PROJECT SUMMARY: Using human brain connectivity to identify the causal neuroanatomical substrate of depression symptoms Depression is the leading cause of disability worldwide. Identifying the brain regions causing depression symptoms can lead to better treatment targets and therapies. Most neuroimaging studies identify brain regions where activity correlates with depression symptoms but cannot determine whether these regions actually cause symptoms. The goal of this project is to causally link depression symptoms to human neuroanatomy. Lesions and brain stimulation can provide causal links to human neuroanatomy. Because symptoms can come from regions connected to the lesion or stimulation site, we study the connectivity of these sites (not just their location) using brain connectivity data from a large cohort of normal subjects (functional connectivity MRI, n=1000). This allows us to map symptoms caused by lesions or stimulation to brain circuits without connectivity data from the patients themselves. With NIMH support, we found that lesions, transcranial magnetic stimulation (TMS) sites, and deep brain stimulation (DBS) sites that cause a change in depression symptoms are all connected to a common brain circuit across 14 independent datasets (Siddiqi et. al 2021 Nature Human Behaviour). Connectivity to this circuit was a better predictor of antidepressant response to TMS or DBS than connectivity to other candidate regions (e.g., subgenual cingulate). However, this circuit requires validation before it can be translated into a target for clinical trials. Here, we will validate our brain circuit for depression using three independent causal sources of information: lesions (Aim 1), DBS (Aim 2), and TMS (Aim 3). For all aims, we will use our published a priori depression circuit to predict overall depression outcomes. We will also perform exploratory data-driven analyses to test whether different circuits are responsible for different symptoms of depression. In Aim 1, we will prospectively test whether our depression circuit can predict depression scores after stroke. In Aim 2, we will test whether our depression circuit can predict change in depression score after DBS across a wide range of DBS patients with different diagnoses. In Aim 3, we will test whether individualized connectivity to our circuit prospectively predicts change in depression symptoms with TMS. Completion of these Aims will validate our depression circuit across different diagnoses and across three independent causal sources of information, providing much stronger validation than could be achieved with one modality alone. If successful, this study will facilitate future trials directly targeting our brain circuit with therapeutic neuromodulation for depression.