Biophysical Modeling of Excitation/Inhibition Balance and Conversion to Psychosis in the Clinical High Risk Syndrome

Julia Rodriguez-Sanchez; Daniel J Hauke; Dimitris A Pinotsis; Lioba C S Berndt; Hope Oloye; Spero C Nicholas; Holly K Hamilton; Brian J Roach; Peter M Bachman; Aysenil Belger; Ricardo E Carrión; Erica Duncan; Jason K Johannesen; Gregory A Light; Margaret A Niznikiewicz; Karl J Friston; Jean Addington; Carrie E Bearden; Kristin S Cadenhead; Diana O Perkins; Elaine F Walker; Scott W Woods; Tyrone D Cannon; Rick A Adams; Daniel H Mathalon

doi:10.1016/j.biopsych.2026.04.007

Biophysical Modeling of Excitation/Inhibition Balance and Conversion to Psychosis in the Clinical High Risk Syndrome

Biol Psychiatry. 2026 Apr 21:S0006-3223(26)01191-1. doi: 10.1016/j.biopsych.2026.04.007. Online ahead of print.

Authors

Julia Rodriguez-Sanchez¹, Daniel J Hauke², Dimitris A Pinotsis³, Lioba C S Berndt⁴, Hope Oloye⁵, Spero C Nicholas⁶, Holly K Hamilton⁷, Brian J Roach⁶, Peter M Bachman⁸, Aysenil Belger⁹, Ricardo E Carrión¹⁰, Erica Duncan¹¹, Jason K Johannesen¹², Gregory A Light¹³, Margaret A Niznikiewicz¹⁴, Karl J Friston¹⁵, Jean Addington¹⁶, Carrie E Bearden¹⁷, Kristin S Cadenhead¹⁸, Diana O Perkins⁹, Elaine F Walker¹⁹, Scott W Woods¹², Tyrone D Cannon²⁰, Rick A Adams⁵, Daniel H Mathalon²¹

Affiliations

¹ Hawkes Institute, University College London, London, United Kingdom; Department of Psychology and Neuroscience, City St. George's, University of London, London, United Kingdom. Electronic address: julia.sanchez.16@ucl.ac.uk.
² Hawkes Institute, University College London, London, United Kingdom.
³ Department of Psychology and Neuroscience, City St. George's, University of London, London, United Kingdom.
⁴ Hawkes Institute, University College London, London, United Kingdom; Department of Psychology, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
⁵ Hawkes Institute, University College London, London, United Kingdom; Institute of Cognitive Neuroscience, University College London, London, United Kingdom.
⁶ San Francisco Veterans Affairs Health Care System, San Francisco, California; Northern California Institute for Research and Education, San Francisco, California.
⁷ Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, California.
⁸ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, Massachusetts.
⁹ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
¹⁰ Northwell, New Hyde Park, New York; Institute of Behavioral Science, Feinstein Institutes for Medical Research, Northwell Health System, Manhasset, New York; Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
¹¹ Atlanta Veterans Affairs Health Care System, Decatur, Georgia; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
¹² Department of Psychiatry, Yale University, School of Medicine, New Haven, Connecticut.
¹³ Department of Psychiatry, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, La Jolla, California.
¹⁴ Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston, Massachusetts; Veterans Affairs Boston Healthcare System, Brockton, Massachusetts.
¹⁵ Wellcome Trust Centre for Human Neuroimaging, Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹⁶ Hotchkiss Brain Institute, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
¹⁷ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California; Department of Psychology, University of California, Los Angeles, Los Angeles, California.
¹⁸ Department of Psychiatry, University of California San Diego, La Jolla, California.
¹⁹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia; Department of Psychology, Emory University, Atlanta, Georgia.
²⁰ Department of Psychiatry, Yale University, School of Medicine, New Haven, Connecticut; Department of Psychology, Yale University, New Haven, Connecticut.
²¹ San Francisco Veterans Affairs Health Care System, San Francisco, California; Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, California.

PMID: 42025866
DOI: 10.1016/j.biopsych.2026.04.007

Abstract

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 North American Prodrome Longitudinal Study (NAPLS 2) and asked 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 the 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 > 0.95 of a group-by-condition interaction effect). In simulations, reduced pyramidal cell excitability suppressed deviant and target ERPs. Within CHR-converters, more severe positive symptoms were associated with disinhibition of pyramidal cells (P > 0.99).

Conclusions: Results mirror previous findings in schizophrenia and suggest that reduced pyramidal cell excitability is present at baseline in future CHR-converters, consistent with 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.

Keywords: Biophysical modeling; Clinical high risk for psychosis; Dynamic causal modeling; E/I balance; MMN; P300.