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Contains fulltext : 291574.pdf (Publisher’s version ) (Open Access) Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

ObjectiveSchizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder.MethodsWe studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps.ResultsIn schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, pspinspin=0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders.ConclusionsCortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.

Cortical folding of the anterior cingulate cortex (ACC), particularly the cingulate (CS) and the paracingulate (PCS) sulci, represents a neurodevelopmental marker. Deviations in in utero development in schizophrenia can be traced using CS and PCS morphometry. In the present study, we measured the length of CS, PCS, and their segments on T1 MRI scans in 93 patients with first- episode schizophrenia and 42 healthy controls. Besides the length, the frequency and the left-right asymmetry of CS/PCS were compared in patients and controls. Distribution of the CS and PCS morphotypes in patients was different from controls. Parcellated sulcal pattern CS3a in the left hemisphere was longer in patients (53.8 ± 25.7 mm vs. 32.7 ± 19.4 mm in controls, p < 0.05), while in CS3c it was reversed—longer in controls (52.5 ± 22.5 mm as opposed to 36.2 ± 12.9 mm, n.s. in patients). Non parcellated PCS in the right hemisphere were longer in patients compared to controls (19.4 ± 10.2 mm vs. 12.1 ± 12.4 mm, p < 0.001). Therefore, concurrent presence of PCS1 and CS1 in the left hemisphere and to some extent in the right hemisphere may be suggestive of a higher probability of schizophrenia.

[Background]: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., [Methods]: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., [Results]: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., [Conclusions]: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., This work was supported by the German Research Foundation (DFG Grant Nos. HA7070/2-2, HA7070/3, HA7070/4 [to TH]) and IZKF of the medical faculty of Münster (Grants No. Dan3/012/17 [to UD] and MzH 3/020/20 [to TH]), and NHMRC projects (Grant No. 1064643 [to BJH] and 1024570 [to CGD]). The CIAM study was supported by the University of Cape Town Research Committee, South African National Research Foundation, and the South African Medical Research Council (principal investigator [PI], Fleur M. Howells) and Grant No. R01MH117601 (to NJ). This work was funded by the German Research Foundation (Grant Nos. FOR2107 JA 1890/7-1 and FOR2107 JA 1890/7-2 [to AJ]) and Swinburne University scholarship/Australian Postgraduate Award (to JK). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to JK). This work was funded by the German Research Foundation (Grant Nos. FOR2107 KI588/14-1 and FOR2107 KI588/14-2 [to TK]). The St. Göran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant Nos. ALF 20170019 and ALFGBG-716801 [to ML]). This work was supported by RFBR (Grant No. 20-013-00748 [to IL, AST]) and funded by the Health Research Board (Grant No. HRA_POR/2011/100 [to CM]). The Australian Schizophrenia Research Bank (ASRB) was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. This work was supported by Deutsche Forschungsgemeinschaft (Grant Nos. DFG NE 2254/2-1, NE 2254/3-1, NE2254/4-1 [to IN]), the University Research Priority Program “Integrative Human Physiology” at the University of Zurich (to ROT), an NHMRC Senior Principal Research Fellowship (Grant No. 1105825 [to CPa]), an NHMRC L3 Investigator Grant (Grant No. 1196508 [to CPa]), and NHMRC Program Grant (Grant No. 1150083 [to CPa]). ASRB was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (Agreement No. 798181 [to GP]). ASRB was supported by the NHMRC (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. The Imaging Genetics in Psychosis study was funded by Project Grants from the NHMRC (Grant Nos. APP630471 and APP1081603 [to YQ]) and the Macquarie University’s Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (Grant No. CE110001021 [to YQ]). This work was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI11/01766 and CPII19/00009 [to JR]), co-financed by European Regional Development Fund funds from the European Commission (“A Way of Making Europe”). ASRB was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. SR was supported by an NHMRC Senior Fellowship (Grant No. GNT1154651). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to SR). This work was supported by NIHR; MRC (to KR), NIH (Grant Nos. MH-094268, MH-105660, and MH-107730 [to ASS]). The Neuroimaging of the Children's Attention Project cohort was funded by NHMRC, Australia (Grant No. 1065895). Earlier funding for the cohort as also provided by NHMRC (Grant No. 1008522) and a grant from the Collier Foundation. The ACPU cohort was funded by NHMRC, Australia (Project Grant Nos. 384419 and 569533 [to TS]). This work was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004, SIG/05028, and SIG /1103), and the Singapore Bioimaging Consortium (RP C009/2006 [to KS]), and the Ministry of Health, Czech Republic - conceptual development of research organization (“Institute for Clinical and Experimental Medicine - IKEM, IN 00023001” [to ASk]). This study was supported by the Italian Ministry of Health (Grant No. RC/17-18-19-20-21/A [to GS]) and Ministry of Health of the Czech Republic (Grant No. NU20-04-00393 [to FS]). The Drakenstein Child Health Study (DCHS) cohort is funded by the Bill and Melinda Gates Foundation (Grant No. OPP 1017641) and the South African Medical Research Council. This DCHS contribution was made possible in part by a grant from Carnegie Corporation of New York. The statements made and views expressed are solely the responsibility of the author (DJS). STRADL study was supported and funded by the Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (Grant No. 104036/Z/14/Z), and the Medical Research Council Mental Health Pathfinder Award “Leveraging routinely collected and linked research data to study the causes and consequences of common mental disorders” (MRC, Grant No. MC_PC_17209). Scottish Bipolar Family Study (SBFS) was supported by National Health Service Research Scotland, through the Scottish Mental Health Research Network (www.smhrn.org.uk), who provided assistance with subject recruitment and assessments. SBFS was conducted at the Brain Research Imaging Centre (http://www.bric.ed.ac.uk), which is supported by SINAPSE (Scottish Imaging Network, a Platform for Scientific Excellence, http://www.sinapse.ac.uk). Processing of the datasets used the resources provided by the Edinburgh Compute and Data Facility (http://www.ecdf.ed.ac.uk/) (ASt). TVR was supported by an NHMRC Early Career Fellowship (Grant No. GNT1088785). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to TVR). EV was supported by the Spanish Ministry of Science and Innovation (PI18/00805) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the FEDER; the Instituto de Salud Carlos III; the CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental); by the CERCA Programme/Generalitat de Catalunya and the Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (Grant No. 2017SGR1355). This study was also supported by the Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016-2020 (Grant No. SLT006/17/00345) and the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing and disease: Grant Nos. 754907 and EU.3.1.3 [to EB]; Treating and managing disease: Grant No. 945151 [to EV]). This study was supported by the National Center for Complementary and Integrative Health (Grant Nos. R21AT009173 and R61AT009864 [to TTY]); by the National Center for Advancing Translational Sciences (CTSI), National Institutes of Health, through UCSF-CTSI (Grant No. UL1TR001872 [to TTY]); by the American Foundation for Suicide Prevention (Grant No. SRG-1-141-18 [to TTY]); by UCSF Research Evaluation and Allocation Committee (REAC) and J. Jacobson Fund (to TTY); by the NIMH (Grant No. R01MH085734 [to TTY]); and by the Brain and Behavior Research Foundation (formerly NARSAD) (to TTY). This work was supported by a personal Veni grant to MH from the Netherlands Organization for Scientific Research (NWO, Grant No. 91619115 [to MH]) and European Community’s Horizon 2020 Programme (H2020/2014 – 2020) (Grant Agreements Nos. 667302 [CoCA], 728018 [Eat2beNICE], and 847879 [PRIME] [to BF]). JBu has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes, which receive support from Innovative Medicines Initiative Joint Undertaking Grant Nos. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon 2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon 2020–supported programme CANDY (Grant No. 847818 [to JBu]). This work is supported by Grant No. NIA T32AG058507 and NIH Grant No. U54EB020403 from the Big Data to Knowledge (BD2K) Program (to CRKC). ENIGMA MDD work is supported by NIH (Grant Nos. U54 EB020403 [to PT], R01 MH116147 [to PT], and R01 MH117601 [to NJ and LS]). LS was supported by an NHMRC Career Development Fellowship (Grant No. 1140764). This work was supported by the National Center for Research Resources at the NIH (Grant Nos. NIH 1 U24 RR021992 [Function Biomedical Informatics Research Network], NIH 1 U24 RR025736-01 [Biomedical Informatics Research Network Coordinating Center; http://www.birncommunity.org]). TGMvE is supported by ENIGMA’s NIH BD2K initiative (Grant No. U54 EB020403), ENIGMA Sex Differences (Grant No. R01MH116147), and ENIGMA-COINSTAC: Advanced Worldwide Transdiagnostic Analysis of Valence System Brain Circuits (Grant No. R01MH121246). This work was supported by the NIH (Grant No. R01MH121246 [to JT, Calhoun, and TGMvE]). This work was supported in part by NIH (Grant No. U54 EB020403 [to PT]).

Background Obesity is highly prevalent in schizophrenia, with implications for psychiatric prognosis, possibly through links between obesity and brain structure. In this longitudinal study in first episode of psychosis (FEP), we used machine learning and structural magnetic resonance imaging (MRI) to study the impact of psychotic illness and obesity on brain ageing/neuroprogression shortly after illness onset. Methods We acquired 2 prospective MRI scans on average 1.61 years apart in 183 FEP and 155 control individuals. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants and calculated BrainAGE by subtracting chronological from the estimated brain age. Results Individuals with FEP had a higher initial BrainAGE than controls (3.39 ± 6.36 vs 1.72 ± 5.56 years; β = 1.68, t(336) = 2.59, P = .01), but similar annual rates of brain ageing over time (1.28 ± 2.40 vs 1.07±1.74 estimated years/actual year; t(333) = 0.93, P = .18). Across both cohorts, greater baseline body mass index (BMI) predicted faster brain ageing (β = 0.08, t(333) = 2.59, P = .01). For each additional BMI point, the brain aged by an additional month per year. Worsening of functioning over time (Global Assessment of Functioning; β = −0.04, t(164) = −2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (β = 0.11, t(175) = 3.11, P = .002) were associated with faster brain ageing in FEP. Conclusions Brain alterations in psychosis are manifest already during the first episode and over time get worse in those with worsening clinical outcomes or higher baseline BMI. As baseline BMI predicted faster brain ageing, obesity may represent a modifiable risk factor in FEP that is linked with psychiatric outcomes via effects on brain structure.

Hajek, Tomas: et al., Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia., NAC et al. were supported by the Agencia Nacional de Investigación y Desarrollo, Chile, through its grants PIA ACT1414, ANID-PIA-ACT 192064, and FONDECYT regular 1200601. This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). The NUDZ and IKEM sites were supported by funding from the Ministry of Health of the Czech Republic (16-32791A, NU20-04-00393) and conceptual development of research organization (Institute for Clinical and Experimental Medicine – IKEM, IN 00023001). This work was also funded by the German Research Foundation (DFG grant FOR2107, KI588/14-1 and FOR2107, KI588/14-2 to TTJK, Marburg, Germany), as well as, the Alexander von Humboldt Foundation, EU and Deutsche Forschungsgemeinschaft (DFG), grants NE2254/1-2, NE2254/3-1, NE2254/4-1. Additional support provided by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/05028), and the Singapore Bioimaging Consortium (RP C009/2006) research grants awarded to KS. EW was supported by the European Union’s Horizon 2020 research and innovation programme (Early Cause, grant n° 848158). Funding for TWW was provided by the National Health and Medical Research Council Australia Project Grant 568807; New South Wales Health, University of New South Wales, Neuroscience Research Australia and the Schizophrenia Research Institute. GD’s research was funded by the European Research Council 677467 and Science Foundation Ireland 16/ERCS/3787. VDC was supported by NIH R01MH118695. PMT was supported by NIMH grant R01MH116147. Lastly, TH was supported by funding from the Canadian Institutes of Health Research (103703, 106469 and 142255), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to TH, Brain & Behavior Research Foundation (formerly NARSAD); 2007 Young Investigator and 2015 Independent Investigator Awards to TH.

BackgroundBipolar disorder (BD) is linked to circadian rhythm disruptions resulting in aberrant motor activity patterns. We aimed to explore whether motor activity alone, as assessed by longitudinal actigraphy, can be used to classify accurately BD patients and healthy controls (HCs) into their respective groups.MethodsNinety-day actigraphy records from 25 interepisode BD patients (ie, Montgomery–Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) ResultsUsing all actigraphy features, this method correctly assigned 88% (sensitivity = 85%, specificity = 91%) of BD patients and HCs to their respective group. The classification success may be confounded by differences in employment between BD patients and HCs. When motor activity features resistant to the employment status were used (the strongest feature being time variation of intradaily variability, Cohen’s d = 1.33), 79% of the subjects (sensitivity = 76%, specificity = 81%) were correctly classified.ConclusionA machine-learning actigraphy-based model was capable of distinguishing between interepisode BD patients and HCs solely on the basis of motor activity. The classification remained valid even when features influenced by employment status were omitted. The findings suggest that temporal variability of actigraphic parameters may provide discriminative power for differentiating between BD patients and HCs while being less affected by employment status.

BACKGROUND Seasonal peaks in hospitalizations for mood disorders and schizophrenia are well recognized and often replicated. The within-subject tendency to experience illness episodes in the same season, that is, seasonal course, is much less established, as certain individuals may temporarily meet criteria for seasonal course purely by chance. AIMS In this population, prospective cohort study, we investigated whether between and within-subject seasonal patterns of hospitalizations occurred more frequently than would be expected by chance. METHODS Using a compulsory, standardized national register of hospitalizations, we analyzed all admissions for mood disorders and schizophrenia in the Czech Republic between 1994 and 2013. We used bootstrap tests to compare the observed numbers of (a) participants with seasonal/regular course and (b) hospitalizations in individual months against empirical distributions obtained by simulations. RESULTS Among 87 184 participants, we found uneven distribution of hospitalizations, with hospitalization peaks for depression in April and November (X2 (11) = 363.66, P

BackgroundPositive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.MethodTo study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.ResultsThe result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.ConclusionThese findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen’s d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

BackgroundThe aim of the current study was to explore the effect of gender, age at onset, and duration on the long-term course of schizophrenia.MethodsTwenty-nine centers from 25 countries representing all continents participated in the study that included 2358 patients aged 37.21 ± 11.87 years with a DSM-IV or DSM-5 diagnosis of schizophrenia; the Positive and Negative Syndrome Scale as well as relevant clinicodemographic data were gathered. Analysis of variance and analysis of covariance were used, and the methodology corrected for the presence of potentially confounding effects.ResultsThere was a 3-year later age at onset for females (P P P P = .001). No significant effects were found concerning duration of illness.DiscussionOur results confirmed a later onset and a possibly more benign course and outcome in females. Age at onset manifested a single peak in both genders, and surprisingly, earlier onset was related to a slower progression of the illness. No effect of duration has been detected. These results are partially in accord with the literature, but they also differ as a consequence of the different starting point of our methodology (a novel staging model), which in our opinion precluded the impact of confounding effects. Future research should focus on the therapeutic policy and implications of these results in more representative samples.

The heritable component of schizophrenia (SCH) as a polygenic trait is represented by numerous variants from a heterogeneous group of genes each contributing a relatively small effect. Various SNPs have already been found and analyzed in genes encoding the NMDAR subunits. However, less is known about genetic variations of genes encoding the AMPA and kainate receptor subunits. We analyzed sixteen iGluR genes in full length to determine the sequence variability of iGluR genes. Our aim was to describe the rate of genetic variability, its distribution, and the co-occurrence of variants and to identify new candidate risk variants or haplotypes. The cumulative effect of genetic risk was then estimated using a simple scoring model. GRIN2A-B, GRIN3A-B, and GRIK4 genes showed significantly increased genetic variation in SCH patients. The fixation index statistic revealed eight intronic haplotypes and an additional four intronic SNPs within the sequences of iGluR genes associated with SCH (p < 0.05). The haplotypes were used in the proposed simple scoring model and moreover as a test for genetic predisposition to schizophrenia. The positive likelihood ratio for the scoring model test reached 7.11. We also observed 41 protein-altering variants (38 missense variants, four frameshifts, and one nonsense variant) that were not significantly associated with SCH. Our data suggest that some intronic regulatory regions of iGluR genes and their common variability are among the components from which the genetic predisposition to SCH is composed.

International audience; Objective: The cerebellum is involved in cognitive processing and emotion control. Cerebellar alterations could explain symptoms of schizophrenia spectrum disorder (SZ) and bipolar disorder (BD). In addition, literature suggests that lithium might influence cerebellar anatomy. Our aim was to study cerebellar anatomy in SZ and BD, and investigate the effect of lithium.Methods: Participants from 7 centers worldwide underwent a 3T MRI. We included 182 patients with SZ, 144 patients with BD, and 322 controls. We automatically segmented the cerebellum using the CERES pipeline. All outputs were visually inspected.Results: Patients with SZ showed a smaller global cerebellar gray matter volume compared to controls, with most of the changes located to the cognitive part of the cerebellum (Crus II and lobule VIIb). This decrease was present in the subgroup of patients with recent-onset SZ. We did not find any alterations in the cerebellum in patients with BD. However, patients medicated with lithium had a larger size of the anterior cerebellum, compared to patients not treated with lithium.Conclusion: Our multicenter study supports a distinct pattern of cerebellar alterations in SZ and BD.

Personal well-being, including people's sleep characteristics, is affected by a variety of factors, one example of which is wide-ranging high-impact public events. In this study, we use a large sleep database obtained through a smartphone application for sleep tracking via anonymized time-sampled data to study the effect of two political events with a wide-ranging impact on people's sleep characteristics: the Brexit referendum in June 2016, and the presidential election of Donald Trump in November 2016 METHOD: Using Sleep as Android - an actigraphy-based sleep monitoring smartphone application - we collected 10.5 million geo-located sleep records from more than 69,000 users in Europe and North America. Population-based changes in sleep around each of these two events, in the United Kingdom and in the United States of America, were assessed using a non-parametric bootstrap test RESULTS: The analysis revealed a significant reduction by 16 min and 21 s in the mean sleep duration of British people in the night after the Brexit poll (p 0.001). Similarly, the analysis of the US presidential election revealed a significant 12 min 49 s drop in the mean sleep duration during the night following the event, in comparison with the whole studied region (p 0.001), and an increase by 5 min and 9 s in the subsequent night (p = 0.0328). Additional analysis comparing the election night to comparable days in preceding years revealed that the actual reduction in sleep length may have been even greater. There is also an increase in the proportion of subjects with very short sleep CONCLUSIONS: The results demonstrate a significant impact of two specific major political events on population sleep characteristics. Our results further underline the potential of mobile applications and informatics approaches in general to provide data that enable us to investigate fundamental physiological variables over time and location.

Background Self-reported mood is a valuable clinical data source regarding disease state and course in patients with mood disorders. However, validated, quick, and scalable digital self-report measures that can also detect relapse are still not available for clinical care. Objective In this study, we aim to validate the newly developed ASERT (Aktibipo Self-rating) questionnaire—a 10-item, mobile app–based, self-report mood questionnaire consisting of 4 depression, 4 mania, and 2 nonspecific symptom items, each with 5 possible answers. The validation data set is a subset of the ongoing observational longitudinal AKTIBIPO400 study for the long-term monitoring of mood and activity (via actigraphy) in patients with bipolar disorder (BD). Patients with confirmed BD are included and monitored with weekly ASERT questionnaires and monthly clinical scales (Montgomery-Åsberg Depression Rating Scale [MADRS] and Young Mania Rating Scale [YMRS]). Methods The content validity of the ASERT questionnaire was assessed using principal component analysis, and the Cronbach α was used to assess the internal consistency of each factor. The convergent validity of the depressive or manic items of the ASERT questionnaire with the MADRS and YMRS, respectively, was assessed using a linear mixed-effects model and linear correlation analyses. In addition, we investigated the capability of the ASERT questionnaire to distinguish relapse (YMRS≥15 and MADRS≥15) from a nonrelapse (interepisode) state (YMRS Results A total of 99 patients with BD were included in this study (follow-up: mean 754 days, SD 266) and completed an average of 78.1% (SD 18.3%) of the requested ASERT assessments (completion time for the 10 ASERT questions: median 24.0 seconds) across all patients in this study. The ASERT depression items were highly associated with MADRS total scores (P Conclusions The ASERT questionnaire is a quick and acceptable mood monitoring tool that is administered via a smartphone app. The questionnaire has a good capability to detect the worsening of clinical symptoms in a long-term monitoring scenario.

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation.

OBJECTIVESchizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.METHODSThe meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.RESULTSMeta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).CONCLUSIONSThis study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

BackgroundThe aim of the current study was to explore the changing interrelationships among clinical variables through the stages of schizophrenia in order to assemble a comprehensive and meaningful disease model.MethodsTwenty-nine centers from 25 countries participated and included 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Multiple linear regression analysis and visual inspection of plots were performed.ResultsThe results suggest that with progression stages, there are changing correlations among Positive and Negative Syndrome Scale factors at each stage and each factor correlates with all the others in that particular stage, in which this factor is dominant. This internal structure further supports the validity of an already proposed four stages model, with positive symptoms dominating the first stage, excitement/hostility the second, depression the third, and neurocognitive decline the last stage.ConclusionsThe current study investigated the mental organization and functioning in patients with schizophrenia in relation to different stages of illness progression. It revealed two distinct “cores” of schizophrenia, the “Positive” and the “Negative,” while neurocognitive decline escalates during the later stages. Future research should focus on the therapeutic implications of such a model. Stopping the progress of the illness could demand to stop the succession of stages. This could be achieved not only by both halting the triggering effect of positive and negative symptoms, but also by stopping the sensitization effect on the neural pathways responsible for the development of hostility, excitement, anxiety, and depression as well as the deleterious effect on neural networks responsible for neurocognition.

Aim Cognitive deficit in psychotic illness is intensively studied, different cognitive subtypes have been suggested. In recent years, there has been an increase in the number of studies in patients with schizophrenia and their relatives searching for endophenotypes of the disease. The aim of our study was to investigate cognitive performance and cognitive subtypes in the siblings of the patients. Methods Four groups of subjects were included: patients with a first episode of psychotic illness, the siblings of these patients, and two control groups. All the study subjects (N = 84) had a battery of neuropsychological tests that measured basic cognitive domains - memory, executive functions, attention, visual-spatial skills, language skills and psychomotor speed - administered to them. The data were assessed with pairwise t-tests for group comparisons. The siblings were distributed into three groups according to their cognitive performance: non-deficit, partial deficit, and global deficit. Subsequently, the patients were assigned into three groups corresponding to their siblings' performance. Results Our results revealed attenuation of abstract thinking in the siblings compared to the controls. As expected, the patients showed impairment across all cognitive domains. The patients and siblings demonstrated similar profiles in each subtype, in the severity of their impairment, and in their patterns of cognitive performance. Conclusions Our results suggest that the cognitive profile can be considered as an endophenotype of psychotic disorders.

Cannabis, and specifically one of its active compounds delta-9-tetrahydrocannabinol in recreational doses, has a variety of effects on cognitive processes. Most studies employ resting state functional magnetic resonance imaging techniques to assess the stationary effects of cannabis and to-date one report addressed the impact of delta-9-tetrahydrocannabinol on the dynamics of whole-brain functional connectivity.Using a repeated-measures, within-subjects design, 19 healthy occasional cannabis users (smoking cannabis ⩽2 per week) underwent resting state functional magnetic resonance imaging scans. Each subject underwent two scans: in the intoxicated condition, shortly after smoking a cannabis cigarette, and in the non-intoxicated condition, with the subject being free from cannabinoids for at least one week before. All sessions were randomized and performed in a four-week interval. Data were analysed employing a standard independent component analysis approach with subsequent tracking of the functional connectivity dynamics, which allowed six connectivity clusters (states) to be individuated.Using standard independent component analysis in resting state functional connectivity, a group effect was found in the precuneus connectivity. With a dynamic independent component analysis approach, we identified one transient connectivity state, characterized by high connectivity within and between auditory and somato-motor cortices and anti-correlation with subcortical structures and the cerebellum that was only found during the intoxicated condition. Behavioural measures of the subjective experiences of changed perceptions and tetrahydrocannabinol plasma levels during intoxication were associated with this state.With the help of the dynamic connectivity approach we could elucidate neural correlates of the transitory perceptual changes induced by delta-9-tetrahydrocannabinol in cannabis users, and possibly identify a biomarker of cannabis intoxication.

M.B. is supported by a NHMRC Senior Principal Research Fellowship (APP1059660 and APP1156072). All authors contributed equally., Fountoulakis, K.N., Dragioti, E., Theofilidis, A.T., Wikilund, T., Atmatzidis, X., Nimatoudis, I., Thys, E., Wampers, M., Hranov, L., Hristova, T., Aptalidis, D., Milev, R., Iftene, F., Spaniel, F., Knytl, P., Furstova, P., From, T., Karlsson, H., Walta, M., Salokangas, R.K.R., Azorin, J.-M., Bouniard, J., Montant, J., Juckel, G., Haussleiter, I.S., Douzenis, A., Michopoulos, I., Ferentinos, P., Smyrnis, N., Mantonakis, L., Nemes, Z., Gonda, X., Vajda, D., Juhasz, A., Shrivastava, A., Waddington, J., Pompili, M., Comparelli, A., Corigliano, V., Rancans, E., Navickas, A., Hilbig, J., Bukelskis, L., Injac Stevovic, L., Vodopic, S., Esan, O., Oladele, O., Osunbote, C., Rybakowski, J.Κ., Wojciak, P., Domowicz, K., Figueira, M.L., Linhares, L., Crawford, J., Panfil, A.-L., Smirnova, D., Izmailova, O., Lecic-Tosevski, D., Temmingh, H., Howells, F., Bobes, J., Garcia-Portilla, M.P., García-Alvarez, L., Erzin, G., Karadaǧ, H., De Sousa, A., Bendre, A., Hoschl, C., Bredicean, C., Papava, I., Vukovic, O., Pejuskovic, B., Russell, V., Athanasiadis, L., Konsta, A., Stein, D., Berk, M., Dean, O., Tandon, R., Kasper, S., De Hert, M.

The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Bipolar Disorder (BD) is an illness with high prevalence and a huge social and economic impact. It is recurrent, with a long-term evolution in most cases. Early treatment and continuous monitoring have proven to be very effective in mitigating the causes and consequences of BD. However, no tools are currently available for a massive and semi-automatic BD patient monitoring and control. Taking advantage of recent technological developments in the field of wearables, this paper studies the feasibility of a BD episodes classification analysis while using entropy measures, an approach successfully applied in a myriad of other physiological frameworks. This is a very difficult task, since actigraphy records are highly non-stationary and corrupted with artifacts (no activity). The method devised uses a preprocessing stage to extract epochs of activity, and then applies a quantification measure, Slope Entropy, recently proposed, which outperforms the most common entropy measures used in biomedical time series. The results confirm the feasibility of the approach proposed, since the three states that are involved in BD, depression, mania, and remission, can be significantly distinguished.

Přehledový clanek pojednava o aplikaci EEG-biofeedbacku u pacientů se schizofrenii se zaměřenim na oblast kognitivnich funkci. EEG-biofeedback je forma neurofeedbacku, při kterem dochazi k zaměrnemu ovlivňovani mozkove aktivity prostřednictvim jejiho realneho zaznamu za pomoci EEG. Pacient je aktivnim ucastnikem při lecbě, což hraje svou roli při kognitivni remediaci. Je zde předkladan přehled abnormalit v oblasti EEG zaznamů u pacientů se schizofrenii. Soucasně předkladame podrobný popis dosavadnich studii věnujicich se aplikaci EEG-biofeedbacku u schizofrenie i jiných neuropsychiatrických poruch a pozornost je věnovana i nedostatkům těchto studi. V zavěru se snažime shrnout přinosy aplikace teto metody.

Background Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness data, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between the predictions and clinical variables. Methods 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI (sMRI) session and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20484 vertices) were extracted. Supervised (linear Support Vector Machine) classification was used to differentiate FEP from HC, within a repeated nested Cross-Validation (CV) framework through the NeuroMiner software. In both inner and outer CVs, a 10-fold CV cycle was employed. We performed repeated nested CV at the outer cross-validation cycle by randomly permuting the participants within their groups (10 permutations) and repeating the CV cycle for each of these permutations. As feature preprocessing, regression of covariates (age, sex, and site), Principal Component Analysis and Scaling were applied. All preprocessing steps were implemented within the CV. Further analyses were conducted by stratifying the sample for MRI scanner, sex and by performing random resampling with increasingly reduced sample sizes. Results Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy (BAC) of 66.2% and an Area Under the Curve of 72%, compared to a BAC of 59% and an Area Under the Curve of 61% obtained with the ROI-based approach. The two BACs were significantly different based on the McNemar’s Test. By stratifying our sample for MRI scanner, we increased the overall BAC to more than 70% and we also increased generalizability across sites. Temporal areas resulted the most influential regions in the classification. The predictive decision scores presented significant correlations with age at onset, duration of treatment and the presence of affective vs non-affective psychosis. Discussion Cortical thickness could represent a valid measure to classify FEP subjects, showing temporal areas as potential markers in the early stages of psychosis. The assessment of site-dependent variables allowed us to increase the across-site generalizability of the model, thus attempting to address an important machine learning limitation, especially in the framework of large multi-site cohort and big data analysis.

Background The self-disturbances (SDs) concept is considered to be part of the Schneider’s first rank symptoms, i.e., thought-withdrawal, thought-insertion, thought-broadcasting, somatic-passivity experiences, mental/motor automatisms, disrupted unitary self-experience (Mishara et al., 2014). SDs were originally described by W. Mayer-Gross (1920), who observed them in psychotic patients. Methods We classified Mayer-Gross’ findings on SDs into the following categories: experience is new/compelling (aberrant salience), reduced access/importance of autobiographical past, cognitions/emotions occur independently from self’s volition, foreign agents have power over self and developed an SDs scale based on these categories and cognitive domains (perception, motor, speech, thinking etc.). Scale is applied as a measure of the frequency of the experiences. In our current study on phenomenology and neurobiology of psychotic symptoms, we administered the scale to a study group of patients with schizophrenia (N=84) and healthy volunteers (N=170). Further, the resting state fMRI was performed and the group was divided into two subgroups with (N=13) and without self-disturbances (N=10) and in healthy individuals (N=39). Results We found substantial differences in the frequency of self-disturbances in patients with schizophrenia compared to healthy controls (total score differences, Z=-5.83, p< 0.001). On a neural level, patients with self-disturbances experienced a decreased functional brain connectivity of the default mode and salience networks as compared to the patients without self-disturbances and healthy controls. The differences were mainly explained by the factor ‘’foreign agents’’ and the novelty of the experience. Discussion The scale identifies self-disturbances in schizophrenia and confirms self-related processing in patients with schizophrenia to be associated with altered activation in the cortical midline structures. Supported by the grant projects MH CR AZV 17-32957A and MEYS NPU4NUDZ: LO1611.

Objectives To evaluate the coherence values of the cortical bands in patients with first episode schizophrenia and schizoaffective disorder during the performance of a mental arithmetic task. Method We analysed EEG coherence in the resting state and subsequently while counting down from 200 in steps of 7 in 32 first episode schizophrenia patients (SZ), 32 patients with first episode schizoaffective disorder (SA) and 40 healthy controls (HC). Results Task performance in HC is characterised by decreased coherence in the alpha bands and increased coherence in the beta 2 and gamma bands in frontal sites. In SZ, coherence decreases in the alpha band, whereas in SA it substantially increases in the alpha, beta1, beta 2 and gamma bands. Conclusions Despite no differences in performance on a behavioural level, SA patients demonstrate a paradoxical increase in both low and fast frequency bands during the performance of a mental arithmetic task, while, patients with SZ show a decreased coherence in the alpha band, presumably alluding to the excessive excitatory (in SA) and inhibitory (in SZ) mechanisms in cognitive processing. Significance The current study provides evidence for the distinction of neurophysiological mechanisms of cognitive processing between SZ and SA.

International audience; Objective: Structural MRI (sMRI) increasingly offers insight into abnormalities inherent to schizophrenia. Previous machine learning applications suggest that individual classification is feasible and reliable and, however, is focused on the predictive performance of the clinical status in cross-sectional designs, which has limited biological perspectives. Moreover, most studies depend on relatively small cohorts or single recruiting site. Finally, no study controlled for disease stage or medication's effect. These elements cast doubt on previous findings' reproducibility. Method: We propose a machine learning algorithm that provides an interpretable brain signature. Using large datasets collected from 4 sites (276 schizophrenia patients, 330 controls), we assessed cross-site prediction reproducibility and associated predictive signature. For the first time, we evaluated the predictive signature regarding medication and illness duration using an independent dataset of first-episode patients. Results: Machine learning classifiers based on neuroanatomical features yield significant intersite prediction accuracies (72%) together with an excellent predictive signature stability. This signature provides a neural score significantly correlated with symptom severity and the extent of cognitive impairments. Moreover, this signature demonstrates its efficiency on first-episode psychosis patients (73% accuracy). Conclusion: These results highlight the existence of a common neuroanatomical signature for schizophrenia, shared by a majority of patients even from an early stage of the disorder.

Background The greater presence of neurodevelopmental antecedants may differentiate schizophrenia from bipolar disorders (BD). Machine learning/pattern recognition allows us to estimate the biological age of the brain from structural magnetic resonance imaging scans (MRI). The discrepancy between brain and chronological age could contribute to early detection and differentiation of BD and schizophrenia. Methods We estimated brain age in 2 studies focusing on early stages of schizophrenia or BD. In the first study, we recruited 43 participants with first episode of schizophrenia-spectrum disorders (FES) and 43 controls. In the second study, we included 96 offspring of bipolar parents (48 unaffected, 48 affected) and 60 controls. We used relevance vector regression trained on an independent sample of 504 controls to estimate the brain age of study participants from structural MRI. We calculated the brain-age gap estimate (BrainAGE) score by subtracting the chronological age from the brain age. Results Participants with FES had higher BrainAGE scores than controls (F(1, 83) = 8.79, corrected P = .008, Cohen’s d = 0.64). Their brain age was on average 2.64 ± 4.15 years greater than their chronological age (matched t(42) = 4.36, P < .001). In contrast, participants at risk or in the early stages of BD showed comparable BrainAGE scores to controls (F(2,149) = 1.04, corrected P = .70, η2 = 0.01) and comparable brain and chronological age. Conclusions Early stages of schizophrenia, but not early stages of BD, were associated with advanced BrainAGE scores. Participants with FES showed neurostructural alterations, which made their brains appear 2.64 years older than their chronological age. BrainAGE scores could aid in early differential diagnosis between BD and schizophrenia.

Obesity and dyslipidemia may negatively affect brain health and are frequent medical comorbidities of schizophrenia and related disorders. Despite the high burden of metabolic disorders, little is known about their effects on brain structure in psychosis. We investigated, whether obesity or dyslipidemia contributed to brain alterations in first-episode psychosis (FEP).120 participants with FEP, who were undergoing their first psychiatric hospitalization, had24 months of untreated psychosis and were 18-35 years old and 114 controls within the same age range participated in the study. We acquired 3T brain structural MRI, fasting lipids and body mass index. We used machine learning trained on an independent sample of 504 controls to estimate the individual brain age of study participants and calculated the BrainAGE score by subtracting the chronological from the estimated brain age.In a multiple regression model, the diagnosis of FEP (B = 1.15, SE B = 0.31, p 0.001) and obesity/overweight (B = 0.92, SE B = 0.35, p = 0.008) were each additively associated with BrainAGE scores (ROverweight/obesity may be an independent risk factor for diffuse brain alterations manifesting as advanced brain age already early in the course of psychosis. These findings raise the possibility that targeting metabolic health and intervening already at the level of overweight/obesity could slow brain ageing in FEP.

Background Early diagnosis of schizophrenia could improve the outcome of the illness. Unlike classical between-group comparisons, machine learning can identify subtle disease patterns on a single subject level, which could help realize the potential of MRI in establishing a psychiatric diagnosis. Machine learning has previously been predominantly tested on gray-matter structural or functional MRI data. In this paper we used a machine learning classifier to differentiate patients with a first episode of schizophrenia-spectrum disorder (FES) from healthy controls using diffusion tensor imaging. Methods We applied linear support-vector machine (SVM) and traditional tract based spatial statistics between group analyses to brain fractional anisotropy (FA) data from 77 FES and 77 age and sex matched healthy controls. We also evaluated the effects of medication and symptoms on the SVM classification. Results The SVM distinguished between patients and controls with significant accuracy of 62.34% (p = 0.005). Participants with FES showed widespread FA reductions relative to controls in a large cluster (N = 56,647 voxels, corrected p = 0.002). The white matter regions, which contributed to the correct identification of participants with FES, overlapped with the regions, which showed lower FA in patients relative to controls. There was no association between the classification performance and medication or symptoms. Conclusions Our results provide a proof of concept that SVM might help differentiate FES patients early in the course of illness from healthy controls using white-matter fractional anisotropy. As there was no effect of medications or symptoms, the SVM classification seemed to be based on trait rather than state markers and appeared to capture the lower FA in FES participants relative to controls.

One of the biggest problems in automated diagnosis of psychiatric disorders from medical images is the lack of sufficiently large samples for training. Sample size is especially important in the case of highly heterogeneous disorders such as schizophrenia, where machine learning models built on relatively low numbers of subjects may suffer from poor generalizability. Via multicenter studies and consortium initiatives researchers have tried to solve this problem by combining data sets from multiple sites. The necessary sharing of (raw) data is, however, often hindered by legal and ethical issues. Moreover, in the case of very large samples, the computational complexity might become too large. The solution to this problem could be distributed learning. In this paper we investigated the possibility to create a meta-model by combining support vector machines (SVM) classifiers trained on the local datasets, without the need for sharing medical images or any other personal data. Validation was done in a 4-center setup comprising of 480 first-episode schizophrenia patients and healthy controls in total. We built SVM models to separate patients from controls based on three different kinds of imaging features derived from structural MRI scans, and compared models built on the joint multicenter data to the meta-models. The results showed that the combined meta-model had high similarity to the model built on all data pooled together and comparable classification performance on all three imaging features. Both similarity and performance was superior to that of the local models. We conclude that combining models is thus a viable alternative that facilitates data sharing and creating bigger and more informative models.