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.

The Tower of London task in children and adolescents with neuropsychiatric disorders.

The Tower of London, Drexel Version, Second Edition (TOL-DX) is purported to measure multiple aspects of executive functions, although it also possesses inherent non-executive demands. Such complexity makes it useful in detecting impairment but difficult in interpreting the neurocognitive cause of impairment, particularly in children. This study investigated the developmental, neurocognitive, and symptom correlates of the TOL-DX in children and adolescents with neuropsychiatric disorders. Two-hundred and thirty-three children and adolescents (7-21 years old) completed the TOL-DX during a neuropsychological evaluation as part of clinical care within a children's psychiatric hospital. Pearson correlation, regression models, and receiver operating characteristic curve (ROC) analyses examined the association among variables. Visuospatial and executive functions (EF) were most consistently related to total moves, execution time, and violations. TOL-DX variables were associated with attention in younger participants and EF in older participants. No TOL-DX scores were related to parent-reported symptoms. The TOL-DX possesses inherent visuospatial and attention/executive demands in children and adolescents which are difficult to differentiate, differ by age group, and not associated to clinical symptoms. Taken together, the TOL-DX is complex to interpret, but psychometrically sound and sensitive to neurocognitive impairment in children and adolescents with transdiagnostic neuropsychiatric disorders.

Frontoparietal beta event characteristics are associated with early life stress and psychiatric symptoms in adults.

Recent work has found that the presence of transient, oscillatory burst-like events, particularly within the beta band (15-29 Hz), is more closely tied to disease state and behavior across species than traditional electroencephalography (EEG) power metrics. This study sought to examine whether features of beta events over frontoparietal electrodes were associated with early life stress (ELS) and the related clinical presentation. Eighteen adults with documented ELS (n = 18; ELS + ) and eighteen adults without documented ELS (n = 18; ELS-) completed eyes-closed resting state EEG as part of their participation in a larger childhood stress study. The rate, power, duration, and frequency span of transient oscillatory events were calculated within the beta band at five frontoparietal electrodes. ELS variables were positively associated with beta event rate at Fp2 and beta event duration at Pz, in that greater ELS was associated with higher resting rates and longer durations. These beta event characteristics were used to successfully distinguish between ELS + and ELS- groups. In an independent clinical dataset (n = 25), beta event power at Pz was positively correlated with ELS. Beta events deserve ongoing investigation as a potential disease marker of ELS and subsequent psychiatric treatment outcomes.

Pre-treatment frontal beta events are associated with executive dysfunction improvement after repetitive transcranial magnetic stimulation for depression: A preliminary report.

Repetitive transcranial magnetic stimulation (rTMS) is an established clinical treatment for major depressive disorder (MDD) that has also been found to improve aspects of executive functioning. The objective of this study was to examine whether oscillatory burst-like events within the beta band (15-29 Hz) prior to treatment could predict subsequent change in self-reported executive dysfunction (EDF) across a clinical course of rTMS for MDD. Twenty-eight adults (64% female) with MDD completed the self-report Frontal Systems Behavior Scale (FrSBe) and provided eyes-closed resting-state electroencephalography (EEG) before and after a clinical course of rTMS therapy for primary MDD. The rate, power, duration, and frequency span of transient EEG measured oscillatory beta events were calculated. Events within delta/theta and alpha bands were examined to assess for beta specificity. After controlling for improvement in primary depressive symptoms, a lower rate of beta events at F3, Fz, F4, and Cz prior to rTMS treatment was associated with a larger improvement in EDF after rTMS treatment. In addition, a decrease in beta event rate at Fz pre-to-post treatment was associated with a larger improvement in EDF after treatment. Results were largely specific to the beta band. In this study, the rate of frontrocentral beta events prior to treatment significantly predicted the likelihood of subsequent improvement in EDF symptoms following a clinical course of rTMS for MDD. These preliminary findings suggest the potential utility of EEG measured beta events and rTMS for targeting EDF across an array of neuropsychiatric disorders.

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.