Targeted modulation of symptom-specific brain circuits with transcranial magnetic stimulation

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Project summary Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for treatment-resistant depression, but clinical outcomes vary. We recently showed that TMS outcomes may be optimized by targeting different circuits to treat different symptoms (Siddiqi et al, Am J Psychiatry 2020). Among patients who received clinical TMS to the left dorsal lateral prefrontal cortex for depression, improvement in “dysphoric” symptoms was associated with TMS to one brain circuit, while improvement in “anxiosomatic” symptoms was associated with TMS to a different brain circuit. However, this study was unable to investigate biomarkers and mechanisms of targeting various brain circuits. Using resting-state fMRI data in a subset of this cohort, we have now generated preliminary data showing that treatment-induced connectivity change within each circuit can be used as a biomarker of which circuit was stimulated and which symptom clusters improved. Further, individualized connectivity between the patient’s TMS site and each of these circuits covaried with TMS-induced connectivity changes, suggesting a potential mechanism. However, these preliminary results are limited by small sample size with a retrospective design that relies on incidental variance in the TMS site rather than targeted stimulation of these two brain circuits. In the current project, we will prospectively target TMS in order to clearly assess its target-specific effects on functional connectivity. In Aim 1, we will test whether our prospective targeting of our two circuits will induce selective connectivity changes within those circuits. In Aim 2, we will test whether the magnitude of these connectivity changes can be predicted by the strength of the TMS site’s individualized connectivity to the underlying circuit. Together, this work will establish whether resting-state fMRI can act as a reliable biomarker of target engagement when seeking to modulate specific brain circuits in patients. Further, it will lend insight into potential mechanisms of previously observed symptom-specific neuromodulation effects. This work is a critical step towards mechanistically-driven clinical trials focused on symptom-specific and circuit-specific neuromodulation in depression, with the long-term goal of personalized and transdiagnostic circuit-targeted therapy for mental illness more generally.