Personalized Closed-loop Theta Burst Stimulation for Treatment of Depression

PROJECT SUMMARY Depressive disorders are increasingly prevalent in modern societies. Clinical depression is the leading cause of disability worldwide and an underlying condition for two-thirds of suicidal attempts in the United States. Precision neuromodulation and particularly transcranial magnetic stimulation (TMS) promise a unique technological approach to the therapy of depression. TMS creates a well-controlled magnetic field that induces a focal electric field in the brain and can elicit action potentials in neurons. Rhythmic TMS is already FDA-approved for major depressive disorder, obsessive-compulsive disorder, and nicotine addiction. Novel TMS protocols such as intermittent theta-burst stimulation (TBS) can rapidly induce lasting potentiation of neural circuits. In 2019, TBS was FDA-approved for depression after it was demonstrated that a three-minute TBS session was as effective as 40 minutes of conventional rhythmic TMS. Despite their initial success, a major challenge for TMS and TBS remains a persistent inter- and intra-individual variability of outcomes. This is likely due to currently limited spatiotemporal precision and lack of personalization. Here, I propose to develop and validate spatiotemporally precise personalized TBS tailored for the therapy of depression. For that, I will create a closed-loop TBS-EEG system that integrates spatial precision by leveraging individual structural magnetic resonance imaging for neuronavigation and temporal precision due to real-time electroencephalography (EEG). Using neuronavigation, I will compensate for known inter-individual variability in the prefrontal anatomy and focus the individual center of DLPFC previously found to be an optimal TMS target in depression. Ongoing EEG will inform the system about the excitatory/inhibitory states of the prefrontal cortex, as reflected in the brain oscillations, to trigger stimulation pulses at the most excitable time. Further, I will improve the functional precision by tagging the individual prefrontal brain oscillations implicated in depressive behavior using EEG during a validated cognitive test. In particular, theta and gamma oscillations are known biomarkers of prefrontal activity and depressive disorders. From the individual theta and gamma frequencies, I will derive the personalized parameters of TBS. Finally, I will conduct a double-blinded, placebo-controlled study in healthy humans and a feasibility study in a clinical population to assess the long-lasting effects of the personalized TBS- EEG on prefrontal electrophysiology and depressive behavior. All these combined efforts will enhance our fundamental understanding of the prefrontal circuitry mechanisms underlying depression and enable novel personalized therapy of depression within the precision-medicine framework.