It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.

We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.

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Retention of motor learning can be enhanced or degraded by subsequent performance of a different task. Neurophysiologically this may reflect interference in synaptic plasticity by ongoing neural activity in the brain. Here we demonstrate that N-methyl-D-aspartate (NMDA) dependent aftereffects of repetitive transcranial magnetic stimulation (rTMS) also are subject to interference effects, suggesting that it may be possible to investigate these basic mechanisms in the intact human brain. We measured the motor-evoked potential (MEP) amplitude and short-interval intracortical inhibition (SICI) in the first dorsal interosseous (FDI) muscle after continuous or intermittent theta burst (cTBS/iTBS) forms of rTMS. In resting subjects, cTBS depressed MEPs and reduced SICI for about 20 min, whereas iTBS had the opposite effect. However, if subjects contracted the FDI during TBS, then effects on the MEP were abolished, although effects of cTBS on SICI remained. Contraction immediately after TBS enhanced the facilitatory effect of iTBS and reversed the usual inhibitory effect of cTBS into facilitation. Contraction 10 min after cTBS (iTBS not tested) had only a transient (3-4 min) effect on MEPs. These interactions with behavior may relate to mechanisms of interference between learning paradigms in human and be similar to effects on synaptic long-term potentiation/depression described in animal experiments.

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.

We used transcranial magnetic stimulation (TMS) in a paired pulse protocol to investigate interhemispheric interactions between the right dorsal premotor (dPM) and left primary motor cortex (M1) using interstimulus intervals of 4, 6, 8, 10, 12, 16 and 20 ms in ten healthy subjects. A conditioning stimulus over right dPM at an intensity of either 90 or 110% resting motor threshold (RMT) suppressed motor-evoked potentials (MEPs) evoked in the first dorsal interosseous (FDI) muscle by stimulation of left M1. Maximum effects occurred for interstimulus intervals (ISIs) of 8-10 ms. There was no effect if the conditioning stimulus was applied 2.5 cm lateral, anterior or medial to dPM. The effect differed from previously described M1 interhemispheric inhibition in that the threshold for the latter was greater than 90% RMT, whereas stimulation of the dPM at the same intensity led to significant inhibition. In addition, voluntary contraction of the left FDI (i.e. contralateral to the conditioning TMS) enhanced interhemispheric inhibition from right M1 but had no effect on the inhibition from right dPM. Finally, conditioning to right dPM at 90% RMT reduced short-interval intracortical inhibition (SICI; at ISI = 2 ms) in left M1 whilst there was no effect if the conditioning stimulus was applied to right M1. We conclude that conditioning TMS over dPM has effects that differ from the previous pattern of interhemispheric inhibition described between bilateral M1s. This may reflect the existence of commissural fibres between dPM and contralateral M1 that may play a role in bimanual coordination.

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