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. Methods: 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 re-assessed after one year. N400 difference waves (unrelated-related) were fit with a connectome-constrained Jansen and 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. Results: 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. Conclusions: Computational modelling 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 excitatory:inhibitory metrics constitute low burden, mechanistically interpretable biomarkers for stratifying psychosis risk and guiding early intervention.