New Insight Into How Brain Stimulation Eases Major Depression

For the first time, researchers understand what happens to the brain when patients with treatment-resistant depression receive repetitive transcranial magnetic stimulation (rTMS).

Using functional magnetic resonance imaging (fMRI), they showed that rTMS induces widespread alterations in functional connectivity in brain regions involved in emotion and motor control.

‘How does rTMS work?’ is one of the most frequent questions I get in clinic. Providing an accurate explanation and narrative to patients who are critical,” senior investigator Fidel Vila-Rodriguez, MD, PhD, director of the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver, told Medscape Medical News.

“Our findings suggest that rTMS might rely on the brain’s capacity for change (neuroplasticity) to exert its effects and that rTMS effects on the brain are widespread beyond the focal area stimulated (functional network effects),” Vila-Rodriguez added.

The study was published online May 18 in the American Journal of Psychiatry.

Mechanistic Insights

Although rTMS has proven efficacy for treatment-resistant depression, the mechanisms behind how it affects the brain are not well understood.

In the current study, researchers used fMRI to assess changes in functional connectivity induced by a single rTMS session in 26 women and 12 men with treatment-resistant depression.

They found that stimulating the dorsolateral prefrontal cortex led to “widespread, acute and transient” changes in functional regions connectivity, particularly in brain involved in multiple function — from managing emotional responses to memory and motor control.

Following a 4-week course of rTMS, these connectivity changes predicted about 30% of the variance of improvement in scores on the Montgomery-Åsberg Depression Rating Scale after rTMS treatment.

The most robust predictive associations involved connections between prefrontal regions and motor, parietal, and insular cortices and between bilateral regions of the thalamus.

“By demonstrating this principle and identifying regions of the brain that are activated by rTMS, we can now try to understand whether this pattern can be used as a biomarker,” Vila-Rodriguez said in a news release.

“This work provides a mechanistic explanation of what rTMS does to treat depression and supports the notion that for rTMS to treat depressive symptoms a distributed change in brain activity (network or circuit base) is necessary,” he told Medscape Medical News.

With funding from the Canadian Institutes of Health Research (CIHR), the team will next see if they can use fMRI to guide rTMS at the individual level, with the ultimate goal of “personalizing” rTMS using individualized functional targets, Vila-Rodriguez said.

New Generation of TMS Researchers

Reached for comment, Jonathan Downar, MD, PhD, Department of Psychiatry, University of Toronto, Ontario, Canada, noted that TMS can be “very effective” for treatment-resistant depression and it has “very clean side effect profile compared to medications.” “

What the field is trying to figure out now is “who it works for and how we can predict more effectively who’s going to benefit from it,” Downar told Medscape Medical News.

He noted that the study’s investigators are part of a “new generation of TMS researchers who are bringing new ideas into the fold and figuring out how to use brain imaging to personalize the treatment.” This study represents “a step” in that direction.

“A challenge for the field is that it’s often pretty easy to demonstrate a change at the group level but the question is whether we can use that at the individual level. That’s a way higher bar to meet and we’re still not there yet, Downar added.

Support for the study was provided by Brain Canada, the Michael Smith Foundation for Health Research and the Vancouver Coastal Health Research Institute. Vila- Rodriguez has received research support from CIHR, Brain Canada, the Michael Smith Foundation for Health Research, the Vancouver Coastal Health Research Institute, and the Weston Brain Institute for investigator-initiated research and philanthropic support from the Seedlings Foundation; he received in-kind equipment support from MagVenture for this contempt-initiated trial; and he has received honoraria for participation on an advisory board for Janssen. Downar has served as an adviser for BrainCheck, NeuroStim TMS, Salience Neuro Health; received research grant from CIHR, National Institute for Mental Health, Brain Canada, Canadian Biomarker Integration Network in Depression, Ontario Brain Institute, Klarman Family Foundation, Arrell Family Foundation and the Edgestone Foundation; received travel stipends from Lundbeck and ANT Neuro; and received in-kind equipment support for contempt-initiated trials from MagVenture.

Am J Psychiatry. Published online May 18, 2022. Full text

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