Yuichiro Shirota

Bidirectional long‐term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation

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.

Primary motor cortical metaplasticity induced by priming over the supplementary motor area

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.

Supplementary motor area stimulation for Parkinson disease A randomized controlled study

Objective: To explore the efficacy and stimulation frequency dependence of repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in Parkinson disease (PD). Methods: In this randomized, double-blind, sham-controlled, multicenter study with a parallel design, a weekly intervention was performed 8 times. The effects were monitored up to 20 weeks. By central registration, participants were assigned to 1 of 3 arms of the study: low-frequency (1-Hz) rTMS, high-frequency (10-Hz) rTMS, and realistic sham stimulation. The primary end point was the score change of the Unified Parkinsons Disease Rating Scale (UPDRS) part III from the baseline. Several nonmotor symptom scales such as the Hamilton Rating Scale for Depression, apathy score, and nonmotor symptoms questionnaire were defined as secondary end points. Results: Of the 106 patients enrolled, 36 were allocated to 1-Hz rTMS, 34 to 10-Hz rTMS, and 36 to realistic sham stimulation. Results show 6.84-point improvement of the UPDRS part III in the 1-Hz group at the last visit of the 20th week. Sham stimulation and 10-Hz rTMS improved motor symptoms transiently, but their effects disappeared in the observation period. Changes in nonmotor symptoms were not clear in any group. No severe adverse event was reported. Conclusions: The 1-Hz rTMS over the SMA was effective for motor, but not nonmotor, symptoms in PD. Level of evidence: This study provides Class I evidence that 1-Hz rTMS over the SMA is effective for motor symptoms in PD.

Quadri-pulse stimulation (QPS) induced LTP/LTD was not affected by Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene

It has been reported that the brain derived neurotrophic factor (BDNF) has some functional roles in inducing plasticity in the adult human brain and the Val66Met BDNF polymorphism affects the plasticity induction. In contrast, some long lasting effects were not fully induced in subjects with non-Val-Val polymorphism. In this communication, we retrospectively investigated whether this polymorphism affects the plastic changes induced by a newly developed stimulation method (quadripulse stimulation (QPS)) in 12 subjects. Both long-term potentiation (LTP) and long-term depression (LTD) like effects were induced by QPS for 30min in any types of BDNF Val66Met polymorphisms. This finding presents a striking contrast to the previous results, which showed reduced long-term effects elicited by some other induction methods in subjects with non-Val-Val polymorphism. Although we are not able to make a final conclusion about the effect of Val66Met BDNF polymorphism on QPS because of the small number of subjects studied, QPS may be less affected by the BDNF polymorphism than several other protocols for inducing LTP/LTD-like effects in humans. Several possibilities may explain this difference. One candidate possibility is that QPS may be long enough for inducing the late LTP/LTD like effect whereas the other stimulation methods may be long enough for early but not enough for late LTP/LTD like effect. It is conspicuous that the QPS for 30min does elicit stable bidirectional long-term effects even in subjects with non-Val-Val polymorphism of BDNF.

Origin of facilitation in repetitive, 1.5 ms interval, paired pulse transcranial magnetic stimulation (rPPS) of the human motor cortex

OBJECTIVE Repetitive paired-pulse TMS (rPPS) given at an interstimulus interval (ISI) of 1.5 ms has been reported to induce a lasting motor evoked potential (MEP) facilitation. This after-effect was considered to be a cortical event because F-waves were not affected by the same rPPS. To confirm its cortical facilitation, we compared the after-effects of rPPS on MEPs to single pulse TMS over the motor cortex (motor cortical MEPs) with those to brainstem stimulation (brainstem MEPs). METHODS Subjects were 10 healthy volunteers. Suprathreshold paired-pulse TMS at an ISI of 1.5 ms was applied to the motor cortex for 30 min at a rate of 0.2 Hz. After intervention, we measured motor cortical MEPs for 30 min. We also studied brainstem MEPs in five subjects. RESULTS Motor cortical MEPs were facilitated to about 190% of baseline (p<0.001) for 10 min post rPPS intervention and returned to the baseline at 10-15 min post intervention. Brainstem MEPs were not affected by the intervention. CONCLUSIONS The facilitation of MEPs after rPPS at an interval of 1.5 ms occurs at the motor cortex. SIGNIFICANCE rPPS at an interval of 1.5 ms is an effective method for increasing motor cortical excitability.

Effects of rTMS of Pre-Supplementary Motor Area on Fronto Basal Ganglia Network Activity during Stop-Signal Task

Stop-signal task (SST) has been a key paradigm for probing human brain mechanisms underlying response inhibition, and the inhibition observed in SST is now considered to largely depend on a fronto basal ganglia network consisting mainly of right inferior frontal cortex, pre-supplementary motor area (pre-SMA), and basal ganglia, including subthalamic nucleus, striatum (STR), and globus pallidus pars interna (GPi). However, causal relationships between these frontal regions and basal ganglia are not fully understood in humans. Here, we partly examined these causal links by measuring human fMRI activity during SST before and after excitatory/inhibitory repetitive transcranial magnetic stimulation (rTMS) of pre-SMA. We first confirmed that the behavioral performance of SST was improved by excitatory rTMS and impaired by inhibitory rTMS. Afterward, we found that these behavioral changes were well predicted by rTMS-induced modulation of brain activity in pre-SMA, STR, and GPi during SST. Moreover, by examining the effects of the rTMS on resting-state functional connectivity between these three regions, we showed that the magnetic stimulation of pre-SMA significantly affected intrinsic connectivity between pre-SMA and STR, and between STR and GPi. Furthermore, the magnitudes of changes in resting-state connectivity were also correlated with the behavioral changes seen in SST. These results suggest a causal relationship between pre-SMA and GPi via STR during response inhibition, and add direct evidence that the fronto basal ganglia network for response inhibition consists of multiple top-down regulation pathways in humans.

Bidirectional effects on interhemispheric resting‐state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation

Several recent studies using functional magnetic resonance imaging (fMRI) have shown that repetitive transcranial magnetic stimulation (rTMS) affects not only brain activity in stimulated regions but also resting‐state functional connectivity (RSFC) between the stimulated region and other remote regions. However, these studies have only demonstrated an effect of either excitatory or inhibitory rTMS on RSFC, and have not clearly shown the bidirectional effects of both types of rTMS. Here, we addressed this issue by performing excitatory and inhibitory quadripulse TMS (QPS), which is considered to exert relatively large and long‐lasting effects on cortical excitability. We found that excitatory rTMS (QPS with interstimulus intervals of 5 ms) decreased interhemispheric RSFC between bilateral primary motor cortices, whereas inhibitory rTMS (QPS with interstimulus intervals of 50 ms) increased interhemispheric RSFC. The magnitude of these effects on RSFC was significantly correlated with that of rTMS‐induced effects on motor evoked potential from the corresponding muscle. The bidirectional effects of QPS were also observed in the stimulation over prefrontal and parietal association areas. These findings provide evidence for the robust bidirectional effects of excitatory and inhibitory rTMSs on RSFC, and raise a possibility that QPS can be a powerful tool to modulate RSFC. Hum Brain Mapp 35:1896–1905, 2014.

Cerebellar dysfunction in progressive supranuclear palsy: A transcranial magnetic stimulation study†

Progressive supranuclear palsy (PSP) rarely shows cerebellar signs and symptoms even though the cerebellar dentate nuclei are involved pathologically. This study evaluates cerebellar function using transcranial magnetic stimulation (TMS) to determine whether subclinical cerebellar involvement is present in PSP patients. We studied 11 patients with PSP, 11 patients with Parkinsons disease (PD), and 10 age‐matched controls. Patients were examined with their usual medications and in their relative on state. Motor evoked potentials (MEPs) were recorded from the hand muscle. Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEPs elicited by TMS over the contralateral motor cortex, which we call cerebellar inhibition (CBI). Interstimulus intervals (ISIs) of 4 to 8 ms were used, and the time course of CBI was analyzed. The CBI was reduced in PSP patients. By contrast, the CBI was normal in PD patients in their on state. Although the CBI in their off state should be examined in future studies, the results described herein suggest that Purkinje cells or the dentato–thalamo–cortical pathway assessed by CBI is involved in PSP. Our results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients.

Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease.

On the basis of the hypothesis that copy number mutations of the genes encoding myelin compact proteins are responsible for myelin disorders in humans, we have explored the possibility of copy number mutations in patients with Charcot‐Marie‐Tooth disease (CMT) whose responsible genes remain undefined.

Influence of Short-Interval Intracortical Inhibition on Short-Interval Intracortical Facilitation in Human Primary Motor Cortex

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.