Quantifying the mechanism of transcranial magnetic stimulation in depression: A preliminary positron emission tomography study of microglia

About This Grant

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation methodology FDA- approved for treatment of major depressive disorder (MDD). While rTMS achieves higher antidepressant efficacy than conventional treatments, reported response and remission rates are highly variable across cohorts. To reduce this variability and enhance overall remission rates, an understanding of the biological mechanisms behind rTMS’s antidepressant efficacy is needed. Recent studies have identified that rTMS works through a common biological mechanism even across multiple neurological disorders being treated: reduction of neuroinflammation, specifically, reduction in microglia activation. This is particularly relevant for MDD, as increased neuroinflammation is well-documented, on average, in groups of patients with MDD, and microglia are reported to be the cells responsible for this neuroinflammation. We and others have shown that people with MDD exhibit a range of neuroinflammation and that only those with high neuroinflammation have an antidepressant response to anti-inflammatory treatment. Taken together, this suggests that the mechanism of action of rTMS may be through the reduction of neuroinflammation (specifically, microglia density) and that the reported heterogeneity in response to rTMS may be due to the heterogeneity of neuroinflammation in MDD itself. We seek to probe this in the proposed high-risk, high-reward proof-of-concept study in n = 10 treatment- seeking participants with MDD, who will undergo rTMS as part of their standard of care – this is not a clinical trial: Aim 1. Explore the relationship between rTMS-associated reductions in depression severity and reductions in microglial density, as measured by microglia-specific [11C]PS13 positron emission tomography (PET) tracer. We expect microglia density to decrease following rTMS based on published animal literature reporting a ~23% reduction in microglia after TMS. Data from our current study examining participants with MDD receiving anti-inflammatory medication suggest that reductions in depression severity will be correlated with this reduction in neuroinflammation. Aim 2. Explore the relationship between pretreatment microglia density as measured by [11C]PS13 PET and antidepressant response to rTMS. Data from our current study suggest that greater pretreatment neuroinflammation will be associated with better response to rTMS. This high-risk, high-reward R21 will be the first study to assess rTMS’s effects on microglia in patients with MDD, advancing our understanding of its mechanism of action, providing proof of concept to support future larger studies, and stimulating the development of both novel neuroinflammation-specific therapeutics and future improvements in rTMS protocols.