Disordered brain circuits linked to diagnostic specificity and comorbidity revealed by multivariate symptom modeling

<jats:p>Modeling how functional network connectivity underlies transdiagnostic symptomatology has promised to advance psychiatric medicine by revealing neurobiological mechanisms related to comorbidity. However, network mapping methods have yet to yield clinically-actionable insights, largely due to complexities in the neurobiological underpinnings of symptom comorbidity across disorders and symptom heterogeneity within disorders. Here, we sought to address this problem by leveraging a large (n=317) transdiagnostic dataset of adults with extensive fMRI scanning (&gt;50 min), using connectome-based predictive modeling (CPM) to identify network correlates of an array of psychiatric symptoms. The symptom networks spanned a complex web of shared and unique networks, in which individuals displayed significant heterogeneity in their edge-level dysfunction. We then constructed 'disordered circuit' models that jointly accounted for an individual's symptom severity, the multivariate network space, and network heterogeneity. Although all the symptoms were highly comorbid and none showed specificity to any single diagnostic category, many features within the disordered circuit models were uniquely associated with individual diagnoses and comorbidity patters. These findings shed mechanistic insights into how transdiagnostic symptoms arise from different neurobiological processes depending on a patient's diagnostic profile. Thus, this approach provides key insights into where an individual's disordered circuits are located, a critical first step in precision psychiatry frameworks.</jats:p>