Resting-state functional connectivity modulation and sustained changes after real-time functional magnetic resonance imaging neurofeedback training in depression

Abstract

Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD) and normalize with remission. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training with the goal of upregulating amygdala activity during recall of happy autobiographical memories (AMs) has been suggested, and recently explored, as a novel therapeutic approach that resulted in improvement in self-reported mood in depressed subjects. In this study, we assessed the possibility of sustained brain changes as well as the neuromodulatory effects of rtfMRI-nf training of the amygdala during recall of positive AMs in MDD and matched healthy subjects. MDD and healthy subjects went through one visit of rtfMRI-nf training. Subjects were assigned to receive active neurofeedback from the left amygdale (LA) or from a control region putatively not modulated by AM recall or emotion regulation, that is, the left horizontal segment of the intraparietal sulcus. To assess lasting effects of neurofeedback in MDD, the resting-state functional connectivity before and after rtfMRI-nf in 27 depressed subjects, as well as in 27 matched healthy subjects before rtfMRI-nf was measured. Results show that abnormal hypo-connectivity with LA in MDD is reversed after rtfMRI-nf training by recalling positive AMs. Although such neuromodulatory changes are observed in both MDD groups receiving feedback from respective active and control brain regions, only in the active group are larger decreases of depression severity associated with larger increases of amygdala connectivity and a significant, positive correlation is found between the connectivity changes and the days after neurofeedback. In addition, active neurofeedback training of the amygdala enhances connectivity with temporal cortical regions, including the hippocampus. These results demonstrate lasting brain changes induced by amygdala rtfMRI-nf training and suggest the importance of reinforcement learning in rehabilitating emotion regulation in depression.

Keywords: amygdala; functional connectivity; major depressive disorder; neurofeedback; real-time fMRI; resting state.

FIG. 1.

(A) Regions where the resting-state functional connectivity with left amygdala (LA, seed) in subjects with major depressive disorder (MDD) differed from healthy control (HC) subjects and also was covaried with the Hamilton Depression Rating Scales (HDRS). The cold colors indicate the region where connectivity with amygdala was larger in healthy subjects than in MDD; (B) pre-neurofeedback (pre-nf) connectivity between left amygdala and pregenual anterior cingulate cortex (pgACC) in MDD subjects significantly linearly decreases with HDRS (cc=−0.41, p=0.04); (C) LA-cuneus pre-nf connectivity in MDD subjects significantly linearly decreases with HDRS (cc=−0.51, p=0.006); Group results of LA-pgACC (D), and LA-cuneus (E) pre-, and post-nf connectivity for MDD group with active, control neurofeedback, and the healthy group. *Indicates significance at p<0.05. nf stands for neurofeedback.

FIG. 2.

Resting-state functional connectivity in regions where the connectivity with LA (seed) in MDD differed from healthy subjects' regardless of co-variation with HDRS. (A) Left Cuneus; (B) Left pgACC; (C) Left angular gyrus; (D) Right medial frontal gyrus; (E) Left Precuneus; (F) Left middle temporal gyrus. Pre- and post-nf connectivity is shown for active and control MDD groups receiving neurofeedback from active and control brain regions (LA and horizontal segment of intraparietal sulcus, respectively). The cold colors indicate brain regions where connectivity with LA was larger in healthy subjects than in MDD; *indicates statistically significant post-nf versus pre-nf changes at p<0.05. **Indicates statistically significant post-nf versus pre-nf changes at p<0.01.

FIG. 5.

Relationship between post-nf versus pre-nf LA-cuneus connectivity changes (post-nf–pre-nf) and days after MDD subjects receiving active neurofeedback (r=0.76, p=0.0015).

FIG. 3.

Maps of group difference of post-nf versus pre-nf connectivity changes (post-nf–pref-nf) with LA (seed). Warm colors indicate active>control. Cold colors indicate active<control. Maps are thresholded at p_corrected<0.05.

FIG. 4.

Maps of group difference of post-nf versus pre-nf connectivity changes (post-nf–pre-nf) with left pgACC (seed). Warm colors indicate active>control. Cold colors indicate active<control. Maps are thresholded at p_corrected<0.05.