PROJECT SUMMARY Depression is the leading cause of disability worldwide and the leading cause of disease burden in the U.S. Up to a third of depressed individuals experience treatment-resistant depression, defined as the failure to achieve adequate improvement after two or more medication trials. A major advance in the field of psychiatry in the last 20 years is the development of a non-pharmacological option for treatment resistant depression using repetitive transcranial magnetic stimulation (rTMS). rTMS has proven an effective treatment modality for those with medication-resistant depression. While this represents a major advance, about half of patients do not benefit from rTMS for depression, and it is not clear why. One of the major impediments to optimizing rTMS and improving the percentage of patients who benefit from rTMS is a lack of understanding with regards to the basic mechanisms of how and why rTMS works. Prior work in this field has been limited by relying heavily on non-invasive measures of brain activity (functional MRI, EEG) and behavior to assess the underlying mechanisms of rTMS. These methods have inherent limitations in spatiotemporal resolution and despite several decades of research have not uncovered a satisfactory understanding of the mechanisms of action of rTMS in humans. The current proposal aims to apply a novel approach that combines invasive and noninvasive methods to evaluate the effects of rTMS with much higher spatiotemporal resolution than has been possible to date. Intracranial electrodes are surgically implanted for clinical reasons in epilepsy patients, and this proposal takes advantage of that unique ability to record directly from the human brain during the administration of stimulation protocols used to treat depression. The goal is to characterize the key signatures of the brain’s response to repeated doses of rTMS with an unparalleled combination of spatial and temporal resolution using intracranial recordings. We do this by evaluating the intracranial effects of focused electrical stimulation to maximize focality and minimize sensory effects (Aim 1), translate stimulation noninvasively by measuring the intracranial effects of rTMS (Aim 2), and translate intracranial recordings noninvasively using simultaneously measured scalp EEG (Aim 3). Our central hypothesis is that rTMS predictably changes evoked responses and oscillatory power locally and in downstream regions, and these changes accumulate across rTMS sessions in brain regions relevant to depression. If successful, this project will inform noninvasive EEG signatures of rTMS response that can be traced back to intracranial physiology. By relating scalp EEG signatures to reliable neural sources, these markers can be leveraged to optimize current treatments, develop new treatments, and overall markedly improve treatment efficacy.

PROJECT NARRATIVE Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but clinical outcome is suboptimal, partially because we are missing biologically-grounded brain markers which show that TMS is modifying activity at the intended target in the brain. The goal of this proposal is to characterize the key markers of the brain’s response to repeated doses of TMS with high resolution using invasive brain recordings in humans, and relate these brain markers to noninvasive recordings. These markers will improve our understanding of TMS and can be used to optimize and enhance clinical efficacy for depression and other psychiatric disorders. Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, but clinical outcome is suboptimal because we don’t understand how rTMS affects the brain and we do not have brain measurements that indicate when stimulation reaches the target location in the brain (target engagement) and when stimulation changes the target (plasticity). The goal of this proposal is to characterize the key signatures of the brain’s response to rTMS with high resolution using invasive brain recordings (Aim 1), investigate how these recordings relate to noninvasive brain measures (Aim 2), and study how noninvasive brain measures relate to clinical outcome after TMS treatment for depression. Linking noninvasive brain measures to both invasive measurements and clinical outcome can greatly improve our understanding of the brain mechanisms underlying TMS-induced clinical outcome and provide a path for optimizing TMS around these measures to improve clinical efficacy. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but clinical outcome is suboptimal with up to half of patients not responding. A critical missing factor that may improve TMS treatment are markers that TMS is modifying activity at the intended target in the brain. The goal of this proposal is to characterize the key signatures of the brain’s response to TMS with high resolution using invasive brain recordings, and relate these measures to noninvasive recordings and clinical outcomes of TMS treatment for depression, which will provide a path for optimizing TMS around these measures to improve clinical efficacy. This research will help our understanding of how transcranial magnetic stimulation (TMS) affects the brain. We will develop new methods of measuring TMS-induced changes in brain activity with high spatial and temporal accuracy that is only possible with intracranial recording and relate them to noninvasive recording measures that are more commonly used and to treatment outcome in depressed patients receiving therapeutic TMS. The research will provide key markers of TMS stimulation that can be used to facilitate the development of better interventions and treatments for depression and potentially other psychiatric diseases. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but clinical outcome is suboptimal, partially because we are missing brain markers that TMS is modifying activity at the intended target in the brain. The goal of this proposal is to characterize the key markers of the brain’s response to TMS with high resolution using invasive brain recordings, and relate these markers to noninvasive recordings and clinical outcomes of TMS treatment for depression. These brain markers can be used to optimize TMS around these measures to improve clinical efficacy for depression and potentially other psychiatric diseases. with up to half of patients not responding. A critical missing factor that may improve TMS treatment are markers that TMS is modifying activity at the intended target in the brain. The goal of this proposal is to characterize the key signatures of the brain’s response to TMS with high resolution using invasive brain recordings, and relate these measures to noninvasive recordings and clinical outcomes of TMS treatment for depression, which will provide a path for optimizing TMS around these measures to improve clinical efficacy.