Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

PROJECT SUMMARY/ABSTRACT FDA-cleared repetitive transcranial magnetic stimulation (rTMS) protocols are known to increase cortical excit- ability in treatment-resistant depression, but for safety and tolerability reasons, many patients receive TMS pro- tocols designed to “quiet” overactive brain networks. Despite their common clinical and research use, we know very little of their mechanism of action, and consequently, improvements in such protocols have been limited. Inhibition induced by continuous theta burst stimulation (cTBS), perhaps the best studied inhibitory rTMS proto- col, is most likely accomplished through either reducing excitation via n-methyl-d-aspartate receptor (NMDAR)-dependent long-term depression (LTD), and/or through enhancing inhibition via gamma-aminobu- tyric acid receptors (GABARs). A knowledge of this mechanism enables us to improve clinical effectiveness, as we have done previously, with mechanism-guided pharmacologic augmentation of an “excitatory” TMS proto- col. Thus, the critical barrier to unlocking the potential of cTBS is that its synaptic mechanism remains un- known. We will test NMDAR-dependent LTD (Aim 1) and GABAR-mediated inhibition (Aim 2) in the dorsolateral pre- frontal cortex (dlPFC) of 70 depressed subjects in a 4-arm double-blind randomized crossover study. Arms in- clude sham cTBS, placebo drug, and active drug and cTBS arms. Pharmacology modulates receptors while cTBS is delivered and cortical excitability is measured with electroencephalography (EEG)-based TMS-evoked potentials (TEPs). Functional integration of synaptic changes measured by the dlPFC-dependent n-back neu- robehavioral task will be a secondary measure. This approach also overcomes the limitations of studying the healthy motor cortex which has un- known translatability to plasticity in the dlPFC and depressed brain. It also overcomes the rate-limiting step to optimizing therapeutic TMS-inhibition to quiet focal brain activity. Results will highlight the path forward to mechanism-guided pharmacologic augmentation for depression and other disorders such as epi- lepsy, addiction, anxiety, posttraumatic stress disorder, which require quieting of brain networks.