Excitation/inhibition imbalance and conversion to psychosis in the clinical high risk syndrome: Biophysical modeling finds reduced pyramidal cell excitability across EEG paradigms
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".