Negative symptoms, cognition, and functional connectivity: optimizing transdiagnostic relationships by leveraging advanced techniques

The National Institute of Mental Health awarded The Washington University $197,600 on September 28, 2025, under the Mental Health Research Grants program (CFDA 93.242) to investigate the cognitive and neurobiological underpinnings of reduced motivation and pleasure symptoms in psychotic and mood disorders with psychosis.

The project integrates ecological momentary assessment, repeatable mobile cognitive testing, naturalistic fMRI stimuli, and individual-specific functional connectivity analysis to advance understanding of symptom heterogeneity across individuals. The research examines whether these advanced assessment approaches reveal more robust relationships between motivation and pleasure symptoms, cognition, and functional connectivity compared to standard in-lab clinical assessments, and whether individual-specific functional connectivity metrics outperform group-based metrics in characterizing these relationships. Findings will inform development of more effective clinical interventions for negative symptoms that current treatments address inadequately.

Performance occurs at Washington University in University City, Missouri, with a period of performance extending through March 31, 2027. The assistance type is a project grant, which at the predoctoral fellowship level under the NRSA program carries a statutory maximum of six years of aggregate support.

Abstract

The current interventions for negative symptoms in psychotic disorders and mood disorders with psychosis, particularly the experiential symptoms of reduced motivation and pleasure (map), are ineffective and wanting. This is a critical area for improvement, given that map symptoms are highly prevalent and strongly associated with disability and distress. However, we have a limited understanding of these symptoms' cognitive and neural bases. Moreover, map symptoms are heterogeneous in their presence, presentation, severity, and origins across individuals. Globally, traditional methods of assessing symptoms, cognition, and functional connectivity (FC) do not capture important variability within and between individuals. Quantifying this variability is necessary to understand the etiology and heterogeneity of map symptoms and develop effective interventions. Recently developed approaches, ecological momentary assessment (EMA), repeatable mobile cognitive testing (rmct), naturalistic fmri stimuli, and individual-specific functional connectivity (is-FC) hold promise in addressing this issue. The proposed project aims to integrate these methods to advance our understanding of map symptoms' cognitive and neurobiological underpinnings in psychotic disorders and mood disorders with psychosis to ultimately inform effective clinical interventions. The overarching aims of this proposal are to a) investigate whether ecological momentary symptom assessment and repeatable mobile cognitive testing reveal more robust relationships between map symptoms to cognition and FC compared to standard in-lab clinical and cognitive assessments, b) examine whether is-FC metrics lead to more robust relationships between FC and map symptoms compared to group-based FC metrics while using FC acquired during the processing of naturalistic stimuli, and c) assess to what extent these relationships are transdiagnostic across psychotic disorders and mood disorders with psychosis. The principal goal is to bolster our current understanding of the nature and etiology of experiential negative symptoms, which will, in turn, inform the development of effective transdiagnostic interventions. This project will be realized through training goals about gaining expertise on functional connectivity, negative symptoms across psychotic and mood disorders, advanced statistical analyses, and developing rigor, reproducibility, and professional development skills.