Investigating the neural mechanisms of repetitive brain stimulation with invasive and noninvasive electrophysiology in humans

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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.