Personalized circuit-based neuromodulation targets for depression

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PROJECT SUMMARY/ABSTRACT This proposal requests support for a five-year program of training and research to better understand how distinct brain circuits can be mapped and selectively stimulated with transcranial magnetic stimulation (TMS) to treat different symptoms of major depression. In the proposed training plan, I will build upon my previous psychiatric and computational experience to perform a multidisciplinary project at Beth Israel Deaconess Medical Center. My career development plan includes training in brain circuit mapping, neuromodulation, biostatistics/data science, psychiatric phenotyping, clinical trials, and general translational research. TMS is an effective treatment for major depression which is capable of modulating specific brain circuits. However, efficacy varies greatly across patients and the mechanisms are not well-understood. Recent work from our lab shows that the efficacy of TMS can be improved by stimulating specific targets based on their connectivity profile. Additionally, different TMS targets can modulate different brain networks which may be involved in different symptoms of depression. The brain circuit connected to each stimulation site can be mapped by using functional connectivity MRI (fcMRI), either at the group level or the individual level. A general estimated map of stimulation site connectivity can be generated from the human connectome, a normative wiring diagram of the human brain based on fcMRI of a thousand healthy controls. A more precise map of connectivity can be generated based on subject-specific fcMRI data. This proposal aims to personalize TMS targets based on symptoms, emotional task performance, and brain connectivity. In my preliminary data, this approach yielded distinct circuits responsible for improvement in “dysphoric” versus “anxiosomatic” symptom clusters. However, these results are limited by retrospective nature, reliance on subjective symptom scales, and reliance on group-based connectivity. In this proposal, I will address these limitations by confirming our results in a prospective randomized trial, incorporating task-based behavioral metrics, and incorporating subject-specific connectivity. More broadly, this research aims to develop a model for mapping specific circuits associated with distinct symptom clusters that can be modulated with therapeutic brain stimulation. This will lay the foundation for personalized approaches to transdiagnostic neuromodulation in clinical psychiatry.