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