LAUSR

While daily repetitive transcranial magnetic stimulation (rTMS) is FDA-approved to treat depression and obsessive-compulsive disorder, we are still unclear about its therapeutic mechanism of action. Better understanding of the fundamental mechanisms of rTMS-induced changes would likely refine and improve this therapy. Animal studies suggest that 10 Hz rTMS may work through long-term potentiation (LTP), a form of synaptic plasticity [1]. In humans, several studies have demonstrated that n-methyl-D-aspartate (NMDA) receptor activity, a critical step in the LTP pathway, is necessary [2,3], but not sufficient [4,5] for 0.1 Hz rTMS paired with ischemic nerve block (INB)and theta burst stimulation (TBS)induced motor plasticity. Surprisingly, there are no pharmacologic studies testing whether 10 Hz rTMS, as used clinically, depends on synaptic plasticity. We hypothesize that 10 Hz rTMS enhances motor excitability through NMDA receptor-dependent LTP of glutamatergic synapses, and that partial agonism of this pathway by Dcycloserine (DCS) is sufficient to further potentiate motor excitability in healthy humans. Consistent with our hypothesis, we observed that participants in this small crossover study appeared to have more cumulative potentiation after 10 Hz rTMS with DCS relative to placebo. We recruited ten healthy adults (6 men, 26e37 years old) into a randomized, double-blind, crossover study approved by the Medical University of South Carolina Institutional Review Board. All participants provided informed consent prior to any research procedures. We included healthy participants without TMS contraindications between the ages of 18 and 50. We randomly assigned participants to begin the crossover study with either 100 mg D-cycloserine (DCS, an NMDA receptor partial agonist) or identical microcrystalline cellulose capsules (Tidewater pharmacy, Mt. Pleasant, SC) in a blinded manner on separate visits. All 10 participants received both medications, half received active drug first. We administered the drug approximately 2 hours before rTMS as done previously [6]. We obtained baseline measurements of motor excitability after drug was administered in order to differentiate whether the drug affected basal excitability (baseline) as opposed to rTMS-induced plasticity (15e60 minutes after rTMS, Fig. 1A). Following baseline measurements, we administered 20 minutes of 10 Hz rTMS. We then remeasured motor excitability at 15 minute increments for 60 minutes.