The after-effects of repetitive transcranial magnetic stimulation (rTMS) are highly variable between individuals. Because different populations of cortical neurons are stimulated more easily or are more excitable in different people at different times, the variability may not be due to differences between individuals in the plasticity of cortical synapses, but may instead be due to individual differences in the recruitment of cortical neurons. In this study, we examined the effects of rTMS in 56 healthy volunteers. The responses to excitatory and inhibitory theta burst stimulation (TBS) protocols were highly variable between individuals. Surprisingly, the TBS effect was highly correlated with the latency of motor-evoked potentials (MEPs) evoked by TMS pulses that induced an anterior-posterior (AP) directed current across the central sulcus. Finally, we devised a new plasticity protocol using closely timed pairs of oppositely directed TMS current pulses across the central sulcus. Again, the after-effects were related to the latency of MEPs evoked by AP current. Our results are consistent with the idea that variation in response to rTMS plasticity probing protocols is strongly influenced by which interneuron networks are recruited by the TMS pulse.

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Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought in some cases to reflect N -methyl-d-aspartate-sensitive changes in synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS-induced plasticity depends on the prior history of cortical activity, conforming to the Bienenstock-Cooper-Munro (BCM) theory. However, experiments exploring these plastic changes have only examined priming-induced effects on a limited number of rTMS protocols, often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this study was to introduce a new rTMS protocol that gives a broad range of after-effects from suppression to facilitation and then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability, as indexed by motor-evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated by interstimulus intervals of 1.5-1250 ms produced a range of after-effects that were compatible with changes in synaptic plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs for more than 75 min. Paired-pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on QPS-induced plasticity was consistent with a BCM-like model of priming that shifts the crossover point at which synaptic plasticity reverses from depression to potentiation. The broad range of after-effects produced by the new rTMS protocol opens up new possibilities for detailed examination of theories of metaplasticity in humans.

Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.

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Paired associative stimulation (PAS) is a method commonly used in human studies of motor cortex synaptic plasticity. It involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21–25 ms, corticospinal excitability is increased for the following 30–60 min via a long term potentiation (LTP)-like effect within the primary motor cortex. Previous work has shown that PAS depends on the present and previous levels of activity in cortex, and that it can be modified by motor learning or attention. Here we show that simultaneous transcranial direct current stimulation (TDCS; 2 mA) over the cerebellum can abolish the PAS effect entirely. Surprisingly, the effect is seen when the PAS interval is 25 ms but not when it is 21.5 ms. There are two implications from this work. First, the cerebellum influences PAS effects in motor cortex; second, LTP-like effects of PAS have at least two different mechanisms. The results are relevant for interpretation of pathological changes that have been reported in response to PAS in people with movement disorders and to changes in healthy individuals following exercise or other interventions.