Mapping Brain-Behavior Space Relationships Along the Psychosis Spectrum

Abstract Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlights a need to develop a neurobiologically-grounded, quantitatively stable mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 cross-diagnostic PSD patients, we derived and replicated a data-driven dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits, which was predictive at the single patient level. In turn, these data-reduced symptom axes mapped onto distinct and replicable univariate brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) did not show stable results. Instead, we show that a univariate brain-behavioral space (BBS) mapping can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and gene expression maps. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable quantitative path that can be iteratively optimized for personalized clinical biomarker endpoints.