Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), but substantial heterogeneity in outcomes remains. We examined a potential mechanism of action of rTMS to normalize individual variability in resting-state functional connectivity (rs-fc) before and after a course of treatment.
Methods: Variability in rs-fc was examined in healthy controls (baseline) and individuals with MDD (baseline and after 4-6 weeks of rTMS). Seed-based connectivity was calculated to 4 regions associated with MDD: left dorsolateral prefrontal cortex (DLPFC), right subgenual anterior cingulate cortex (sgACC), bilateral insula, and bilateral precuneus. Individual variability was quantified for each region by calculating the mean correlational distance of connectivity maps relative to the healthy controls; a higher variability score indicated a more atypical/idiosyncratic connectivity pattern.
Results: We included data from 66 healthy controls and 252 individuals with MDD in our analyses. Patients with MDD did not show significant differences in baseline variability of rs-fc compared with controls. Treatment with rTMS increased rs-fc variability from the right sgACC and precuneus, but the increased variability was not associated with clinical outcomes. Interestingly, higher baseline variability of the right sgACC was significantly associated with less clinical improvement ( p = 0.037, uncorrected; did not survive false discovery rate correction). Limitations: The linear model was constructed separately for each region of interest.
Conclusion: This was, to our knowledge, the first study to examine individual variability of rs-fc related to rTMS in individuals with MDD. In contrast to our hypotheses, we found that rTMS increased the individual variability of rs-fc. Our results suggest that individual variability of the right sgACC and bilateral precuneus connectivity may be a potential mechanism of rTMS.
Competing Interests: Competing interests:: J. Downar declared grants from the National Institutes of Health (NIH), Canadian Institutes of Health Research (CIHR), Brain Canada, and the Ontario Brain Institute. He also declared consulting fees from TMS Neuro Solutions and Arc Health Partners. He is the co-founder and holds equity in Ampa Health. S. Nestor declared a research project award application to the Labatt Family Network for Research on the Biology of Depression, Labatt Family Discovery Program, Department of Psychiatry, University of Toronto. F. Vila-Rodriguez declared support from Seedlings Foundation, CIHR, and Brain Canada. He is a volunteer director with the BC Schizophrenia Society board of directors, and he has received in-kind equipment support from Magventure for investigator-initiated research. Z.J. Daskalakis serves on the advisory board of Brainsway Inc. He also declared receipt of research grant materials from Magventure Inc. and Brainsway Inc. D.M. blumberger declared grants from CIHR, Brain Canada, NIH, and the Patient-Centered Outcomes Research Institute. He is a paid scientific advisory board member of Sooma, and serves as co-chair of the clinical standards committee (unpaid) of the Clinical TMS Society. He has stock options from Sooma and has received in-kind equipment support from Magventure Inc. and Brainsway Inc. for investigator-initiated studies. C. Hawco declared funding from the National Institute of Mental Health, CIHR and Centre for Addiction and Mental Health Foundation paid to his institution. No other competing interests were declared.
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