A causal wiring diagram of transdiagnostic brain functions

Brain imaging has long been criticized for revealing correlations rather than causes. In recent years, there has been a rapid growth of focal brain stimulation technology, which can bring us closer to studying causes. If stimulating a specific brain circuit causes a specific behavioral change, then that circuit can be inferred to have a causal role in that behavior. However, the number of potential stimulation sites is practically infinite. This makes it difficult to test the causal relevance of every possible stimulation target and every possible behavior. There is a need for a systematic wiring diagram that narrows the field of potential options, enabling researchers and clinicians to make informed decisions about stimulation targets. In this proposal, we will develop this wiring diagram. Using highly-sampled resting-state functional MRI scans as well as cutting-edge brain stimulation protocols, we will randomly apply stimulation to different targets in each participant. To address the problem of a near-infinite target space, we will narrow it down by mapping whole-brain connectivity of each target, not just its location. As a result, we will have information about every brain region for every participant, enabling us to draw whole-brain-level contrasts. Using this information, we will map the circuitry connected to TMS sites that modulate a wide range of different behaviors relevant to mental illness, including transdiagnostic behaviors and diagnosis-specific symptoms. We will include patients with major depression, obsessive- compulsive disorder, schizophrenia, and generalized anxiety disorder. If successful, the study will yield a multidimensional atlas of causal brain circuitry, which can be used by future researchers and clinicians to select a stimulation target that is appropriate for the a specific patient based on their symptoms and objective emotional testing.