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Background: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity. Methods: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations. Results: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-D-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMSinduced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression. Limitations: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs. Conclusion: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease., Introduction Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation technique that induces electrical currents in underlying brain parenchyma through electromagnetic induction. (1) It is one of the most established noninvasive [...]

Background: Caffeine is a widely used psychostimulant. In the brain, caffeine acts as a competitive, non-selective adenosine receptor antagonist of A1 and A2A, both known to modulate long-term potentiation (LTP), the cellular basis of learning and memory. Repetitive transcranial magnetic stimulation (rTMS) is theorized to work through LTP induction and can modulate cortical excitability as measured by motor evoked potentials (MEPs). The acute effects of single caffeine doses diminish rTMS-induced corticomotor plasticity. However, plasticity in chronic daily caffeine users has not been examined., Method: We conducted a post hoc secondary covariate analysis from two previously published plasticity-inducing pharmaco-rTMS studies combining 10 Hz rTMS and D-cycloserine (DCS) in twenty healthy subjects., Results: In this hypothesis-generating pilot study, we observed enhanced MEP facilitation in non-caffeine users compared to caffeine users and placebo., Conclusion: These preliminary data highlight a need to directly test the effects of caffeine in prospective well-powered studies, because in theory, they suggest that chronic caffeine use could limit learning or plasticity, including rTMS effectiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vigne, Kweon, Sharma, Greenberg, Carpenter and Brown.)