Blame-rebalance fMRI neurofeedback in major depressive disorder: A randomised proof-of-concept trial

Roland Zahn, Julie H Weingartner, Rodrigo Basilio, Patricia Bado, Paulo Mattos, João R Sato, Ricardo de Oliveira-Souza, Leo F Fontenelle, Allan H Young, Jorge Moll, Roland Zahn, Julie H Weingartner, Rodrigo Basilio, Patricia Bado, Paulo Mattos, João R Sato, Ricardo de Oliveira-Souza, Leo F Fontenelle, Allan H Young, Jorge Moll

Abstract

Previously, using fMRI, we demonstrated lower connectivity between right anterior superior temporal (ATL) and anterior subgenual cingulate (SCC) regions while patients with major depressive disorder (MDD) experience guilt. This neural signature was detected despite symptomatic remission which suggested a putative role in vulnerability. This randomised controlled double-blind parallel group clinical trial investigated whether patients with MDD are able to voluntarily modulate this neural signature. To this end, we developed a fMRI neurofeedback software (FRIEND), which measures ATL-SCC coupling and displays its levels in real time. Twenty-eight patients with remitted MDD were randomised to two groups, each receiving one session of fMRI neurofeedback whilst retrieving guilt and indignation/anger-related autobiographical memories. They were instructed to feel the emotion whilst trying to increase the level of a thermometer-like display on a screen. Active intervention group: The thermometer levels increased with increasing levels of ATL-SCC correlations in the guilt condition. Control intervention group: The thermometer levels decreased when correlation levels deviated from the previous baseline level in the guilt condition, thus reinforcing stable correlations. Both groups also received feedback during the indignation condition reinforcing stable correlations. We confirmed our predictions that patients in the active intervention group were indeed able to increase levels of ATL-SCC correlations for guilt vs. indignation and their self-esteem after training compared to before training and that this differed significantly from the control intervention group. These data provide proof-of-concept for a novel treatment target for MDD patients and are in keeping with the hypothesis that ATL-SCC connectivity plays a key role in self-worth. https://ichgcp.net/clinical-trials-registry/NCT01920490.

Keywords: Anger; Anterior temporal lobe; Clinical trial; Guilt; Major depressive disorder; Real-time fMRI; Self-esteem; Subgenual cingulate cortex; fMRI neurofeedback.

Conflict of interest statement

RZ: Lundbeck-sponsored presentation on neurofeedback, co-investigator Livanova-funded study; Industry advice via Guidepoint Global; Industry collaborations with EMIS PLC and Alloc Modulo LTD. Private Clinical Practice at The London Depression Institute. AHY: Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen; Consultant to Johnson & Johnson; Lead Investigator for Embolden Study (AZ), BCI Neuroplasticity study and Aripiprazole Mania Study; Investigator initiated studies from AZ, Eli Lilly, Lundbeck, Wyeth, Janssen. JM: Shareholder of Rede D'Or hospitals (Brazil) and a managing partner of VHM LLC. (US). All these interests are unrelated to the study. The other authors have no conflicts of interest to declare.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1|
Fig. 1|
Panel a&b) Thermometer-like displays were used for visual feedback. Participants were instructed to increase the level of the colour bar (a: low level, b: high level) while thinking about the autobiographical memory related to the cue word. Panel c) & d) Displayed are the a priori anatomical regions of interest (ROI) used for extracting signal for neurofeedback training (c: ATL, d: SCC). As only the 10% most activated voxels were used for training in each subject, there was individual variability as to the sub-regions of the smoothed ROIs used for training. Colour-coded overlays indicate for how many participants a given voxel was included in their individualized ROI. Panel e) & f) Displayed are SCC voxels (Sagittal slices MNI z = −4 in e), −1 in f)) included in the training ROI for at least 4 participants overlaid with the unsmoothed anterior subgenual cingulate ROI in blue underpinning the design of this study in which we previously demonstrated self-blame-selective hypo-connectivity(Green et al., 2012) and in red the more posterior inferior subgenual cortex cluster showing self-blame-selective hyper-connectivity in remitted MDD who develop another episode in the next year in a later paper(Lythe et al., 2015). Panel g) This bar chart compares the intervention groups on neurofeedback training effects (Cohen's D for post- vs pre-training differences) in ATL-SCC connectivity for guilt vs. indignation (measured by using standardised regression coefficients). As shown in Table 2, there was a significant difference between groups in the expected direction such that connectivity for guilt vs. indignation increased with training in the active intervention group, but slightly decreased in the control intervention group. Supplementary Fig. 7 shows the individual variability in correlations during neurofeedback.

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