Reducing neural perseveration through closed loop real time fMRI neurofeedback to alleviate depressive symptoms

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ABSTRACT Current treatment strategies for major depression, the leading cause of disability worldwide, leave more than half of patients with no meaningful treatment benefit. This R61/R33 proposal was developed in keeping with NIMH Strategic Objective 3.1 to “Develop new interventions based on discoveries in genomics, neuroscience and behavioral science.” We will test the efficacy of a new psychotherapeutic strategy, the first real-time fMRI neurofeedback therapy to use cloud-based pattern classification to decode the patient’s attentional state and dynamically modulate task stimuli (in a “closed loop”) based on this state, rather than the standard approach of conveying feedback through a separate gauge that tracks activation in a localized region of interest. The overall objective of this R61/R33 is to test whether closed-loop real-time fMRI neurofeedback that specifically targets our hypothesized attentional mechanism of depression (i.e., neural perseveration of negative states) reduces depression severity. This study will be the first dose-finding test of real-time fMRI effect on negative attention bias. During the R61 Phase 60 participants with MDD ages 18-65 years will be randomly assigned to treatment with active neurofeedback (n=30) vs sham feedback (n=30). We have three aims: 1) Establish neural target engagement using pre-post change in neural perseveration of negative attentional states in active vs sham neurofeedback; 2) Determine the lowest “dose” of training necessary to reduce neural perseveration of negative states; 3) (Exploratory) Establish behavioral target engagement using perseveration on negative images in an eye gaze task comparing active vs sham neurofeedback. Go/No-Go Criteria for R61: There will be at least a medium effect size (Cohen’s d ≥ 0.4) in neural perseveration reduction comparing real to sham NF. Our pilot study (Mennen et al 20) found an effect size of 0.83. Therefore this criterion is both clinically meaningful and realistic and will demonstrate target engagement. During the R33 Phase 80 participants with MDD ages 18-65 will be randomly assigned to treatment with active neurofeedback (n=40) vs sham feedback (n=40). We have three aims: 1) To conduct a randomized controlled trial (RCT) to compare the effect of real-time neurofeedback vs. sham on depression outcome; 2) To determine the relationship between the markers of neural perseveration established in the R61 phase and the reduction in depressive symptoms; and 3) To determine the durability of the treatment effect by comparing MADRS scores at 3 months followup between those who received real as compared to sham NF. Impact. This project will establish real-time fMRI neurofeedback as a means of reducing neural perseveration of negative states as a treatment for MDD. Results from this line of research will inform feedback strategies and improve understanding of neural mechanisms underlying negative attention and MDD. Our cloud based platform would be readily scalable and allow dissemination to thousands of hospital and research facilities.