Real-Time fMRI Functional Connectivity Neurofeedback Reducing Repetitive Negative Thinking in Depression: A Double-Blind, Randomized, Sham-Controlled Proof-of-Concept Trial

Abstract

<b><i>Introduction:</i></b> Repetitive negative thinking (RNT) is a cognitive process focusing on self-relevant and negative experiences, leading to a poor prognosis of major depressive disorder (MDD). We previously identified that connectivity between the precuneus/posterior cingulate cortex (PCC) and right temporoparietal junction (rTPJ) was positively correlated with levels of RNT. <b><i>Objective:</i></b> In this double-blind, randomized, sham-controlled, proof-of-concept trial, we employed real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) to delineate the neural processes that may be causally linked to RNT and could potentially become treatment targets for MDD. <b><i>Methods:</i></b> MDD-affected individuals were assigned to either active (<i>n</i> = 20) or sham feedback group (<i>n</i> = 19). RNT was measured by the Ruminative Response Scale-brooding subscale (RRS-B) before and 1 week after the intervention. <b><i>Results:</i></b> Individuals in the active but not in the sham group showed a significant reduction in the RRS-B; however, a greater reduction in the PCC-rTPJ connectivity was unrelated to a greater reduction in the RRS-B. Exploratory analyses revealed that a greater reduction in the retrosplenial cortex (RSC)-rTPJ connectivity yielded a more pronounced reduction in the RRS-B in the active but not in the sham group. <b><i>Conclusions:</i></b> RtfMRI-nf was effective in reducing RNT. Considering the underlying mechanism of rtfMIR-nf, the RSC and rTPJ could be part of a network (i.e., default mode network) that might collectively affect the intensity of RNT. Understanding the relationship between the functional organization of targeted neural changes and clinical metrics, such as RNT, has the potential to guide the development of mechanism-based treatment of MDD.

Trait repetitive negative thinking in depression is associated with functional connectivity in negative thinking state rather than resting state

“…Twenty-eight medically and psychiatrically healthy (HC) individuals and forty-two individuals with MDD participated in the study. Each participant performed resting and rumination-inducing negative thinking (NT) tasks, which followed by other task runs including neurofeedback training (Tsuchiyagaito et al, 2023; Tsuchiyagaito et al, 2021). The present study analyzed their fMRI data during the resting-state and NT tasks.…”

“…MDD participants met the DMS-5 (American Psychiatric Association, 2013) criteria for unipolar MDD based on the Mini-International Neuropsychiatric Interview 7.0.2 (Sheehan et al, 1998), and had current depressive symptoms with Montgomery-Åsberg Depression Rating Scale (MADRS) score > 6 (Montgomery and Åsberg, 1979). See Tsuchiyagaito et al (2021) and Tsuchiyagaito et al (2023) for detailed inclusion and exclusion criteria. The study protocols were approved by the Western Institutional Review Board, and all participants gave informed consent to participate in the study.…”

Whole-brain Mechanism of Neurofeedback Therapy: Predictive Modeling of Neurofeedback Outcomes on Repetitive Negative Thinking in Depression

“…We analyzed the data of the previous NF study for a treatment of repetitive negative thinking in depressed participants 22 . The original study was registered on ClinicalTrials.gov (NCT04941066).…”

“…Further details of the inclusion and exclusion criteria were shown in Tsuchiyagaito, Misaki 22 , and the CONSORT diagram is in the Supplementary Information (SI). All participants provided written informed consent.…”

“…The current study explores the whole-brain mechanisms underlying NF treatment, utilizing data from a prior double-blind, randomized controlled trial (RCT) 22 . This earlier study demonstrated a significant decrease in symptoms of repetitive negative thinking exclusively in the active group following connectivity NF training, but not in the sham control group.…”