Comparing synaptic mechanisms of iTBS and 10-Hz rTMS corticomotor plasticity.

Introduction: Intermittent theta burst stimulation (iTBS) and 10-Hz repetitive transcranial magnetic stimulation (rTMS) appear clinically equivalent for the treatment of depression, but whether they share the same mechanism of action at the synaptic level is unknown. Methods: In this randomized, double-blind, placebo-controlled, eight-arm crossover study, we directly compared the influence of N-methyl-D-aspartate receptor (NMDAR) and gamma-aminobutyric acid receptor (GABAR) activity on iTBS and 10-Hz rTMS induced corticomotor plasticity in six healthy subjects using both permutation analysis and a linear mixed model with repeated measures of motor-evoked potentials (MEPs). Results: iTBS and 10-Hz produced nearly identical corticomotor plasticity in the placebo condition (p = 1.0), consistent with clinical equivalency. However, 10-Hz rTMS benefitted from NMDAR agonism with d-cycloserine (DCS) more than iTBS (β = 0.516, p < 0.001), which was partially attenuated by adding NMDAR antagonist dextromethorphan (DXM) to DCS. To test whether GABAR removal contributes to enhanced MEP excitability, as suggested by animal studies with 10-Hz, we reasoned that inhibition induced by GABAR agonism via lorazepam (LZP) would be less than at baseline, after GABAR removal by TMS. Instead, we found that neither protocol increased MEPs, but rather, MEPs were reduced in both protocols immediately (β = -0.172, p = 0.027) and 30 min after TMS (β = -0.183, p = 0.019). Discussion: Our exploratory pilot study is preliminary and requires replication to make any conclusions. Nevertheless, it is the first to compare the synaptic-level mechanisms of iTBS and 10-Hz rTMS, suggesting both iTBS and 10-Hz act predominantly through NMDAR-dependent LTP-like mechanisms rather than GABAergic mechanisms. The differential effects between protocols (i.e., 10-Hz produced more facilitation with DCS and more inhibition with LZP) could be accounted for by iTBS producing occlusion with DCS and compensatory facilitation with LZP, but this is speculative and requires preclinical work to confirm.