NMDA and GABA Receptor-Mediated Plasticity Induced by 10-Hz Repetitive Transcranial Magnetic Stimulation.

Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we have yet to fully understand the mechanism through which rTMS induces therapeutic and durable changes in the brain. Two competing theories have emerged suggesting that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), or alternatively, removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in healthy subjects. We tested motor-evoked potentials (MEPs) before and after 10-Hz rTMS in the presence of four drugs separated by 1-week each: placebo, NMDAR partial agonist d-cycloserine (DCS 100mg), DCS 100mg + NMDAR partial antagonist dextromethorphan (DMO 150mg; designed to "knock down" DCS-mediated facilitation), and GABAR agonist lorazepam (LZP 2.5mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability more than placebo. This enhancement was blocked by combining DCS with NMDAR antagonist, DMO. If GABARs are removed by rTMS, GABAR agonism via LZP should lack its inhibitory effect yielding higher post/pre MEPs. However, MEPs were reduced after rTMS indicating stability of GABAR numbers. These data suggest that 10-Hz rTMS facilitation in the healthy motor cortex may enact change in the brain through NMDAR-mediated LTP-like mechanisms rather than through GABAergic reduction.

Critically Assessing the Unanswered Questions of How, Where, and When to Induce Plasticity in the Posttraumatic Stress Disorder Network with Transcranial Magnetic Stimulation.

Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in post-traumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation (LTP) of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (rTMS) is thought to work through LTP-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. Our recent failed randomized controlled trial (1) emphasizes the necessity of correctly identifying cortical targets, directionality of TMS protocol, and role of memory activation. Here we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature searching for rTMS clinical trials involving PTSD patients and outcomes. We searched MEDLINE through October 25th, 2023 for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k=17 randomized controlled trials (RCTs), k=14 open label). RCT protocols were varied in TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority across protocols of low-frequency (k=5) vs. high-frequency protocols (k=6), or by stimulation location. Memory provocation or exposure protocols (k=7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.

Practice makes plasticity: 10-Hz rTMS enhances LTP-like plasticity in musicians and athletes.

Motor skill learning has been linked to functional and structural changes in the brain. Musicians and athletes undergo intensive motor training through the practice of an instrument or sport and have demonstrated use-dependent plasticity that may be subserved by long-term potentiation (LTP) processes. We know less, however, about whether the brains of musicians and athletes respond to plasticity-inducing interventions, such as repetitive transcranial magnetic stimulation (rTMS), differently than those without extensive motor training. In a pharmaco-rTMS study, we evaluated motor cortex excitability before and after an rTMS protocol in combination with oral administration of D-cycloserine (DCS) or placebo. In a secondary covariate analysis, we compared results between self-identified musicians and athletes (M&As) and non-musicians and athletes (non-M&As). Three TMS measures of cortical physiology were used to evaluate plasticity. We found that M&As did not have higher baseline corticomotor excitability. However, a plasticity-inducing protocol (10-Hz rTMS in combination with DCS) strongly facilitated motor-evoked potentials (MEPs) in M&As, but only weakly in non-M&As. Placebo and rTMS produced modest facilitation in both groups. Our findings suggest that motor practice and learning create a neuronal environment more responsive to plasticity-inducing events, including rTMS. These findings may explain one factor contributing to the high inter-individual variability found with MEP data. Greater capacity for plasticity holds implications for learning paradigms, such as psychotherapy and rehabilitation, by facilitating LTP-like activation of key networks, including recovery from neurological/mental disorders.

Chronic caffeine consumption curbs rTMS-induced plasticity.

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.