Improvement of tactile perception and enhancement of cortical excitability through intermittent theta burst rTMS over human primary somatosensory cortex

Adopting the patterns of theta burst stimulation (TBS) used in brain-slice preparations, a novel and rapid method of conditioning the human brain has recently been introduced. Using short bursts of high-frequency (50 Hz) repetitive transcranial magnetic stimulation (rTMS) has been shown to induce lasting changes in brain physiology of the motor cortex. In the present study, we tested whether a few minutes of intermittent theta burst stimulation (iTBS) over left primary somatosensory cortex (SI) evokes excitability changes within the stimulated brain area and whether such changes are accompanied by changes in tactile discrimination behavior. As a measure of altered perception we assessed tactile discrimination thresholds on the right and left index fingers (d2) before and after iTBS. We found an improved discrimination performance on the right d2 that was present for at least 30 min after termination of iTBS. Similar improvements were found for the ring finger, while left d2 remained unaffected in all cases. As a control, iTBS over the tibialis anterior muscle representation within primary motor cortex had no effects on tactile discrimination. Recording somatosensory evoked potentials over left SI after median nerve stimulation revealed a reduction in paired-pulse inhibition after iTBS that was associated but not correlated with improved discrimination performance. No excitability changes could be found for SI contralateral to iTBS. Testing the performance of simple motor tasks revealed no alterations after iTBS was applied over left SI. Our results demonstrate that iTBS protocols resembling those used in slice preparations for the induction of long-term potentiation are also effective in driving lasting improvements of the perception of touch in human subjects together with an enhancement of cortical excitability. An erratum to this article can be found at     

Modulation of rodent cortical motor excitability by somatosensory input

It is assumed that somatosensory input is required for motor learning and recovery from focal brain injury. In rodents and other mammals, corticocortical projections between somatosensory and motor cortices are modified by patterned input. Whether and how motor cortex function is modulated by somatosensory input to support motor learning is largely unknown. Recent human evidence suggests that input changes motor excitability. Using transcranial magnetic stimulation (TMS), this study tested whether motor cortex excitability is affected by patterned somatosensory stimulation in rodents. Motor potentials evoked in gastrocnemius muscles in response to TMS (MEP(TMS)) and to cervical electrical stimulation (MEP(CES)) were recorded bilaterally. Initially, the first negative peak of the MEP(TMS) was identified as a cortical component because it disappeared after decortication in three animals. Subsequently, we studied the effects of 2 h of electrical stimulation of one sciatic nerve on the cortical component of the MEP(TMS), i.e., on motor cortex excitability. After stimulation, its amplitude increased by 117 +/- 45% ( P<0.01) in the stimulated limb. A significantly smaller effect was found in the unstimulated limb ( P<0.02) and no effect was observed in unstimulated control animals. The subcortically evoked MEP(CES) were not affected by stimulation. It is concluded that somatosensory input increases motor excitability in rat. This increase outlasts the stimulation period and is mediated by supraspinal structures, likely motor cortex. Modulation of motor cortex excitability by somatosensory input may play a role in motor learning and recovery from lesion.     

A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex

Synaptic plasticity is conspicuously dependent on the temporal order of the pre- and postsynaptic activity. Human motor cortical excitability can be increased by a paired associative stimulation (PAS) protocol. Here we show that it can also be decreased by minimally changing the interval between the two associative stimuli. Corticomotor excitability of the abductor pollicis brevis (APB) representation was tested before and after repetitively pairing of single right median nerve simulation with single pulse transcranial magnetic stimulation (TMS) delivered over the optimal site for activation of the contralateral APB. Following PAS, depression of TMS-evoked motor-evoked potentials (MEPs) was induced only when the median nerve stimulation preceded the TMS pulse by 10 ms, while enhancement of cortical excitability was induced using an interstimulus interval of 25 ms, suggesting an important role of the sequence of cortical events triggered by the two stimulation modalities. Experiments using F-wave studies and electrical brain stem stimulation indicated that the site of the plastic changes underlying the decrease of MEP amplitudes following PAS (10 ms) was within the motor cortex. MEP amplitudes remained depressed for approximately 90 min. The decrease of MEP amplitudes was blocked when PAS(10 ms) was performed under the influence of dextromethorphan, an N-methyl-d-aspartate-receptor antagonist, or nimodipine, an L-type voltage-gated calcium-channel antagonist. The physiological profile of the depression of human motor cortical excitability following PAS(10 ms) suggests long-term depression of synaptic efficacy to be involved. Together with earlier findings, this study suggests that strict temporal Hebbian rules govern the induction of long-term potentiation/long-term depression-like phenomena in vivo in the human primary motor cortex.     

Combined effect of motor imagery and peripheral nerve electrical stimulation on the motor cortex

Although motor imagery enhances the excitability of the corticospinal tract, there are no peripheral afferent inputs during motor imagery. In contrast, peripheral nerve electrical stimulation (ES) can induce peripheral afferent inputs; thus, a combination of motor imagery and ES may enhance the excitability of the corticospinal tract compared with motor imagery alone. Moreover, the level of stimulation intensity may also be related to the modulation of the excitability of the corticospinal tract during motor imagery. Here, we evaluated whether a combination of motor imagery and peripheral nerve ES influences the excitability of the corticospinal tract and measured the effect of ES intensity on the excitability induced during motor imagery. The imagined task was a movement that involved touching the thumb to the little finger, whereas ES involved simultaneous stimulation of the ulnar and median nerves at the wrist. Two different ES intensities were used, one above the motor threshold and another above the sensory threshold. Further, we evaluated whether actual movement with afferent input induced by ES modulates the excitability of the corticospinal tract as well as motor imagery. We found that a combination of motor imagery and ES enhanced the excitability of the motor cortex in the thenar muscle compared with the other condition. Furthermore, we established that the modulation of the corticospinal tract was related to ES intensity. However, we found that the excitability of the corticospinal tract induced by actual movement was enhanced by peripheral nerve ES above the sensory threshold.     

Modulation of synaptic zinc in barrel cortex by whisker stimulation

The cortical representation of the body surface is not fixed, but rather, is continuously modified by ongoing changes in sensory experience. Although the cellular and molecular mechanisms that subserve these changes are uncertain, increasing evidence suggests that synaptically-released zinc may play a role. Zinc is released from a subset of glutamatergic neurons and can modulate postsynaptic excitability by regulating the activation of glutamate and GABA receptor-gated ion channels. Previously, we have shown that whisker plucking, a manipulation commonly used to induce cortical map plasticity, results in a rapid and robust increase in staining levels for synaptic zinc in deprived regions of the barrel cortex. In the present study, we examined the effect of increased whisker activity, analogous to what may happen during tactile learning or exploratory behavior in a natural setting, on synaptic zinc levels in the adult barrel cortex. Our results indicate that stimulation of whiskers caused a selective decrease in zinc levels within layer 4 of the barrel hollow corresponding to the stimulated whisker. Quantitatively, levels of staining were significantly reduced at 3 h, and showed even greater reductions following 12 and 24 h of stimulation. However, these changes were not long-lasting, as levels of staining in the stimulated barrel returned to control values within 24 h after stimulation had ceased. These data indicate that zincergic circuits are highly sensitive to ongoing changes in sensory experience and may participate in moment-to-moment changes in the functional connectivity of the cerebral cortex.     

Induction of persistent changes in the organisation of the human motor cortex

Motor learning must involve changes in the organisation of the brain, and it seems axiomatic that afferent signals generated during repeated motor practice contribute to this. In this study, motor-point stimulation of the first dorsal interosseous (FDI) muscle was paired with transcranial magnetic stimulation of the human motor cortex on three successive days to determine whether repeated stimulation sessions result in enduring reorganisation of the motor cortex. This repeated "dual" stimulation induced significant changes in the excitability of the motor cortex together with expansion of the area of scalp from which these responses were elicited. The expansion in muscle representation was accompanied by large movements in the centre of gravity (CoG), suggesting a true reorganisation of the underlying cortical representational zone. The changes persisted for at least 2 days following the last stimulation session. It is concluded that repeated dual stimulation is capable of inducing long-lasting reorganisation within the motor cortex. These changes may be similar in nature to those seen in the motor cortex during motor learning. Moreover, these observations suggest that it may be possible to induce the motor cortex of patients who have suffered strokes to reorganise in a way that improves the voluntary control of the weakened muscles.     

Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex

The aim of the present study was to investigate whether muscarinic receptor blockade with scopolamine modifies the excitability of specific cortical networks of the human motor cortex as tested with transcranial magnetic stimulation. The effects of scopolamine on the excitability of human motor cortex were investigated in four healthy subjects using transcranial magnetic stimulation before and after an intravenous dose of scopolamine (0.006 mg/kg). We measured the threshold for motor responses, amplitude of motor responses, the duration of the cortical silent period, intracortical inhibition and facilitation, and short-latency inhibition produced by somatosensory input from the hand. In addition, we evaluated the amplitude of motor responses evoked by electrical anodal stimulation, since these responses originate from direct activation of corticospinal axons in the white matter and are not sensitive to changes in cortical excitability. Scopolamine decreased the threshold to magnetic stimuli and increased the amplitude of motor responses evoked by magnetic stimulation. In contrast, motor responses evoked by electrical stimulation were unaffected by administration of scopolamine. Scopolamine also led to a highly significant reduction in the amount of short-latency inhibition produced by somatosensory input from the hand. In contrast, short-latency intracortical inhibition and facilitation were not modified by scopolamine. The differential effect of scopolamine on motor responses evoked by magnetic and electrical stimulation of the motor cortex and the selective effect on somatosensory inhibition demonstrate that muscarinic blockade modifies the excitability of specific cortical networks in the human motor cortex.     

Online maintenance of sensory and motor representations: effects on corticospinal excitability

Flexible behavior requires the ability to delay a response until it is appropriate. This can be achieved by holding either a sensory or a motor representation online. Here we assess whether maintenance of sensory or motor material drives the motor system to different functional states, as indexed by alterations of corticospinal excitability. We used single-pulse TMS to measure corticospinal excitability evoked during the delay period of a novel paradigm in which task contingencies, rather than explicit verbal instructions, induced participants to use either sensory or motor codes to solve a delay-nonmatch-to-sample (DNMS) task. This approach allowed us to probe the state of the motor system while the participants were retaining either sensory or motor codes to cross the delay period, rather than the control of short-term storage driven by verbal instructions. When participants could prepare the movement in advance (preparation trials), the excitability of the motor cortex contralateral to the moving hand increased, whereas the excitability of the ipsilateral motor cortex decreased. The increase in excitability was confined to the prime mover, whereas the decrease in excitability extended to cortical territories controlling muscles unrelated to the response. Crucially, these changes in excitability were evoked only during preparation trials and not during trials in which subjects needed to maintain sensory items online (memory trials). We infer that short-term storage of sensory information and preparation of motor responses have differential and specific access to the output stage of the motor system.     

Manipulation of phosphene thresholds by transcranial direct current stimulation in man

Transcranial direct current stimulation (tDCS) can modulate the excitability of the human motor cortex, as revealed by the amplitude of the motor-evoked potentials (MEP). The aim of our study has been to produce localized changes of cerebral excitability of the visual cortex in the intact human by weak anodal and cathodal stimulation. For quantification of current-induced excitability changes, we measured phosphene threshold (PT) using short trains of 5-Hz transcranial magnetic stimulation (TMS) pulses in nine healthy subjects before, immediately after, 10 min, and 20 min after the end of tDCS. PTs are suggested as representative values of visual cortex excitability changes. Reduced PT was detected immediately and 10 min after the end of anodal stimulation, while cathodal stimulation resulted in an opposite effect. Our results show that tDCS elicits a transient, reversible excitability alteration of the visual cortex, thus representing a promising tool for neuroplasticity research. Electronic Publication     

Dynamical changes in corticospinal excitability during imagery of unimanual and bimanual wrist movements in humans: a transcranial magnetic stimulation study

This study explored the dynamical changes in corticospinal excitability during the imagination of cyclical unimanual and bimanual wrist flexion-extension movements. Transcranial magnetic stimulation was applied over the left motor cortex to evoke motor evoked potentials in the right wrist flexor and extensor muscles. Findings provided evidence for increased reciprocal excitability changes during imagery of symmetrical in-phase movements as compared to asymmetrical (anti-phase) or unimanual movements. This suggests that in-phase movements may reinforce whereas anti-phase movements may reduce the temporal representation of the task in the corticospinal motor networks of the brain.     

Transcranial direct current stimulation effects on I-wave activity in humans

Transcranial direct current stimulation (tDCS) of the human cerebral cortex modulates cortical excitability noninvasively in a polarity-specific manner: anodal tDCS leads to lasting facilitation and cathodal tDCS to inhibition of motor cortex excitability. To further elucidate the underlying physiological mechanisms, we recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation of the primary motor cortex before and after a 5-min period of anodal or cathodal tDCS in eight conscious patients who had electrodes implanted in the cervical epidural space for the control of pain. The effects of anodal tDCS were evaluated in six subjects and the effects of cathodal tDCS in five subjects. Three subjects were studied with both polarities. Anodal tDCS increased the excitability of cortical circuits generating I waves in the corticospinal system, including the earliest wave (I1 wave), whereas cathodal tDCS suppressed later I waves. The motor evoked potential (MEP) amplitude changes immediately following tDCS periods were in agreement with the effects produced on intracortical circuitry. The results deliver additional evidence that tDCS changes the excitability of cortical neurons.     

Role of sustained excitability of the leg motor cortex after transcranial magnetic stimulation in associative plasticity

Changes in the strength of corticospinal projections to muscles in the upper and lower limbs are induced in conscious humans after paired associative stimulation (PAS) to the motor cortex. We tested whether an intervention of PAS consisting of 90 low-frequency (0.1-Hz) stimuli to the common peroneal nerve combined with suprathreshold transcranial magnetic stimulation (TMS) produces specific changes to the motor-evoked potentials (MEPs) in lower leg muscles if the afferent volley from peripheral stimulation is timed to arrive at the motor cortex after TMS-induced firing of corticospinal neurons. Unlike PAS in the hand, MEP facilitation in the leg was produced when sensory inputs were estimated to arrive at the motor cortex over a range of 15 to 90 ms after cortical stimulation. We examined whether this broad range of facilitation occurred as a result of prolonged subthreshold excitability of the motor cortex after a single pulse of suprathreshold TMS so that coincident excitation from sensory inputs arriving many milliseconds after TMS can occur. We found that significant facilitation of MEP responses (>200%) occurred when the motor cortex was conditioned with suprathreshold TMS tens of milliseconds earlier. Likewise, it was possible to induce strong MEP facilitation (85% at 60 min) when afferent inputs were directly paired with subthreshold TMS. We argue that in the leg motor cortex, facilitation of MEP responses from PAS occurred over a large range of interstimulus intervals as a result of the paired activation of sensory inputs with sustained, subthreshold activity of cortical neurons that follow a pulse of suprathreshold TMS.     

Experiments on functional role of peripheral input to motor cortex during voluntary movements in the monkey

The functional role of sensory input to the motor cortex was studied by interrupting two major input pathways. One was the dorsal column, which sends the input directly through the thalamus to the motor cortex, and the other was the sensory cortex, which transfers its input through association fibers. Removal of the sensory cortex produced very little motor disturbances and the function recovered within a week. Section of the dorsal column produced some motor deficit, but the deficit was not severe and the animals recovered nearly completely within 2 wk. Combination of dorsal column section and sensory cortex removal produced severe motor deficits. These consisted of loss of orientation within extrapersonal space and loss of dexterity of individual fingers. These deficits never recovered within the duration of observation, which lasted 4-5 wk. It is concluded that the direct sensory input from the thalamus plays an important role in the control of voluntary movements, but loss of its function can be compensated by the input from the sensory cortex. The possible neuronal basis for the observed motor deficits is discussed and it is proposed that the sensory input functions by selectively changing the excitability of cortical efferent zones before and during the execution of voluntary movements. Recovery of motor function following dorsal column section occurred in parallel with the recovery of sensory input to the motor cortex. The recovered function and sensory input disappeared again following section of the association fibers from the sensory cortex. Neuronal mechanism for this observation is also discussed.     

Long-lasting modulation of human motor cortex following prolonged transcutaneous electrical nerve stimulation (TENS) of forearm muscles: evidence of reciprocal inhibition and facilitation

Several lines of evidence indicate that motor cortex excitability can be modulated by manipulation of afferent inputs, like peripheral electrical stimulation. Most studies in humans mainly dealt with the effects of prolonged low-frequency peripheral nerve stimulation on motor cortical excitability, despite its being known from animal studies that high-frequency stimulation can also result in changes of the cortical excitability. To investigate the possible effects of high-frequency peripheral stimulation on motor cortical excitability we recorded motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) of the left motor cortex from the right flexor carpi radialis (FCR), extensor carpi radialis (ECR), and first dorsal interosseous (FDI) in normal subjects, before and after transcutaneous electrical nerve stimulation (TENS) of 30 min duration applied over the FCR. The amplitude of MEPs from the FRC was significantly reduced from 10 to 35 min after TENS while the amplitude of MEPs from ECR was increased. No effects were observed in the FDI muscle. Indices of peripheral nerve (M-wave) and spinal cord excitability (H waves) did not change throughout the experiment. Electrical stimulation of the lateral antebrachial cutaneous nerve has no significant effect on motor cortex excitability. These findings suggest that TENS of forearm muscles can induce transient reciprocal inhibitory and facilitatory changes in corticomotoneuronal excitability of forearm flexor and extensor muscles lasting several minutes. These changes probably may occur at cortical site and seem to be mainly dependent on stimulation of muscle afferents. These findings might eventually lead to practical applications in rehabilitation, especially in those syndromes in which the excitatory and inhibitory balance between agonist and antagonist is severely impaired, such as spasticity and dystonia.M. Tinazzi and S. Zarattini contributed equally to the work     

Modulating neural networks with transcranial magnetic stimulation applied over the dorsal premotor and primary motor cortices

Our study uses the combined transcranial magnetic stimulation/positron emission tomography (TMS/PET) method for elucidating neural connectivity of the human motor system. We first altered motor excitability by applying low-frequency repetitive TMS over two cortical motor regions in separate experiments: the dorsal premotor and primary motor cortices. We then assessed the consequences of modulating motor excitability by applying single-pulse TMS over the primary motor cortex and measuring: 1) muscle responses with electromyography and 2) cerebral blood flow with PET. Low-frequency repetitive stimulation reduced muscle responses to a similar degree in both experiments. To map networks of brain regions in which activity changes reflected modulation of motor excitability, we generated t-statistical maps of correlations between reductions in muscle response and differences in cerebral blood flow. Low-frequency repetitive stimulation altered neural activity differently in both experiments. Neural modulation occurred in multiple brain regions after dorsal premotor cortex stimulation; these included motor regions in the frontal cortex as well as more associational regions in the parietal and prefrontal cortices. In contrast, neural modulation occurred in a smaller number of brain regions after primary motor cortex stimulation, many of these confined to the motor system. These findings are consistent with the known differences between the dorsal premotor and primary motor cortices in the extent of cortico-cortical anatomical connectivity in the monkey.     

Identification of the central vestibular projections in man: a positron emission tomography activation study

The cerebral representation of space depends on the integration of many different sensory inputs. The vestibular system provides one such input and its dysfunction can cause profound spatial disorientation. Using positron emission tomography (PET), we measured regional cerebral perfusion with various vestibular stimulations to map central vestibular projections and to investigate the cerebral basis of spatial disorientation. We showed that the temporoparietal cortex, the insula, the putamen, and the anterior cingulate cortex are the cerebral projections of the vestibular system in man and that the spatial disorientation caused by unilateral vestibular stimulation is associated with their asymmetric activation.     

Modulation of motor cortex excitability by median nerve and digit stimulation

We investigated the time course of changes in motor cortex excitability after median nerve and digit stimulation. Although previous studies showed periods of increased and decreased corticospinal excitability following nerve stimulation, changes in cortical excitability beyond 200 ms after peripheral nerve stimulation have not been reported. Magnetoencephalographic studies have shown an increase in the 20-Hz rolandic rhythm from 200 to 1000 ms after median nerve stimulation. We tested the hypothesis that this increase is associated with reduced motor cortex excitability. The right or left median nerve was stimulated and transcranial magnetic stimulation (TMS) was applied to left motor cortex at different conditioning-test (C-T) intervals. Motor-evoked potentials (MEPs) were recorded from the right abductor pollicis brevis (APB), first dorsal interosseous (FDI), and extensor carpi radialis (ECR) muscles. Right median nerve stimulation reduced test MEP amplitude at C-T intervals from 400 to 1000 ms for APB, at C-T intervals from 200 to 1000 ms for FDI, and at C-T intervals of 200 and 600 ms for ECR, but had no effect on FDI F-wave amplitude at a C-T interval of 200 ms. Left median nerve (ipsilateral to TMS) stimulation resulted in less inhibition than right median nerve stimulation, but test MEP amplitude was significantly reduced at a C-T interval of 200 ms for all three muscles. Digit stimulation also reduced test MEP amplitude at C-T intervals of 200–600 ms. The time course for decreased motor cortex excitability following median nerve stimulation corresponds well to rebound of the 20-Hz cortical rhythm and supports the hypothesis that this increased power represents cortical deactivation. Received: 11 December 1998 / Accepted: 30 April 1999     

Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex

Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input–output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short- and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input–output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.     

Changes in spinal excitability after PAS

Repetitive pairing of a peripheral stimulation with a magnetic transcortical stimulation (PAS) is widely used to induce plastic changes in the human motor cortex noninvasively. Based on the contrast between PAS-induced increase of corticospinal excitability and absence of PAS-induced increase of the spinal F wave size, it has been generally accepted that PAS-induced plasticity is cortical in origin. Here, instead of F waves, we used H reflex recruitment curves to assess spinal excitability, and we demonstrate that PAS induces parallel changes in cortical and spinal excitability.