals. While the default mode was activated less frequently in schizophrenia, the duration of each activation was on average 4-5 s longer than the comparison group. Severity of positive symptoms was associated with a longer proportion of time spent in states characterized by inactive default mode and executive networks, together with heightened activity in sensory networks. Furthermore, classifiers trained on the state descriptors predicted individual diagnostic status with an accuracy of 76-85%., (© 2019 Wiley Periodicals, Inc.)

Recent studies have revealed that several psychotic symptom changes observed in the 'at risk mental state' (ARMS) are associated with changes in the striatum. We investigated if structural changes in the striatum are associated with recovery of sub-threshold psychotic symptoms in subjects with an ARMS who did not develop psychosis (ARMS-N). Sixteen healthy controls and 42 subjects with an ARMS participated in this study. Striatal volumes (caudate, putamen, and nucleus accumbens) were analyzed using MRI. The sub-threshold psychotic symptoms of the subjects with an ARMS were measured using the SOPS. Imaging and symptoms were reevaluated after 52 weeks. Significant right putamen volume reduction was observed at the follow-up in ARMS-N subjects. Improvement in sub-threshold positive symptoms significantly correlated with an increase in volume in the right accumbens at follow up. No relationship was found for negative symptoms. From these findings, the association between improvement in sub-threshold positive symptoms and an increase in the volume of the right accumbens may suggest that changes in the accumbens, which is a major site for dopamine innervation, are associated with symptom recovery. These findings may point to neurobiological resilience that may be associated with lower transition to psychosis., (Copyright © 2019. Published by Elsevier B.V.)

Theory of mind (ToM), the ability to infer one's own and others' mental states, is the social cognitive process shown to have the greatest impact on functional outcome in schizophrenia. It is not yet known if neural abnormalities underlying ToM present early, during the first episode of psychosis (FEP). Fourteen FEP participants and twenty-two healthy control participants, aged 15-25, were included in analyses. All participants had a 3T magnetic resonance imaging scan and completed a block-design picture-story attribution-of-intentions ToM fMRI task, and completed a battery of behavioral social cognitive measures including a ToM task. General linear model analyses were carried out. Post-hoc regression analyses were conducted to explore whether aberrant ToM-related activation in FEP participants was associated with symptomatology and global social and occupational functioning. FEP participants, when compared to healthy controls, had significantly less activity in the right temporoparietal junction, right orbitofrontal cortex and left middle prefrontal/inferior frontal cortex, when making social attributions. Aberrant ToM-related activation in the right temporoparietal junction was associated with severity of overall psychopathology, but not functional outcome. Specific regions of the social brain network, associated with ToM, are dysfunctional in young people with FEP. Future research should determine whether alteration of normal brain functioning in relation to ToM occurs before or during illness onset., (Copyright © 2018. Published by Elsevier B.V.)

Identifying distinctive subtypes of schizophrenia could ultimately enhance diagnostic and prognostic accuracy. We aimed to uncover neuroanatomical subtypes of chronic schizophrenia patients to test whether stratification can enhance computer-aided discrimination of patients from control subjects. Unsupervised, data-driven clustering of structural MRI (sMRI) data was used to identify 2 subtypes of schizophrenia patients drawn from a US-based open science repository (n = 71) and we quantified classification improvements compared to controls (n = 74) using supervised machine learning. We externally validated the unsupervised and supervised learning models in a heterogeneous German validation sample (n = 316), and characterized symptom, cognition, and longitudinal symptom change signatures. Stratification improved classification accuracies from 68.5% to 73% (subgroup 1) and 78.8% (subgroup 2), respectively. Increased accuracy was also found when models were externally validated, and an average gain of 9% was found in supplementary analyses. The first subgroup was associated with cortical and subcortical volume reductions coupled with substantially longer illness duration, whereas the second subgroup was mainly characterized by cortical reductions, reduced illness duration, and comparatively less negative symptoms. Individuals within each subgroup could be identified using just 10 clinical questions at an accuracy of 81.2%, and differential cognitive and symptom course signatures were suggested in multivariate analyses. Our findings suggest that sMRI-based subtyping enhances the neuroanatomical discrimination of schizophrenia by identifying generalizable brain patterns that align with a clinical staging model of the disorder. These findings could be used to improve illness stratification for biomarker-based computer-aided diagnoses.

Structural Magnetic Resonance Imaging (MRI) studies have attempted to use brain measures obtained at the first-episode of psychosis to predict subsequent outcome, with inconsistent results. Thus, there is a real need to validate the utility of brain measures in the prediction of outcome using large datasets, from independent samples, obtained with different protocols and from different MRI scanners. This study had three main aims: 1) to investigate whether structural MRI data from multiple centers can be combined to create a machine-learning model able to predict a strong biological variable like sex; 2) to replicate our previous finding that an MRI scan obtained at first episode significantly predicts subsequent illness course in other independent datasets; and finally, 3) to test whether these datasets can be combined to generate multicenter models with better accuracy in the prediction of illness course. The multi-center sample included brain structural MRI scans from 256 males and 133 females patients with first episode psychosis, acquired in five centers: University Medical Center Utrecht (The Netherlands) (n=67); Institute of Psychiatry, Psychology and Neuroscience, London (United Kingdom) (n=97); University of São Paulo (Brazil) (n=64); University of Cantabria, Santander (Spain) (n=107); and University of Melbourne (Australia) (n=54). All images were acquired on 1.5-Tesla scanners and all centers provided information on illness course during a follow-up period ranging 3 to 7years. We only included in the analyses of outcome prediction patients for whom illness course was categorized as either "continuous" (n=94) or "remitting" (n=118). Using structural brain scans from all centers, sex was predicted with significant accuracy (89%; p<0.001). In the single- or multi-center models, illness course could not be predicted with significant accuracy. However, when reducing heterogeneity by restricting the analyses to male patients only, classification accuracy improved in some samples. This study provides proof of concept that combining multi-center MRI data to create a well performing classification model is possible. However, to create complex multi-center models that perform accurately, each center should contribute a sample either large or homogeneous enough to first allow accurate classification within the single-center., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Volumetric studies examining brain structure in depression subtypes are limited and inconclusive. The aim of the current study was to compare the volumes of brain regions previously implicated in depression among patients with melancholic major depressive disorder (MDD), patients with psychotic MDD and normal controls., Methods: Twenty two patients with melancholic MDD, 17 with psychotic MDD and 18 normal controls were included in the study. Hippocampal (HV), amygdala (AV), anterior (ASCV) and posterior (PSCV) subgenual cortex volumes were measured on magnetic resonance volumetric images., Results: There were no volumetric differences between patients with melancholic and psychotic subgroups. We identified larger AVs and smaller left ASCVs in both patient groups compared to controls with medium to large effect sizes. Regression analysis revealed that AVs were predicted by the presence of depression, late depression-onset, insomnia and left hippocampal tail volume in patients, but not in controls. There were no differences in HVs, right ASCVs and PSCVs across the 3 groups., Limitations: Small sample size, a possible inclusion of paracingulate gyrus in ASCV and PSCV tracings, significant differences in education level and medication status are discussed as limitations., Conclusions: Diagnostically delineated melancholic and psychotic MDD patients do not differ in medial temporal and cingulate volumes. However, significant volumetric differences were detected between both patient-groups and controls., (Copyright © 2012 Elsevier B.V. All rights reserved.)

It remains unclear whether brain structural abnormalities observed before the onset of psychosis are specific to schizophrenia or are common to all psychotic disorders. This study aimed to measure regional gray matter volume prior to the onset of schizophreniform and of affective psychoses. We investigated 102 subjects at ultrahigh risk (UHR) of developing psychosis recruited from the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia. Twenty-eight of these subjects developed psychosis subsequent to scanning: 19 schizophrenia, 7 affective psychoses, and 2 other psychoses. We examined regional gray matter volume using 1.5 mm thick, coronal, 1.5 Tesla magnetic resonance imaging and voxel-based morphometry methods of image analysis. Subjects were scanned at presentation and were followed up clinically for a minimum of 12 months, to detect later transition to psychosis. We found that both groups of subjects who subsequently developed psychosis (schizophrenia and affective psychosis) showed reductions in the frontal cortex relative to UHR subjects who did not develop psychosis. The subgroup that subsequently developed schizophrenia also showed smaller volumes in the parietal cortex and, at trend level, in the temporal cortex, whereas those who developed an affective psychosis had significantly smaller subgenual cingulate volumes. These preliminary findings suggest that volumetric abnormalities in UHR individuals developing schizophrenia vs affective psychoses comprise a combination of features that predate both disorders and others that may be specific to the nature of the subsequent disorder.

Background: Recent evidence from genetic and familial studies revitalized the debate concerning the validity of the distinction between schizophrenia and bipolar disorder. Comparing brain imaging findings is an important avenue to examine similarities and differences and, therefore, the validity of the distinction between these conditions. However, in contrast to bipolar disorder, most patient samples in studies of schizophrenia are predominantly male. This a limiting factor for comparing schizophrenia and bipolar disorder since male gender is associated with more severe neurodevelopmental abnormalities, negative symptoms and cognitive deficits in schizophrenia., Method: We used a coordinate-based meta-analysis technique to compare grey matter (GM) abnormalities in male-dominated schizophrenia, gender-balanced schizophrenia and bipolar disorder samples based on published voxel-based morphometry (VBM) studies. In total, 72 English-language, peer reviewed articles published prior to January 2011 were included. All reports used VBM for comparing schizophrenia or bipolar disorder with controls and reported whole-brain analyses in standard stereotactic space., Results: GM reductions were more extensive in male-dominated schizophrenia compared to gender-balanced bipolar disorder and schizophrenia. In gender-balanced samples, GM reductions were less severe. Compared to controls, GM reductions were restricted to dorsal anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex in schizophrenia and ACC and bilateral fronto-insular cortex in bipolar disorder., Conclusions: When gender is controlled, GM abnormalities in bipolar disorder and schizophrenia are mostly restricted to regions that have a role in emotional and cognitive aspects of salience respectively. Dorsomedial and dorsolateral prefrontal cortex were the only regions that showed greater GM reductions in schizophrenia compared to bipolar disorder.

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis., Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy ((1)H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and (1)H-MRS percentage change scores between scans were compared using repeated measures ANOVA and correlated with behavioural change scores., Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects was seen for any brain metabolites as measured with (1)H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU., Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Context: People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent., Objective: To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites., Design: Case-control study., Setting: Multisite., Participants: A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not., Main Outcome Measures: Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry., Results: The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not., Conclusions: Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.

The aim of this study is to compare the volumes of hippocampus, amygdala and subgenual prefrontal cortex among patients with melancholic depression, patients with psychotic depression and normal controls. Thirty nine patients with a diagnosis of major depression (22 with melancholic and 17 with psychotic subtype) and 18 normal controls were included in the study. Hippocampal, amygdala, anterior and posterior subgenual cortex volumes were measured by manual tracings on magnetic resonance volumetric images and compared across the 3 groups. We identified larger amygdala volumes and smaller left anterior subgenual cortex volumes in both patient groups compared to controls. There were no differences in hippocampal, right anterior and posterior subgenual cortex volumes across the 3 groups. In conclusion, melancholic and psychotic depression were not differentiated regarding the volumes of the hippocampus, the amygdala, and anterior and posterior subgenual cortex, even though amygdala volumes and left anterior subgenual cortex volume of both patient groups were differentiated compared to controls.

Background: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been reported in bipolar disorder (BD), but previous magnetic resonance imaging (MRI) studies of pituitary gland volume in BD have yielded inconsistent findings. In addition, the contribution of genetic factors to the pituitary changes in BD remains largely unknown., Method: We used MRI to investigate the pituitary volume in 29 remitted patients with BD, 49 of their first-degree relatives (of whom 15 had a diagnosis of Major Depressive Disorder), and 52 age- and gender-matched healthy controls., Results: BD patients had a significantly larger pituitary volume compared with their relatives and healthy controls. Pituitary volume did not differ between controls and healthy relatives or relatives diagnosed with major depression., Limitations: Direct measures of HPA function (i.e., hormonal levels) were not available., Conclusions: These findings suggest that enlarged pituitary volume is associated with disease expression but not genetic susceptibility to BD., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Functional abnormalities of the superior temporal gyrus (STG) have been implicated in the pathophysiology of bipolar disorder, but magnetic resonance imaging (MRI) studies of this region have yielded inconsistent findings., Method: We used MRI to examine the volumes of the STG and its gray matter subregions [planum polare (PP), Heschl gyrus (HG), planum temporale (PT), and lateral STG (rostral and caudal regions)] in 26 patients with established bipolar I disorder (8 males and 18 females, mean age=38.4 years) and 24 age and gender-matched healthy controls (7 males and 17 females, mean age=38.7 years)., Results: Bipolar patients had significantly smaller volumes of the PT and caudal STG compared with controls in the left hemisphere. The STG white matter volume did not differ between the groups. There was no association between the STG volume and number of manic/depressive episodes, family history, or clinical subtype (i.e., psychotic and nonpsychotic), but daily dosage of lithium treatment at the time of scanning was positively correlated with right PP and right rostral STG volumes., Limitations: Entire clinical data (e.g., lifetime medication, symptomatology) were not available., Conclusions: These findings implicate a role for the STG gray matter, especially its left posterior regions, in the neurobiology of bipolar disorder. Our findings may also support the notion of lithium-induced gray matter expansion., (Copyright 2009 Elsevier B.V. All rights reserved.)

This structural magnetic resonance imaging study investigated insular cortex volume in 26 patients with bipolar I disorder and 24 matched controls. While insular volume did not differ between these groups, exploratory analyses demonstrated that the number of depressive episodes correlated negatively with the anterior insular volume in the patients, suggesting it may have a role in the pathophysiology of bipolar disorder., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Morphologic changes of cortico-limbic regions have been reported in bipolar disorder, but it remains unclear whether midline brain abnormalities relevant to cortico-limbic connectivity are also present., Methods: We used magnetic resonance imaging to investigate the size of the adhesio interthalamica (AI) and cavum septi pellucidi (CSP), as well as third ventricular volume, in 26 patients with bipolar I disorder and 24 matched controls., Results: CSP length and prevalence of a large CSP did not differ between the groups, but bipolar patients had significantly shorter AI and larger third ventricles compared to controls., Limitations: A comprehensive investigation of medication effects was not possible due to incomplete medication data., Conclusions: These findings implicate a role for the AI and connected brain regions in the neurobiology of bipolar disorder., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Background: Functional neuroimaging studies have implicated the insular cortex in emotional processing, including the evaluation of one's own emotion, as well as in the neurobiology of major depressive disorder (MDD). Nevertheless, it remains largely unknown whether MDD patients exhibit morphologic changes of the insular cortex, and whether such changes reflect state or trait markers of the disorder., Methods: We delineated the anterior and posterior insular cortices using magnetic resonance imaging in 29 currently depressed patients (mean age=32.5 years, 7 males), 27 remitted depressed patients (mean age=35.1 years, 9 males), and 33 age- and gender-matched healthy control subjects (mean age=34.0 years, 12 males)., Results: Both current and remitted MDD patients showed significant volume reduction of the left anterior insular cortex as compared with healthy controls, but there was no group difference in the posterior insular cortex volume. Insular volumes did not correlate with the severity of depressive symptoms. Furthermore, the presence of melancholia and co-morbidity with anxiety disorders did not affect insular cortex volumes., Limitations: Although there was no difference in the insular cortex volume between medicated and unmedicated patients, a comprehensive investigation of medication effects was not possible, as complete data (e.g., dose, duration) were not available., Conclusions: These findings suggest that the morphologic abnormality of the anterior insular cortex, which plays a major role in introspection and emotional control, may be a trait-related marker of vulnerability to major depression, supporting the notion that MDD involves pathological alterations of limbic and related cortical structures., (Copyright 2009 Elsevier B.V. All rights reserved.)

Context: Neurobiological models of obsessive-compulsive disorder (OCD) emphasize disturbances in the function and connectivity of brain corticostriatal networks, or "loops." Although neuroimaging studies of patients have supported this network model of OCD, very few have applied measurements that are sensitive to brain connectivity features., Objective: Using resting-state functional magnetic resonance imaging, we tested the hypothesis that OCD is associated with disturbances in the functional connectivity of primarily ventral corticostriatal regions, measured from coherent spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal., Design: Case-control cross-sectional study., Setting: Hospital referral OCD unit and magnetic resonance imaging facility., Participants: A total of 21 patients with OCD (10 men, 11 women) and 21 healthy control subjects matched for age, sex, and estimated intelligence., Main Outcome Measures: Voxelwise statistical parametric maps testing the strength of functional connectivity of 4 striatal seed regions of interest (dorsal caudate nucleus, ventral caudate/nucleus accumbens, dorsal putamen, and ventral putamen) with remaining brain areas., Results: For both groups, there was a clear distinction in the pattern of cortical connectivity of dorsal and ventral striatal regions, consistent with the notion of segregated motor, associative, and limbic corticostriatal networks. Between groups, patients with OCD had significantly increased functional connectivity along a ventral corticostriatal axis, implicating the orbitofrontal cortex and surrounding areas. The specific strength of connectivity between the ventral caudate/nucleus accumbens and the anterior orbitofrontal cortex predicted patients' overall symptom severity (r(2) = 0.57; P < .001). Additionally, patients with OCD showed evidence of reduced functional connectivity of the dorsal striatum and lateral prefrontal cortex, and of the ventral striatum with the region of the midbrain ventral tegmental area., Conclusions: This study directly supports the hypothesis that OCD is associated with functional alterations of brain corticostriatal networks. Specifically, our findings emphasize abnormal and heightened functional connectivity of ventrolimbic corticostriatal regions in patients with OCD.

Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness.

Objective: Although several studies have confirmed the occurrence of gray-matter abnormalities in obsessive-compulsive disorder (OCD), the literature on white matter in OCD is more limited. In this study, we reviewed the role of white-matter abnormalities in the pathophysiology of OCD., Method: We reviewed the PubMed studies investigating white-matter integrity in patients with OCD between 1980 and 2010., Results: Case studies of patients who developed obsessive-compulsive symptoms secondary to multiple sclerosis, cerebrovascular diseases, and paraneoplastic leucoencephalopathy and controlled studies of patients with OCD examined with neuroimaging techniques (eg, structural, diffusion, and spectroscopic magnetic resonance imaging) were all consistent with the existence of abnormalities in specific white-matter tracts (eg, internal capsule, cingulate bundle, and corpus callosum) of individuals with OCD., Conclusions: Our review emphasizes that the reported white-matter alterations in OCD complement the broader gray-matter abnormalities identified and may well suggest that OCD is associated with large-scale disruption in brain systems or networks, as opposed to being a consequence of disturbances in isolated brain regions.

The anterior cingulate cortex (ACC) is a functionally heterogeneous region involved in diverse cognitive and emotional processes that support goal-directed behaviour. Structural magnetic resonance imaging (MRI) and neuropathological findings over the past two decades have converged to suggest abnormalities in the region may represent a neurobiological basis for many of the clinical manifestations of schizophrenia. However, while each approach offers complimentary information that can provide clues regarding underlying patholophysiological processes, the findings from these 2 fields are seldom integrated. In this article, we review structural neuroimaging and neuropathological studies of the ACC, focusing on the unique information they provide. The available imaging data suggest grey matter reductions in the ACC precede psychosis onset in some categories of high-risk individuals, show sub-regional specificity, and may progress with illness duration. The available post-mortem findings indicate these imaging-related changes are accompanied by reductions in neuronal, synaptic, and dendritic density, as well as increased afferent input, suggesting the grey matter differences observed with MRI arise from alterations in both neuronal and non-neuronal tissue compartments. We discuss the potential mechanisms that might facilitate integration of these findings and consider strategies for future research.

Morphologic abnormalities of the superior temporal gyrus (STG) have been reported in schizophrenia, but have not been extensively studied in other psychotic disorders such as affective psychosis. In the present study, magnetic resonance imaging was used to examine the volumes of the STG and its subregions [planum polare (PP), Heschl gyrus (HG), planum temporale (PT), rostral STG, and caudal STG] in 162 first-episode patients with various psychotic disorders [46 schizophrenia (31 schizophrenia and 15 schizoaffective disorder), 57 schizophreniform disorder, 34 affective psychosis, and 25 other psychoses] and 62 age- and sex-matched healthy controls. The first-episode schizophrenia patients had significantly less gray matter in HG, PT, and caudal STG bilaterally compared with all other groups, but there was no difference between the controls and affective psychosis, schizophreniform disorder, or other psychoses for any STG subregion. The STG white matter volume did not differ between groups. Our findings indicate that morphologic abnormalities of the STG gray matter are specific to schizophrenia among various psychotic disorders, implicating its role in the underlying pathophysiology of schizophrenia.

Reductions in the size of the anterior callosum have been described for both first-episode and established schizophrenia and bipolar affective disorder, but never in individuals with psychotic bipolar disorder. We recruited 110 first-episode psychosis subjects (74 schizophrenia spectrum and 36 affective psychosis) and 36 age- and gender-matched controls. The callosum was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images, and total area, length and curvature of the callosum were compared. The schizophrenia-spectrum group showed reductions in thickness of the genu across schizophreniform and schizoaffective disorder and schizophrenia, and the schizoaffective disorder group also showed an increase in thickness in the splenium and isthmus. None of these changes were seen in the affective disorder group, although a non-significant increase in the region of the isthmus and splenium was seen, particularly in the depressed group. Psychotic affective disorders do not show the anterior callosal reductions that are seen in the schizophrenia-spectrum group at first episode. The schizoaffective patients show additional posterior callosal expansions that may be a marker of an affective diathesis. This suggests that schizoaffective disorder may represent two interacting illness processes or be mid-way along a continuum of these two broad categories of illness at first psychosis.

Background: The corpus callosum enables the efficient linking of the two cerebral hemispheres. Reductions in the size of the anterior callosum have been described in geriatric depression, although findings in young adults have been much more equivocal., Methods: Data was acquired in 26 currently depressed (mean age 32.15 years, 5/26 male) and 28 remitted non-geriatric adults (mean age 36.36 years, 7/28 male), and 32 control subjects (mean age 34.41 years, 11/32 male). The total area, length and curvature of the callosum, and regional thickness along 39 points, from a mid-sagittal T1-weighted magnetic resonance image were compared across the groups., Results: Total area, length and curvature did not differ between the groups. The currently-depressed group showed expansions in the thickness of the posterior body and isthmus when compared to controls; this was not seen in remitted patients. Similar expansions were seen when comorbidly anxious patients were compared to depressed patients without anxiety. There was no difference between melancholic and non-melancholic patients, and medication status did not affect the results., Limitations: Currently-depressed patients showed higher rates of co-morbid anxiety and medication usage than remitted patients, although in the depression group as a whole there was no difference between medicated and unmedicated patients., Discussion: The corpus callosum shows expansions in regions connecting frontal, temporal and parietal regions in currently depressed patients only, suggestive of state-related changes in white matter in major depression that may reflect the effects of state-related factors on white matter structure.

Purpose of Review: Although structural magnetic resonance imaging (sMRI) and neuropathological investigations offer complementary information that can be used to formulate and test hypotheses about pathophysiological mechanisms in psychiatric disorders, the findings from these two fields are seldom integrated in a systematic manner. In this study, we overview recent sMRI findings in schizophrenia and bipolar disorder and consider how they relate to neuropathological data., Recent Findings: sMRI research indicates that schizophrenia is associated with volumetric reductions in a network of frontal, temporal, limbic, striatal, and thalamic regions. Some of these abnormalities are apparent prior to psychosis onset and may progress with ongoing illness. sMRI findings in bipolar disorder have been more variable, with both volumetric increases and decreases being reported across several brain regions at different illness stages. Neuropathological studies of both patient groups suggest the cellular changes associated with these volumetric differences affect diverse tissue compartments in a regionally heterogeneous way., Summary: These findings suggest that any putative pathophysiological mechanism in schizophrenia or bipolar disorder should account for the dynamic, complex, and regionally heterogeneous brain abnormalities seen in these patients. We contend that greater integration of the findings from these two fields will facilitate more targeted and hypothesis-driven research in the future.

Context: Longitudinal magnetic resonance imaging studies have shown progressive gray matter reduction in the superior temporal gyrus during the earliest phases of schizophrenia. It is unknown whether these progressive processes predate the onset of psychosis., Objective: To examine gray matter reduction of the superior temporal gyrus over time in individuals at risk for psychosis and in patients with first-episode psychosis., Design: Cross-sectional and longitudinal comparisons., Setting: Personal Assessment and Crisis Evaluation Clinic and Early Psychosis Preventions and Intervention Centre., Participants: Thirty-five ultrahigh-risk individuals (of whom 12 later developed psychosis [UHRP] and 23 did not [UHRNP]), 23 patients with first-episode psychosis (FEP), and 22 control subjects recruited from the community., Main Outcome Measures: Volumes of superior temporal subregions (planum polare, Heschl gyrus, planum temporale, and rostral and caudal regions) were measured at baseline and follow-up (mean, 1.8 years) and were compared across groups., Results: In cross-sectional comparisons, only the FEP group had significantly smaller planum temporale and caudal superior temporal gyrus than other groups at baseline, whereas male UHRP subjects also had a smaller planum temporale than controls at follow-up. In longitudinal comparison, UHRP and FEP patients showed significant gray matter reduction (approximately 2%-6% per year) in the planum polare, planum temporale, and caudal region compared with controls and/or UHRNP subjects. The FEP patients also exhibited progressive gray matter loss in the left Heschl gyrus (3.0% per year) and rostral region (3.8% per year), which were correlated with the severity of delusions at follow-up., Conclusions: A progressive process in the superior temporal gyrus precedes the first expression of florid psychosis. These findings have important implications for underlying neurobiologic features of emerging psychotic disorders and emphasize the importance of early intervention during or before the first episode of psychosis.

Morphologic abnormalities of the insular cortex have been described in psychotic disorders such as schizophrenia, but it remains unknown whether these abnormalities develop progressively over the course of the illness. In the current study, longitudinal magnetic resonance imaging data were obtained from 23 patients with first-episode psychosis (FEP), 11 patients with chronic schizophrenia, and 26 healthy controls. The volumes of the short (anterior) and long (posterior) insular cortices were measured on baseline and follow-up (between 1 and 4 years later) scans and were compared across groups. In cross-sectional comparison at baseline, the FEP and chronic schizophrenia patients had significantly smaller short insular cortex than did controls. In longitudinal comparison, the FEP patients showed significant gray matter reduction of the insular cortex over time (-4.3%/2.0 years) compared with controls (0.3%/2.2 years) without significant subregional effects, but there was no difference between chronic schizophrenia patients (-1.7%/2.4 years) and controls. The gray matter loss of the left insular cortex over time in FEP patients was correlated with the severity of positive and negative symptoms at follow-up. These findings indicate that patients with psychotic disorders have smaller gray matter volume of the insular cortex especially for its anterior portion (short insula) at first expression of overt psychosis, but also exhibit a regional progressive pathological process of the insular cortex during the early phase after the onset, which seems to reflect the subsequent symptomatology.

An increased prevalence of large cavum septum pellucidum (CSP), a marker of midline neurodevelopmental abnormality, has been reported in schizophrenia. However, not all studies have been able to replicate this finding and very few studies have been conducted in large samples. In the current study, magnetic resonance imaging was used to assess the presence of an abnormal CSP in 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, 135 ultra high-risk (UHR) individuals, and 87 controls. The prevalence of a large CSP (>5.6 mm) did not differ between the groups (9.3% of the FEP patients, 11.2% of the chronic schizophrenia patients, 11.1% of the UHR individuals, and 11.5% of the controls). The length of the CSP was not associated with sulcal morphology of the anterior cingulate cortex (ACC), suggesting different biological processes responsible for the CSP enlargement versus ACC folding. These findings suggest that the CSP is not a neurodevelopmental marker of psychosis and cast doubt over the notion that it plays a major role in the neurobiology of psychosis.

Reductions in the size of the anterior callosum have been described for both first-episode schizophrenia-spectrum psychosis and established schizophrenia, but have not been examined in individuals at ultra-high risk for psychosis (UHR). We compared 100 UHR individuals (27 of whom later developed psychosis) with 38 age-matched control subjects on measures of size and shape of the corpus callosum to determine if changes previously demonstrated in first-episode and established schizophrenia are present in the pre-psychotic phase. Each individual's callosum was extracted from the mid-sagittal slice from T1-weighted magnetic resonance images, and total area, length and curvature of the callosum was compared using one-way ANOVA, and 39 regional thicknesses via a non-parametric permutation method to account for non-independence of adjacent measures. Total area, length and curvature did not differ between the groups. Compared to both the UHR-NP group and controls, the UHR-P group showed significant regional reductions in the region of the anterior genu of the callosum. The UHR-NP group did not differ from controls. Positive and negative symptoms did not affect regional thickness in either of the patient groups. Cox regression showed that mean anterior genu thickness was highly predictive of a transition to psychosis. Reductions in the thickness of the anterior callosum differentiate between high-risk individuals who transition to psychosis and those who do not, and is highly predictive of transition. These changes may reflect primary pathology of orbitofrontal and medial frontal cortex, or deficits in anterior interhemispheric myelination.

It is not known whether the fronto-limbic volume reductions found in adults with established borderline personality disorder (BPD) are present early in the disorder. The aim of the study was to investigate orbitofrontal cortex (OFC), hippocampal and amygdala volumes in a first-presentation teenage BPD sample with minimal exposure to treatment. Groups of 20 BPD patients and 20 healthy control participants underwent magnetic resonance imaging. Hippocampal, amygdala, OFC and whole brain volumes were estimated and compared between the two groups. Analysis of variance revealed reversal of the normal (right>left) asymmetry of OFC grey matter volume in the BPD group, reflecting right-sided OFC grey matter loss in the BPD group compared with control participants. No significant differences were found for amygdala or hippocampal volumes comparing BPD with control participants. We identified OFC but not hippocampal or amygdala volumetric differences early in the course of BPD. Hippocampal and amygdala volume reductions observed in adult BPD samples might develop during the course of the disorder, although longitudinal studies are needed to examine this.

Objective: Temperament refers to enduring behavioral characteristics that underpin individual differences in human behavior, including risk for psychopathology. Research attempting to investigate the neurobiological basis of temperament represents an important step toward elucidating the biological mechanisms underlying these individual differences. In the present study, we examined the relation between four core temperament dimensions and anatomically defined regions of the limbic and prefrontal cortices., Method: We used a cross-sectional design to examine a large sample (N = 153; mean age 12.6 years, SD 0.4, range 11.4-13.7) of healthy early adolescents who were selected from a larger sample to maximize variation in temperament. The main outcome measures were psychometric measures of temperament (four factors: effortful control, negative affectivity, surgency, and affiliativeness) based on the Early Adolescent Temperament Questionnaire-Revised, and volumetric measures of a priori brain regions of interest (anterior cingulate cortex [ACC], orbitofrontal cortex, amygdala, and hippocampus)., Results: We found regional brain volumes to account for small but significant amounts of the variance in self-reported temperament scores. Specifically, higher effortful control was associated with larger volume of the left orbitofrontal cortex and hippocampus. Higher negative affectivity was associated with smaller volume of the left dorsal paralimbic relative to limbic portion of the ACC. Higher affiliativeness was associated with larger volume of the right rostral/ventral limbic portion of the ACC. Affiliativeness and surgency also showed a number of female-specific associations, primarily involving the rostral/ventral ACC., Conclusions: Our results provide support for a neuroanatomical basis for individual differences in temperament and have implications for understanding the neurobiological mechanisms underlying the development of a number of psychiatric disorders.

Context: Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term effect on the human brain., Objective: To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor-rich regions of the brain, the hippocampus and the amygdala., Design: Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging., Setting: Participants were recruited from the general community and underwent imaging at a hospital research facility., Participants: Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years)., Main Outcome Measures: Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured., Results: Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group., Conclusions: These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.

This structural magnetic resonance imaging study examined the relationship between pituitary gland volume (PGV) and lifetime number of parasuicidal behaviors in a first-presentation, teenage borderline personality disorder (BPD) sample with minimal exposure to treatment. Hierarchical regression analysis revealed that age and number of parasuicidal behaviors were significant predictors of PGV. These findings indicate that parasuicidal behavior in BPD might be associated with greater activation of the hypothalamic-pituitary-adrenal (HPA) axis. Further studies are required using direct neuroendocrine measures and exploring other parameters of self-injurious behavior, such as recency of self-injurious behavior, intent to die and medical threat.

The anterior cingulate cortex (ACC) appears to be critically involved in the pathophysiology of schizophrenia, but past attempts at characterizing pathological changes in the region using magnetic resonance imaging have been restricted by a limited appreciation of its functional and anatomical diversity and a reliance on relatively coarse metrics (e.g., volume) to index anatomical change. In this study, we applied a novel, surface-based protocol to T1-weighted scans acquired from 40 first episode schizophrenia patients and 40 healthy controls individually matched for age, sex, and morphology of the paracingulate sulcus, a major anatomical variation that has been shown to affect morphometric estimates in the region. The surface-based approach enabled calculation of regional grey matter volume, surface area and curvature, cortical thickness, and depth of the cingulate sulcus, with sub-millimeter precision. Relative to controls, schizophrenia patients displayed a bilateral reduction in thickness of paralimbic regions of the ACC, along with a concomitant increase in surface area of both the limbic and paralimbic ACC. No differences were identified for regional grey matter volume, surface curvature, or CS depth. These findings illustrate the advantages of moving beyond traditional volume-based approaches when investigating cortical morphometry, and indicate that the early stages of schizophrenia are associated with a specific pattern of ACC abnormalities that cannot be attributed to variations in sulcal and gyral morphology., ((c) 2007 Wiley-Liss, Inc.)

Abnormalities of the anterior cingulate cortex (ACC) are thought to be involved in the pathophysiology of bipolar disorder, but structural Magnetic Resonance Imaging (MRI) studies have reported variable findings. Reasons for this include a failure to consider variability in regional cortical folding patterns and a reliance on relatively coarse measures (e.g., volume) to index anatomical change. We sought to overcome these limitations by combining a novel protocol for parcellating the ACC and adjacent paracingulate cortex (PaC) that accounts for inter-individual variations in sulcal and gyral morphology with a cortical surface-based approach that allowed calculation of regional grey matter volume, surface area and cortical thickness in 24 patients with bipolar I disorder and 24 matched controls. No changes in grey matter volume or surface area were identified in any region, but patients did show significant reductions in cortical thickness in the left rostral PaC and right dorsal PaC that were not attributable to group differences in cortical folding patterns. These findings suggest that bipolar disorder is associated with more pronounced changes in the PaC, and that reliance on volumetric measures alone may obscure more subtle differences.

Objective: Functional abnormalities of the dorsal anterior cingulate (dAC) region have been emphasized in schizophrenia, particularly in relation to cognitive deficits. In this study, we sought to further evaluate the notion of dAC hypofunction in chronic schizophrenia patients using a cognitive task specifically designed to activate this region, enabling both group and single-subject level analyses., Method: Twelve male schizophrenia patients and 14 male healthy subjects were studied with functional magnetic resonance imaging (fMRI) and the multi-source interference task (MSIT). Patients and healthy subjects were matched for age, gender, education, task performance and gross surface morphology of the AC region. fMRI analyses were conducted at the group and single-subject levels using stringent whole-brain activation thresholds., Results: Multi-source interference task performance was associated with large and significant activation of the dAC and supplementary motor area (SMA) in patients and healthy subjects. Standard comparison of the two groups indicated that the patients were comparable with healthy subjects in their dAC activation, but had a small cluster of greater SMA activation, while single-subject analyses identified minimal differences in the magnitude or spatial dispersion of dAC activation between the groups., Conclusion: These findings challenge existing notions of impaired dAC activation in chronic schizophrenia and suggest that the functional pathophysiology of this medial-wall region should be considered beyond straightforward models of hypoactivation.

Context: The medial frontal cortex (MFC), including the dorsal anterior cingulate and the supplementary motor area, is critical for adaptive and inhibitory control of behavior. Abnormally high MFC activity has been a consistent finding in functional neuroimaging studies of obsessive-compulsive disorder (OCD). However, the precise regions and the neural alterations associated with this abnormality remain unclear., Objective: To examine the functional and biochemical properties of the MFC in patients with OCD., Design: Cross-sectional study combining volume-localized proton magnetic resonance spectroscopy and functional magnetic resonance imaging with a task encompassing inhibitory control processes (the Multi-Source Interference Task) designed to activate the MFC., Setting: Healthy control participants and OCD patients recruited from the general community., Participants: Nineteen OCD patients (10 males and 9 females) and 19 age-, sex-, education-, and intelligence-matched control participants recruited from the general community., Main Outcome Measures: Psychometric measures of symptom severity, Multi-Source Interference Task behavioral performance, blood oxygen level-dependent activation, and proton magnetic resonance spectroscopy brain metabolite concentrations., Results: Multi-Source Interference Task behavioral performance did not differ between OCD patients and control subjects. Reaction time interference and response errors were correlated with blood oxygen level-dependent activation in the dorsal anterior cingulate region in both groups. Compared with controls, OCD patients had greater relative activation of the supplementary motor area and deactivation of the rostral anterior cingulate during high- vs low-conflict (incongruent > congruent) trials. Patients with OCD also showed reduced levels of neuronal N-acetylaspartate in the dorsal anterior cingulate region, which was negatively correlated with their blood oxygen level-dependent activation of the region., Conclusions: Hyperactivation of the MFC during high- vs low-conflict conditions in patients with OCD may be a compensatory response to a neuronal abnormality in the region. This relationship may partly explain the nature of inhibitory control deficits that are frequently seen in this group and may serve as a focus of future treatment studies.

Task-induced deactivations (TIDs) of midline cortical regions are readily observed in fMRI studies and may reflect elements of a 'default-mode' of brain function associated with self-directed mental processes at rest. In this study, we examined this TID phenomenon in schizophrenia and its relevance to patients' symptoms, task performance and level of emotional awareness. Relative to control subjects, patients showed significantly greater TID of the rostral anterior cingulate (rAC)/medial prefrontal cortex (mPFC) and precuneus (PrC)/posterior cingulate cortex (PC). The magnitude of prefrontal TIDs was associated with patients' task performance and emotional awareness for others. The nature of these associations suggests a complex interchange between cognitive and emotional influences on the resting-state activity of these prefrontal 'default mode' regions in schizophrenia.

Objective: We sought to identify neurobiological correlates of Melbourne-Sydney rivalry through neuroimaging measures of a key brain region involved in cognitive and emotional regulation., Method: Twenty subjects from each city were recruited from two large neuroimaging databases, and were scanned on a GE Signa 1.5 T magnetic resonance imaging scanner. Cortical thickness of the anterior cingulate cortex (ACC) was measured using a tessellated mesh method, after image segmentation. These measures were compared with key sporting, financial and academic variables., Results: Residents of Melbourne had a significantly thicker ACC (p < 0.0001) than Sydney residents, and this difference remained significant when age and intracranial volume were controlled for (p = 0.001). This difference mirrored that in variables measuring wealth, sporting and academic success., Conclusions: The thinner ACC seen in Sydney-siders may reflect the effects of increased stress due to elevated property prices, relative lack of sporting success and other variables. An alternative explanation is that a thinner ACC is the result of increasing cortical refinement and efficiency, and a marker of a more mature city. However, if these findings are a result of latitudinal effects, this may have significant implications for residents of more northern regions of the Australian continent.

Context: Magnetic resonance imaging studies have identified hippocampal volume reductions in schizophrenia and amygdala volume enlargements in bipolar disorder, suggesting different medial temporal lobe abnormalities in these conditions. These studies have been limited by small samples and the absence of patients early in the course of illness., Objective: To investigate hippocampal and amygdala volumes in a large sample of patients with chronic schizophrenia, patients with first-episode psychosis, and patients at ultra-high risk for psychosis compared with control subjects., Design: Cross-sectional comparison between patient groups and controls., Setting: Individuals with chronic schizophrenia were recruited from a mental health rehabilitation service, and individuals with first-episode psychosis and ultra-high risk were recruited from the ORYGEN Youth Health Service. Control subjects were recruited from the community., Participants: The study population of 473 individuals included 89 with chronic schizophrenia, 162 with first-episode psychosis, 135 at ultra-high risk for psychosis (of whom 39 subsequently developed a psychotic illness), and 87 controls., Main Outcome Measures: Hippocampal, amygdala, whole-brain, and intracranial volumes were estimated on high-resolution magnetic resonance images and compared across groups, including first-episode subgroups. We used 1- and 2-way analysis of variance designs to compare hippocampal and amygdala volumes across groups, correcting for intracranial volume and covarying for age and sex. We investigated the effects of medication and illness duration on structural volumes., Results: Patients with chronic schizophrenia displayed bilateral hippocampal volume reduction. Patients with first-episode schizophrenia but not schizophreniform psychosis displayed left hippocampal volume reduction. The remaining first-episode subgroups had normal hippocampal volumes compared with controls. Amygdala volume enlargement was identified only in first-episode patients with nonschizophrenic psychoses. Patients at ultra-high risk for psychosis had normal baseline hippocampal and amygdala volumes whether or not they subsequently developed a psychotic illness. Structural volumes did not differ between patients taking atypical vs typical antipsychotic medications, and they remained unchanged when patients treated with lithium were excluded from the analysis., Conclusions: Medial temporal structural changes are not seen until after the onset of a psychotic illness, and the pattern of structural change differs according to the type of psychosis. These findings have important implications for future neurobiological studies of psychotic disorders and emphasize the importance of longitudinal studies examining patients before and after the onset of a psychotic illness.

A wide range of neuropathological abnormalities have been detected in schizophrenia sufferers, and emerging evidence points to neural substrates of connectivity as having a key role in the development of disease. This article reviews the available evidence for white matter pathology in schizophrenia, and examines its possible role as a substrate of impaired connectivity. Neuropathological data is suggestive of abnormalities in glial structure and function, and myelinated structures have also been implicated. A number of studies, particularly using gene array technology, are pointing towards significant disruption in expression of myelination genes. Magnetic resonance imaging has tended to focus on, and detect, more grey than white matter abnormalities, although non-volumetric techniques are suggestive of changes in the microstructure of white matter in schizophrenia. Myelinated structures are an attractive candidate for an anatomical substrate for disconnectivity, and may act synergistically with synaptic changes to result in functional disconnectivity although the relationship between white and grey matter changes in the illness remains unclear.

Functional imaging and neuropsychological data suggest that interconnected brain structures including the orbito-frontal cortex (OFC), anterior cingulate cortex (ACC) and caudate nucleus (CN) are involved in the pathophysiology of obsessive-compulsive disorder (OCD), but structural imaging studies investigating these regions have yielded inconclusive results. This may be due to inconsistencies in the identification of anatomical boundaries and methodologies utilised (i.e. automated vs. manual tracing). This magnetic resonance imaging study used manual tracing to measure volumes of selected brain regions (OFC, ACC and CN) in OCD patients and compared them with samples of healthy (HC) and psychiatric (schizophrenia; SCZ) controls (n=18 in each group). Concurrently, automated voxel-based analysis was also used to detect subtle differences in cerebral grey and white matter. For the OCD vs. HC comparison, there were no significant volumetric differences detected using the manual or the automated method (although the latter revealed a deficit in the subcortical white matter of the right temporal region). A direct comparison of the two patient groups showed no significant differences using the manual method. However, a moderate effect size was detected for OFC grey matter (reduced in SCZ), which was supported by findings of reduced OFC volume in the automated analysis. Automated analyses also showed reduced volumes in the dorsal (white matter) and ventral ACC (grey and white matter), as well as the left posterior cingulate (grey and white matter) in SCZ. The findings suggest that in contrast to findings in SCZ, there are very few (if any) gross structural anomalies in OCD.

Using covariance-based multivariate analysis, we examined patterns of functional connectivity in rCBF on a practice-extended version of the Stroop color-word paradigm. Color-word congruent and incongruent conditions were presented in six AB trials to healthy subjects during 12 H2(15)O PET scans. Analyses identified two reproducible canonical eigenimages (CE) from the PET data, which were converted to a standard Z score scale after cross-validation resampling and correction for random subject effects. The first CE corresponded to practice-dependent changes in covarying rCBF that occurred over early task repetitions and correlated with improved behavioral performance. This included many regions previously implicated by PET and fMRI studies of this task, which we suggest may represent two "parallel" networks: (i) a cingulo-frontal system that was initially engaged in selecting and mapping a task-relevant response (color naming) when the attentional demands of the task were greatest; and (ii) a ventral visual processing stream whose concurrent decrease in activity represented the task-irrelevant inhibition of word reading. The second CE corresponded to a consistent paradigmatic effect of Stroop interference on covarying rCBF. Coactivations were located in dorsal and ventral prefrontal regions as well as frontopolar cortex. This pattern supports existing evidence that prefrontal regions are involved in maintaining attentional control over conflicting response systems. Taken together, these findings may be more in line with theoretical models that emphasize a role for practice in the emergence of Stroop phenomena. These findings may also provide some additional insight into the nature of anterior cingulate- and prefrontal cortical contributions to implementing cognitive control in the brain.

Background: Psychotic disorders, such as schizophrenia, are associated with neuroanatomical abnormalities, but whether these predate the onset of symptoms or develop progressively over the course of illness is unclear. We investigated this issue with MRI to study people with prodromal symptoms who are at ultra high-risk for the development of psychosis., Methods: We did two comparisons, cross-sectional and longitudinal. For the cross-sectional comparison, 75 people with prodromal signs of psychosis were scanned with MRI. After at least 12 months of follow-up, 23 (31%) had developed psychosis and 52 (69%) had not. Baseline MRI data from these two subgroups were compared. For the longitudinal comparison, 21 of the ultra high-risk individuals were scanned again with MRI after at least 12 months. Ten of these had developed psychosis and 11 had not. MRI data from baseline and follow-up were compared within each group of people., Findings: In the cross-sectional comparison, compared with people who did not develop psychosis, those who did develop the disorder had less grey matter in the right medial temporal, lateral temporal, and inferior frontal cortex, and in the cingulate cortex bilaterally. In the longitudinal comparison, when re-scanned, individuals who had developed psychosis showed a reduction in grey matter in the left parahippocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In those who had not become psychotic, longitudinal changes were restricted to the cerebellum., Interpretation: Some of the grey-matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear in association with their first expression.