Modeling Negative Symptom Domain Neurobiology: Protocol for an Observational, Transdiagnostic, Translational Study

Negative symptoms (NS) such as anhedonia (reduced pleasure), avolition (reduced motivation), asociality (social withdrawal), blunted affect (diminished emotional expression), and alogia (poverty of speech) are associated with poor functional outcomes in psychiatric and neurological disorders and are an unmet treatment need. Current medication primarily targets positive or affective symptoms, leaving NS neurobiology unaddressed. A critical research gap exists in understanding whether these symptoms share a common biological architecture across different diagnoses or whether they emerge from distinct pathological pathways.

This observational, single-center study aims to characterize NS across a transdiagnostic sample of individuals with mental disorders and related conditions, with a particular focus on avolition, its biological correlates, and associated neurocognitive and electrophysiological profiles and the aim of determining whether particular NS consistently occupy central positions across disorders or centrality patterns differ by diagnosis. By linking these symptom profiles to underlying neurocognitive, electrophysiological, and genetic markers, the study seeks to disentangle shared versus disorder-specific mechanisms.

In total, 300 participants with a primary diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, autism, or dementia will be recruited, with a target of at least 50 individuals in each diagnostic group. Over a 4-day schedule, participants will undergo clinical (Brief Negative Symptom Scale, Positive and Negative Syndrome Scale, Hamilton Depression Rating Scale, Personal and Social Performance Scale, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, and Barnes Akathisia Rating Scale), neurocognitive (Brief Assessment of Cognition in Schizophrenia, and Temporal Experience of Pleasure Scale), and biological (resting-state electroencephalography and blood sampling for polygenic risk score) assessments. Network analysis will compute symptom centrality to determine if avolition acts as a transdiagnostic hub. Structural equation modeling will link network profiles to neurophysiological and genetic data. This methodology is designed to identify convergent biological markers, clarify avolition's role in symptom heterogeneity, and refine understanding of NS as multidimensional phenomena beyond traditional diagnostic boundaries.

The initial version of the study protocol was developed in February 2024. The finalized protocol was completed on May 8, 2024, and updated on January 11, 2025, to incorporate minor methodological clarifications. Participant recruitment and data collection commenced on July 1, 2024, and are ongoing at the time of manuscript submission. By March 2026, the study had enrolled 286 participants. Data quality control and preliminary analyses are performed concurrently with data collection. Final statistical analyses and dissemination of results are planned following completion of the recruitment phase.

This study will provide critical insights into the characterization and underlying mechanisms of NS across psychiatric disorders. By focusing on avolition, reward processing, and their interaction with neurocognitive and social cognitive deficits, it will help identify potential biological and electrophysiological markers of NS. The findings may guide the development of more precise assessment tools and inform novel therapeutic strategies, with broad translational impact for improving outcomes in individuals with serious mental illnesses and related conditions.