Resting state functional connectivity subtypes predict discrete patterns of cognitive-affective functioning across levels of analysis among patients with treatment-resistant depression.

Abstract Resting state functional connectivity (RSFC) in ventral affective (VAN), default mode (DMN) and cognitive control (CCN) networks may partially underlie heterogeneity in depression. The current study used data-driven parsing of RSFC to identify subgroups of patients with treatment-resistant depression (TRD; n = 70) and determine if subgroups generalized to transdiagnostic measures of cognitive-affective functioning relevant to depression (indexed across self-report, behavioral, and molecular levels of analysis). RSFC paths within key networks were characterized using Subgroup-Group Iterative Multiple Model Estimation. Three connectivity-based subgroups emerged: Subgroup A, the largest subset and containing the fewest pathways; Subgroup B, containing unique bidirectional VAN/DMN negative feedback; and Subgroup C, containing the most pathways. Compared to other subgroups, subgroup B was characterized by lower self-reported positive affect and subgroup C by higher self-reported positive affect, greater variability in induced positive affect, worse response inhibition, and reduced striatal tissue iron concentration. RSFC-based categorization revealed three TRD subtypes associated with discrete aberrations in transdiagnostic cognitive-affective functioning that were largely unified across levels of analysis and were maintained after accounting for the variability captured by a disorder-specific measure of depressive symptoms. Findings advance understanding of transdiagnostic brain-behavior heterogeneity in TRD and may inform novel treatment targets for this population.