fMRI Neurofeedback-Enhanced Cognitive Reappraisal Training in Depression: A Double-Blind Comparison of Left and Right vlPFC Regulation

Abstract

Affective disorders are associated with maladaptive emotion regulation strategies. In particular, the left more than the right ventrolateral prefrontal cortex (vlPFC) may insufficiently regulate emotion processing, e.g., in the amygdala. A double-blind cross-over study investigated NF-supported cognitive reappraisal training in major depression (n = 42) and age- and gender-matched controls (n = 39). In a randomized order, participants trained to upregulate either the left or the right vlPFC during cognitive reappraisal of negative images on two separate days. We wanted to confirm regional specific NF effects with improved learning for left compared to right vlPFC (ClinicalTrials.gov NCT03183947). Brain responses and connectivity were studied with respect to training progress, gender, and clinical outcomes in a 4-week follow-up. Increase of vlPFC activity was stronger after NF training from the left- than the right-hemispheric ROI. This regional-specific NF effect during cognitive reappraisal was present across patients with depression and controls and supports a central role of the left vlPFC for cognitive reappraisal. Further, the activity in the left target region was associated with increased use of cognitive reappraisal strategies (r = 0.48). In the 4-week follow-up, 75% of patients with depression reported a successful application of learned strategies in everyday life and 55% a clinically meaningful symptom improvement suggesting clinical usability.

Keywords: cognitive reappraisal; depression; emotion regulation; lateral PFC; real-time fMRI neurofeedback.

Figure 1

(A) Experimental procedure. The NF training entailed 5 visits to the lab, starting with initial assessment and cognitive reappraisal training (Visit 1), followed by baseline cognitive reappraisal runs and anatomical recordings (Visit 2), two NF training days (Visit 3 and 4) and a follow-up assessment (Visit 5). (B) Experimental paradigm during NF training. All participants completed 4 NF runs on each of the two NF days. Each NF run entailed 9 view-regulate cycles. During “view” trials (“x”), participants passively viewed the picture and could allow spontaneous thoughts and emotions. On “regulate” trials (“+”) participants reappraised the picture to reduce the negative affect and upregulate the BOLD signal in the target area. Each picture was presented for 12 s, followed by a 6-s fixation cross and 4-s (pseudo-) neurofeedback interval.

Figure 2

Brain behavior relationship. Association between within run learning during the first NF day and change in cognitive reappraisal use was significant for left (r = 0.484, p = 0.002) but not right (r = 0.170, p = 0.150) vlPFC feedback.

Figure 3

Neural correlates of emotion regulation. (A) The main effect of group revealed a widespread network active during NF including the bilateral prefrontal cortex, precentral gyrus, SMA, MCC, bilateral occipital and superior parietal areas, thalamus, and cerebellum. Healthy individuals showed a stronger engagement of prefrontal areas while patients showed more activation in cingulate areas. (B) The main effect of gender revealed engagement of an extensive network during emotion regulation in males including the bilateral prefrontal cortex, SMA, dmPFC, bilateral precentral and occipital gyrus and bilateral thalamus. Female participants showed stronger activation in the bilateral angular gyrus. (C) Learning and reduction across NF runs 1 to 4. Overall, participants showed an increase in the bilateral fusiform gyrus and occipital lobe as well as a decrease of activation in the right insula and the MCC.

Figure 4

Psychophysiological interaction during regulation. Results of the generalized psychophysiological interaction analysis for the contrast ‘regulate – view’ with bilateral vlPFC as seed. Healthy controls showed increased coupling between the seed region and bilateral superior parietal cortex and negative coupling between the seed and ACC as well as PCC. Patients showed positive coupling between the seed and bilateral occipital cortex. Compared with healthy controls, patients with depression showed significantly reduced coupling between the bilateral vlPFC and left superior parietal cortex. All results are reported at p < 0.001 voxel threshold and p < 0.05 FDR-corrected at cluster level. Bar plots indicate size of effect (beta values) at the voxel showing the maximum coupling effect.

Figure 5

Change of severity of depression and emotion regulation ability from baseline to follow-up. (A) Symptom severity measured by BDI-II showing a significant decrease of symptom scores from baseline to follow-up only in patients with depression [9.2 ± 11.8; t₍₂₈₎ = 4.2, p < 0.001]. (B) Patients showed a significant increase of cognitive reappraisal and a stable level of suppression strategies. Healthy individuals had stable levels of cognitive reappraisal and suppression. Error bars indicate standard errors. **p < 0.001, *p < 0.05.