Connectome-wide search for functional connectivity locus associated with pathological rumination as a target for real-time fMRI neurofeedback intervention

•Introduced connectome-wide approach of neurofeedback target identification.•Identified connectivity related to rumination severity with resting-state data.•Positively correlated precuneus-RTPJ connectivity with rumination severity.•Performed simulation analysis to design the optimal neurofeedback signal.•The two-point method was optimal online connectivity measure robust to motion. Real-time fMRI neurofeedback (rtfMRI-nf) enables noninvasive targeted intervention in brain activation with high spatial specificity. To achieve this promise of rtfMRI-nf, we introduced and demonstrated a data-driven framework to design a rtfMRI-nf intervention through the discovery of precise target location associated with clinical symptoms and neurofeedback signal optimization. Specifically, we identified the functional connectivity locus associated with rumination symptoms, utilizing a connectome-wide search in resting-state fMRI data from a large cohort of mood and anxiety disorder individuals (N = 223) and healthy controls (N = 45). Then, we performed a rtfMRI simulation analysis to optimize the online functional connectivity neurofeedback signal for the identified functional connectivity. The connectome-wide search was performed in the medial prefrontal cortex and the posterior cingulate cortex/precuneus brain regions to identify the precise location of the functional connectivity associated with rumination severity as measured by the ruminative response style (RRS) scale. The analysis found that the functional connectivity between the loci in the precuneus (-6, −54, 48 mm in MNI) and the right temporo-parietal junction (RTPJ; 49, −49, 23 mm) was positively correlated with RRS scores (depressive, p