Brain-wide Disruptions of Anatomical Connectivity in Antipsychotic-Naive First Episode Psychosis

OBJECTIVE: Disruptions of axonal connectivity are thought to be a core pathophysiological feature of psychotic illness, but whether they are present early in the illness, prior to antipsychotic exposure, and whether they can predict clinical outcome remains unknown. METHODS: We acquired diffusion-weighted MRI to map axonal connectivity between each pair of 319 parcellated brain regions in 61 antipsychotic-naive individuals with First Episode Psychosis (FEP; 15-25 years, 46% female) and a demographically matched sample of 27 control participants, along with clinical follow-up data in patients 3 months and 12 months after the scan. We used connectome-wide analyses to map disruptions of inter-regional pairwise connectivity coupled with connectome-based predictive modelling to predict longitudinal change in symptoms and functioning. RESULTS: Individuals with FEP showed disrupted connectivity in a brain-wide network linking all brain regions when compared with controls (pFWE=.03). Baseline structural connectivity significantly predicted change in functioning over 12 months (r=.44; pFWE=.041), such that lower connectivity within fronto-striato-thalamic systems predicted worse functional outcomes. CONCLUSIONS: Brain-wide reductions of structural connectivity exist during the early stages of psychotic illness and cannot be attributed to antipsychotic medication. Moreover, baseline measures of structural connectivity can predict change in patient functional outcomes up to one year after engagement with treatment services. ### Competing Interest Statement ERO is supported by a Graduate Education Fund Scholarship from the American Australian Association, and a Postdoctoral Fellowship from the Kavli Institute for Neuroscience at Yale University. SF, MAJ and AF reported receiving grants from the Australian National Health & Medical Research Council (NHMRC) and Australian Research Council (ARC) during the conduct of the study. CP reported receiving grants from the Australian NHMRC and from the Lundbeck Foundation and personal fees from Lundbeck Australia Pty Ltd Advisory Board for talks presented at educational meetings organized by Lundbeck. PM reported receiving grants from the Australian NHMRC, the Colonial Foundation, the National Alliance for Research on Schizophrenia and Depression, the Stanley Foundation, the National Institutes of Health, Wellcome Trust, the Australian and Victorian governments, and Janssen-Cilag (unrestricted investigator-initiated grant) during the conduct of the study; past unrestricted grant funding from Janssen-Cilag, AstraZeneca, Eli Lilly, Novartis, and Pfizer; honoraria for consultancy and teaching from Janssen-Cilag, Eli Lilly, Pfizer, AstraZeneca, Roche, Bristol Myers Squibb, and Lundbeck. BN was supported by an NHMRC Senior Research Fellowship (1137687) and VC was supported by an NHMRC EL2 Fellowship (1177370). BN, KA and VCwere supported by a University of Melbourne Dame Kate Campbell Fellowship. Data processing was conducted using Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE; Goscinski, 2014). SC reports receiving a scholarship from the American Australian Association. ### Funding Statement The trial took place at the Early Psychosis Prevention and Intervention Centre, which is part of Orygen Youth Health, Melbourne, Australia. Janssen-Cilag partially supported the early years of this study with an unrestricted investigator-initiated grant and provided risperidone, paliperidone and matched placebo for the first 30 participants. The study was then funded by an Australian National Health and Medical Research Project grant (1064704). The funders had no role in study design, data collection, data analysis, data interpretation, writing, approval or submission of this manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The current study uses data from a larger trial registered with the Australian New Zealand Clinical Trials Registry in November 2007 (ACTRN12607000608460) and received ethics approval from the Melbourne Health Human Research and Ethics committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. Code use for analysis is available online at https://github.com/sidchop/PsychosisConnectome.