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.

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS-induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor-related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico-cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS-induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor-evoked potential sizes on its own but specifically modulated the excitatory I-wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.

No abstract

Using the paired-pulse paradigm, transcranial magnetic stimulation (TMS) has revealed much about the human primary motor cortex (M1). A preceding subthreshold conditioning stimulus (CS) inhibits the excitability of the motor cortex, which is named short-interval intracortical inhibition (SICI). In contrast, facilitation is observed when the first pulse (S1) is followed by a second one at threshold (S2), named short-interval intracortical facilitation (SICF). SICI and SICF have been considered to be mediated by different neural circuits within M1, but more recent studies reported relations between them. In this study, we performed triple-pulse stimulation consisting of CS-S1-S2 to further explore putative interactions between these two effects. Three intensities of CS (80-120% of active motor threshold: AMT) and two intensities of S2 (120 and 140% AMT) were combined. The SICF in the paired-pulse paradigm exhibited clear facilitatory peaks at ISIs of 1.5 and 3 ms. The second peak at 3 ms was significantly suppressed by triple-pulse stimulation using 120% AMT CS, although the first peak was almost unaffected. Our present results obtained using triple-pulse stimulation suggest that each peak of SICF is differently modulated by different intensities of CS. The suppression of the second peak might be ascribed to the findings in the paired-pulse paradigm that CS mediates SICI by inhibiting later I waves such as I3 waves and that the second peak of SICF is most probably related to I3 waves. We propose that CS might inhibit the second peak of SICF at the interneurons responsible for I3 waves.

Postural tremor is a common initial symptom in spinal and bulbar muscular atrophy (SBMA), but its pathophysiological mechanisms remain to be studied. This study was undertaken to examine the physiological mechanisms underlying postural tremor in SBMA. For eight patients (36-63 years old) with genetically confirmed SBMA, we recorded surface electromyograms (EMGs) from the forearm muscles and hand movements with an accelerometer (ACC) while maintaining a posture with and without a weight load. We then analyzed their power spectra and coherence. The peak tremor frequency was 6-9 Hz in seven patients and 2-3 Hz in one patient. Oscillatory movements were associated with EMG activity in five patients, but not in three patients. Weight loads and postural changes affected the tremor frequency in all patients. Tremor was classified as "reflex tremor" in five patients and "mechanical tremor" in three patients. These results suggest that peripheral factors play important roles in tremor genesis in SBMA, although its clinical features resemble essential tremor. Subclinical sensory disturbance or a decrease of motor unit numbers might be candidates for such peripheral factors contributing to tremor genesis in SBMA.

Using near-infrared spectroscopy (NIRS) and multichannel probes, we studied hemoglobin (Hb) concentration changes when single-pulse transcranial magnetic stimulation (TMS) was applied over the left hemisphere primary motor cortex (M1). Seventeen measurement probes were centered over left M1. Subjects were studied in both active and relaxed conditions, with TMS intensity set at 100%, 120%, and 140% of the active motor threshold. The magnetic coils were placed so as to induce anteromedially directed currents in the brain. Hb concentration changes were more prominent at channels over M1 and posterior to it. Importantly, Hb concentration changes at M1 after TMS differed depending on whether the target muscle was in an active or relaxed condition. In the relaxed condition, Hb concentration increased up to 3-6 s after TMS, peaking at ∼6 s, and returned to the baseline. In the active condition, a smaller increase in Hb concentrations continued up to 3-6 s after TMS (early activation), followed by a decrease in Hb concentration from 9 to 12 s after TMS (delayed deactivation). Hb concentration changes in the active condition at higher stimulus intensities were more pronounced at locations posterior to M1 than at M1. We conclude that early activation occurs when M1 is activated transsynaptically. The relatively late deactivation may result from the prolonged inhibition of the cerebral cortex after activation. The posterior-dominant activation at higher intensities in the active condition may result from an additional activation of the sensory cortex due to afferent inputs from muscle contraction evoked by the TMS.

No abstract

The aim of this study was to investigate physiological mechanisms underlying ataxia in patients with ataxic hemiparesis. Subjects were three patients with ataxic hemiparesis, whose responsible lesion was located at the posterior limb of internal capsule (case 1), thalamus (case 2), or pre- and post-central gyri (case 3). Paired-pulse transcranial magnetic stimulation (TMS) technique was used to evaluate connectivity between the cerebellum and contralateral motor cortex. The conditioning cerebellar stimulus was given over the cerebellum and the test stimulus over the primary motor cortex. We studied how the conditioning stimulus modulated motor evoked potentials (MEPs) to the cortical test stimulus. In non-ataxic limbs, the cerebellar stimulus normally suppressed cortical MEPs. In ataxic limbs, the cerebellar inhibition was not elicited in patients with a lesion at the posterior limb of internal capsule (case 1) or thalamus (case 2). In contrast, normal cerebellar inhibition was elicited in the ataxic limb in a patient with a lesion at sensori-motor cortex (case 3). Lesions at the internal capsule and thalamus involved the cerebello-thalamo-cortical pathways and reduced the cerebellar suppression effect. On the other hand, a lesion at the pre- and post-central gyri should affect cortico-pontine pathway but not involve the cerebello-thalamo-cortical pathways. This lack of cerebello-talamo-cortical pathway involvement may explain normal suppression in this patient. The cerebellar TMS method can differentiate cerebellar efferent ataxic hemiparesis from cerebellar afferent ataxic hemiparesis.