Neurocomputational modelling for characterizing neurocognitive pathophysiology in clinical high risk for psychosis

Background The N400 semantic-priming event-related potential (ERP) is attenuated in schizophrenia and in youth at clinical high risk for psychosis (CHRP); however, the circuit mechanisms linking this abnormality to functional outcome remain unclear.

We recorded 32-channel EEG while 46 CHRP outpatients and 38 demographically matched healthy controls (HC) performed a word-pair priming task (80 related, 80 unrelated pairs; prime-to-target stimulus-onset asynchronies [SOA]=300ms or 750ms). Twenty-six CHRP participants were reassessed after one year. N400 difference waves (unrelated–related) were fit with a connectome-constrained Jansen–Rit neural-mass model in 200 cortical parcels. Local gains, synaptic time constants and effective connectivity parameters were optimised with the WhoBPyt framework, and principal-component trajectories of the inferred excitatory–inhibitory |E − I| balance were analysed with partial least squares.

Under the long-SOA (750ms)/unrelated condition, CHRP showed a sharply elevated early |E −I| peak at 70–100ms relative to HC (p=0.0004), driven by greater pyramidal excitatory gain (parameter A), stronger excitatory-to-pyramidal coupling and faster inhibitory decay, indicating cortical disinhibition. The amplitude of this early peak predicted poorer social functioning at one-year follow-up (r=–0.56,p=0.003). Conversely, in the short-SOA (300ms)/related condition CHRP exhibited a larger N400-window |E−I| peak (350ms) associated with enhanced inhibitory-to-pyramidal feedback (parameter C3) and lengthened inhibitory decay (parameter b); this putative compensatory inhibition correlated with better functional outcome (r=0.60,p=0.001). Network-level analyses revealed an amplified early sensory-network burst and attenuated default-mode and salience-network responses, consistent with a systems-wide shift toward disinhibition in CHRP.

Computational modeling demonstrates that N400 abnormalities in CHRP arise from temporally specific E–I imbalances: early cortical disinhibition that forecasts functional decline and a later inhibitory reinforcement that may confer resilience. These time-resolved E–I metrics constitute low-burden, mechanistically interpretable biomarkers for stratifying psychosis risk and guiding early intervention. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by the Canadian Institutes of Health Research. 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: Ethics committee/IRB of the Centre for Addiction and Mental Health affiliated with the University of Toronto gave ethical approval for this work. 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 Data Availability All data produced in the present study are available upon reasonable request to the authors.