Excitation/inhibition imbalance and conversion to psychosis in the clinical high risk syndrome: Biophysical modeling finds reduced pyramidal cell excitability across EEG paradigms

Background Reduced mismatch negativity (MMN) and P300 event-related potential (ERP) components are widely replicated in schizophrenia and are also observed in individuals at clinical high risk for psychosis (CHR-P) who subsequently convert to psychosis. It is unknown whether they reflect changes in excitatory and/or inhibitory synaptic function, both implicated in schizophrenia and considered potential drug targets. Methods We analyzed baseline MMN and P300 ERPs from the NAPLS2 study, asking whether altered synaptic excitation, inhibition, or both could explain amplitude reductions in CHR-P (n=583). CHR-P participants who converted to psychosis (CHR-Converters; n=77) or remitted by 24-month follow-up (CHR-Remitters; n=94) were compared on MMN evoked by pitch+duration double-deviant tones and P300 elicited by target tones from passive and active auditory oddball paradigms, respectively. Biophysical modeling was used to infer (excitatory) pyramidal cell and (inhibitory) interneuron function from both MMN and P300 ERPs. Results MMN and P300 amplitude reductions in future CHR-Converters relative to CHR-Remitters were best explained by reduced pyramidal cell excitability (posterior probability P>.95 of a group-by-condition interaction effect). In simulations, reduced pyramidal cell excitability suppressed deviant and target ERPs. Within CHR-Converters, but not CHR-Remitters, more severe positive symptoms were associated with disinhibition of pyramidal cells (P>.99). Conclusions Results mirror previous findings in schizophrenia and suggest that reduced pyramidal cell excitability is present at baseline in future CHR-Converters, supporting the hypothesis that hypofunction of pyramidal cells is a primary pathology in schizophrenia, rather than a consequence of chronic illness. Positive symptoms among CHR-Converters may reflect compensatory downregulation of inhibition.