Real-time fMRI amygdala neurofeedback positive emotional training normalized resting-state functional connectivity in combat veterans with and without PTSD: a connectome-wide investigation

Self-regulation of brain activation using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) is an emerging approach for treating mood and anxiety disorders. The effect of neurofeedback training on resting-state functional connectivity warrants investigation as changes in spontaneous brain activation could reflect the association between sustained symptom relief and brain alteration. We investigated the effect of amygdala-focused rtfMRI-nf training on resting-state functional connectivity in combat veterans with and without posttraumatic stress disorder (PTSD) who were trained to increase a feedback signal reflecting left amygdala activity while recalling positive autobiographical memories (Zotev et al., 2018). The analysis was performed in three stages: i) first, we investigated the connectivity in the left amygdala region; ii) next, we focused on the abnormal resting-state functional connectivity identified in our previous analysis of this data (Misaki et al., 2018); and iii) finally, we performed a novel data-driven longitudinal connectome-wide analysis. We introduced a longitudinal multivariate distance matrix regression (MDMR) analysis to comprehensively examine neurofeedback training effects beyond those associated with abnormal baseline connectivity.These comprehensive exploratory analyses suggested that abnormal resting-state connectivity for combat veterans with PTSD was partly normalized after the training. This included hypoconnectivities between the left amygdala and the left ventrolateral prefrontal cortex (vlPFC) and between the supplementary motor area (SMA) and the dorsal anterior cingulate cortex (dACC). The increase of SMA-dACC connectivity was associated with PTSD symptom reduction. Longitudinal MDMR analysis found a connectivity change between the precuneus and the left superior frontal cortex. The connectivity increase was associated with a decrease in hyperarousal symptoms. The abnormal connectivity for combat veterans without PTSD - such as hypoconnectivity in the precuneus with a superior frontal region and hyperconnectivity in the posterior insula with several regions - could also be normalized after the training. These results suggested that the rtfMRI-nf training effect was not limited to a feedback target region and symptom relief could be mediated by brain modulation in several regions other than in a feedback target area. While further confirmatory research is needed, the results may provide valuable insight into treatment effects on the whole brain resting-state connectivity. Keywords: combat veterans, neurofeedback, amygdala, positive memories, prefrontal cortex, precuneu