Abnormal responses to repetitive transcranial magnetic stimulation in multiple system atrophy.

We studied the response of the motor cortex to brief trains of suprathreshold repetitive transcranial magnetic stimulations (rTMS) in patients with the Parkinson-variant of multiple system atrophy (MSA-P) and compared it to patients with idiopathic Parkinson's disease (PD) and healthy controls. Eight subjects were studied in each group, and patients were matched for disease severity as assessed by Hoehn & Yahr stages. rTMS was delivered at rest and during low-level contractions in trains of 10 stimulations at 5 Hz, and stimulation intensity was set to result in an motor evoked potential (MEP) in the first dorsal interosseus muscle of 0.5 to 1.0 mV. In MSA-P, MEP amplitude at rest was already reduced after the second stimulus and remained so, while it did not change in PD and controls. During contraction, MEP size did not change during the train in any group. The silent period that followed the last stimulus was of similar duration as the first stimulus in MSA-P, but was increased in PD and controls. These findings indicate that abnormal inhibition occurs within the motor cortex in MSA-P, despite dopaminergic treatment and indicate differences in cortical dysfunction between MSA-P and PD. We suggest that these abnormalities reflect the motor cortex pathology found in MSA-P.     

Role of intracortical mechanisms in the late part of the silent period to transcranial stimulation of the human motor cortex

Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the human motor cortex produce a silent period (SP) following motor evoked potentials (MEPs). The early part of the SP can be explained by decreased alpha motor neuron excitability, whereas the late part is presumably due to suprasegmental mechanisms. In order to determine the level of the suprasegmental contribution to the generation of SPs, we recorded excitatory and inhibitory responses to TMS, TES, and percutaneous electrical brainstem stimulation (PBS) in the voluntarily activated first dorsal interosseous muscle of the hand. Stimulus intensities were set so that PBS and TES induced MEPs with areas equal to or larger than those of MEPs obtained with TMS. This procedure revealed that SPs were 49% and 83% shorter with TES and PBS, respectively, than with TMS. As TMS is more effective than TES or PBS in activating cortical interneurons, these findings support the idea that a significant component of the SP arises from intracortical mechanisms.     

Covariation of corticospinal efficiency and silent period in motoneuron diseases

For a better understanding of the changes affecting the cortically induced silent period (SP) in motoneuron disease, the excitatory and inhibitory effects of transcranial magnetic stimulation were explored repeatedly in 8 patients with amyotrophic lateral sclerosis (ALS), 3 patients with Kennedy's disease (KD), and 10 healthy subjects. In KD, the background electromyogram (EMG) and the motor evoked potential (MEP) area were both enhanced. However, neither the corticospinal efficiency (MEP gain, the ratio between MEP and background EMG) nor the duration of the SP differed from healthy subjects. In ALS patients, the MEP gain and the SP duration decreased conspicuously with time. We conclude that use of the MEP gain improves detection of corticospinal dysfunction in ALS patients. Part of the SP shortening in ALS seems to reflect the reduced activation of cortical or spinal inhibitory networks by the abnormal corticospinal pathway.     

Excitability Profile of Motor Evoked Potentials and Silent Periods

The aim of this study was to confirm the excitability profile of human cortical circuits on the motor evoked potential (MEP) and the silent period (SP) after paired transcranial magnetic stimulation (TMS) with variable interstimulus intervals (ISI), and to compare the time courses of MEP and SP after paired TMS at variable ISIs. MEPs were elicited at the hypothenar muscles at rest, and during tonic muscle contraction by applying paired TMS to the motor cortex. The authors measured the MEP amplitude during rest and the duration of SP during tonic muscle contraction at various ISIs. The response to paired stimuli was inhibited by an ISI of 1–5 ms and facilitated by an ISI of 10–20 ms. The SP at an ISI of 1–5 ms was shorter than that at the single suprathreshold stimulus, but the SP at an ISI of 15–25 ms was longer than this. A significant correlation was observed between the MEP amplitude and the duration of SP at ISIs of 1–20 ms and for a CS of 80% of threshold. These results may provide useful data for the study of the function of cortical excitability in disease states and suggest that the neural circuits underlying MEP and SP differ partly.     

Automated-parameterization of the motor evoked potential and cortical silent period induced by transcranial magnetic stimulation

ObjectiveTo standardize the characterization of motor evoked potential (MEP) and cortical silent period (CSP) recordings elicited with transcranial magnetic stimulation (TMS).MethodsA computer-based, automated-parameterization program (APP) was developed and tested which provides a comprehensive set of electromyography (EMG) magnitude and temporal measures. The APP was tested using MEP, CSP, and isolated CSP (iCSP) TMS stimulus–response data from a healthy adult population (N = 13).ResultsThe APP had the highest internal reliability (Cronbach’s alpha = .98) for CSP offset time compared with two prominent automated methods. The immediate post-CSP EMG recovery level was 49% higher than the pre-TMS EMG level. MEP size (peak amplitude, mean amplitude, peak-to-peak amplitude, and area) correlated higher with effective E-field (E_eff) than other intensity measures (r ≈ 0.5 vs. r ≈ 0.3) suggesting that E_eff is better suited for standardizing MEP stimulus–response relationships.ConclusionsThe APP successfully characterized individual and mean epochs containing MEP, CSP, and iCSP responses. The APP provided common signal and temporal measures consistent with previous studies and novel additional parameters.SignificanceWith the use of the APP modeling method and the E_eff, a standard approach for the analysis and reporting of MEP–CSP complex and iCSP measurements is achievable.     

The cortical silent period and amyotrophic lateral sclerosis

The cortical silent period (C-SP) was elicited by transcranial magnetic stimulation in 25 normal subjects and 19 patients with amyotrophic lateral sclerosis (ALS). The inhibitory (S-X) period was highly stimulus intensity (Sl)-dependent (mean r² = 0.89 for both normals and patients with ALS). The range of the C-SP (difference between maximum and minimum S-X intervals) was age-dependent for normals (r² = 0.701, P < 0.001) but not patients with ALS. Means, maximums and ranges for the C-SP were not significantly different between normal and ALS groups and thresholds to cortical stimulation were also comparable. There was a significant, linear, relation between the maximum C-SP and disease duration of ALS (P = 0.002). The maximum C-SP was shorter early in the disease. It is hypothesized that the reduced inhibition early in the course of ALS might reflect glutamate-induced corticomotoneuronal excitotoxicity. © 1994 John Wiley & Sons, Inc.     

Vibration prolongs the cortical silent period in an antagonistic muscle

We tested whether the silent period, an indicator of inhibitory neuronal activity, is modulated by muscle vibration. Vibration was applied to the right extensor carpi radialis (ECR) muscle in 17 healthy subjects and, as a control experiment, to the dorsal terminal phalanges in 5 subjects. Data before vibration were compared with those during vibration. The cortical silent period (CSP) was evoked by transcranial magnetic stimuli (TMS) during voluntary wrist flexion or during voluntary wrist extension. TMS‐evoked motor potentials (MEPs) of the flexor carpi radialis (FCR) muscle were recorded during muscle relaxation. The mixed nerve silent period (MNSP) was obtained by electrical stimulation of the median nerve during wrist flexion. ECR vibration induced a significant prolongation of the CSP in FCR. CSP increases induced by vibration of the dorsal terminal phalanges were significantly less pronounced. In ECR, the CSP tended to be shortened. MEPs and MNSP remained unchanged. We conclude that vibration enhances inhibitory neuronal properties in a non‐vibrated antagonistic muscle, presumably at a supraspinal level. These results may be relevant for the treatment of spasticity of the upper extremity. Muscle Nerve, 2009     

Effect of different approaches to target force on transcranial magnetic stimulation responses

Introduction: The aim of this study was to determine whether the manner in which a target force is approached can influence the electromyographic (EMG) and mechanical parameters evoked by transcranial magnetic stimulation (TMS) during brief muscle contractions. Methods: The amplitude of motor‐evoked potentials (MEP) and superimposed twitch and the duration of the silent period were recorded in 8 healthy participants in response to TMS delivered during brief isometric voluntary contractions of the quadriceps maintaining a target force (10% and 50% of maximal voluntary force) or gradually increasing or decreasing to reach this point. Results: MEP and superimposed twitch, unlike the silent period, are influenced by the manner of reaching a low force. Conclusions: Clear instructions must be provided to research participants and patients. Rapidly increasing to a target force without exceeding it and maintaining the force before the delivery of TMS results in stable, representative MEP amplitudes. Muscle Nerve 48 : 430–432, 2013     

Task-dependent modulation of silent period duration in focal hand dystonia.

Focal hand dystonia (FHD) is a movement disorder that is also associated with impaired sensory function and sensorimotor integration. The aim of this study was to assess the modulation of inhibitory function in the motor cortex during the performance of four motor tasks (isometric pinch grip, writing, texture discrimination, and a phasic control task) in 8 FHD and 8 control subjects. The affected hands of the FHD subjects and the dominant hands of the control subjects were tested. Inhibitory function was assessed using transcranial magnetic stimulation to evoke a silent period in the ongoing electromyographic activity of the target muscle (first dorsal interosseous). There was no difference between FHD subjects and control subjects in silent period duration, which was significantly longer during the phasic texture discrimination and phasic control task than during the isometric pinch or writing. This finding suggests that the phasic nature of the task may increase cortical inhibitory function, rather than the sensory discrimination task itself. The accuracy of texture discrimination was significantly lower in FHD subjects than in control subjects. Sensory discrimination tasks do not appear to directly modulate the inhibitory processes responsible for the duration of the silent period.     

Transcranial magnetic stimulation shows impaired transcallosal inhibition in Marchiafava–Bignami syndrome

A case of Marchiafava–Bignami (MB) syndrome with selective callosal involvement was evaluated by clinical examination and magnetic resonance imaging (MRI) in the acute phase and 6 months after the onset of symptoms; at the same time, the corticospinally and transcallosally mediated effects elicited by transcranial magnetic stimulation (TMS) were investigated. The first MRI study showed the presence of extensive abnormal signal intensity throughout the entire corpus callosum. After high-dose corticosteroid administration her symptoms rapidly resolved, in parallel with the reversion of MRI changes, except for severe cognitive impairment. Follow-up TMS examination revealed persistent transcallosal inhibition (TI) abnormalities. This report indicates that the measurement of TI during the course of MB syndrome is useful for evaluating functional changes to the corpus callosum, including their evaluation with time and after treatment and for elucidating the pathophysiology of MB syndrome.     

Long‐term progressive motor skill training enhances corticospinal excitability for the ipsilateral hemisphere and motor performance of the untrained hand

It is well established that unilateral motor practice can lead to increased performance in the opposite non‐trained hand. Here, we test the hypothesis that progressively increasing task difficulty during long‐term skill training with the dominant right hand increase performance and corticomotor excitability of the left non‐trained hand. Subjects practiced a visuomotor tracking task engaging right digit V for 6 weeks with either progressively increasing task difficulty (PT) or no progression (NPT). Corticospinal excitability (CSE) was evaluated from the resting motor threshold (rMT) and recruitment curve parameters following application of transcranial magnetic stimulation (TMS) to the ipsilateral primary motor cortex (iM1) hotspot of the left abductor digiti minimi muscle (ADM). PT led to significant improvements in left‐hand motor performance immediately after 6 weeks of training (63 ± 18%, P < 0.001) and 8 days later (76 ± 14%, P < 0.001). In addition, PT led to better task performance compared to NPT (19 ± 15%, P = 0.024 and 27 ± 15%, P = 0.016). Following the initial training session, CSE increased across all subjects. After 6 weeks of training and 8 days later, only PT was accompanied by increased CSE demonstrated by a left and upwards shift in the recruitment curves, e.g. indicated by increased MEP_max (P = 0.012). Eight days after training similar effects were observed, but 14 months later motor performance and CSE were similar between groups. We suggest that progressively adjusting demands for timing and accuracy to individual proficiency promotes motor skill learning and drives the iM1‐CSE resulting in enhanced performance of the non‐trained hand. The results underline the importance of increasing task difficulty progressively and individually in skill learning and rehabilitation training.     

Cortical silent period duration and its implications for surround inhibition of a hand muscle

Surround inhibition is a neural mechanism that assists in the focusing of excitatory drive to muscles responsible for a given movement (agonist muscles) by suppressing unwanted activity in muscles not relevant to the movement (surround muscles). The purpose of the study was to determine the contribution of γ‐aminobutyric acid_B receptor‐mediated intracortical inhibition, as assessed by the cortical silent period (CSP), to the generation of surround inhibition in the motor system. Eight healthy adults (five women and three men, 29.8 ± 9 years) performed isometric contractions with the abductor digiti minimi (ADM) muscle in separate conditions with and without an index finger flexion movement. The ADM motor evoked potential amplitude and CSP duration elicited by transcranial magnetic stimulation were compared between a control condition in which the ADM was activated independently and during conditions involving three phases (pre‐motor, phasic, and tonic) of the index finger flexion movement. The motor evoked potential amplitude of the ADM was greater during the control condition compared with the phasic condition. Thus, the presence of surround inhibition was confirmed in the present study. Most critically, the CSP duration of the ADM decreased during the phasic stage of finger flexion compared with the control condition, which indicated a reduction of this type of intracortical inhibition during the phasic condition. These findings indicate that γ‐aminobutyric acid_B receptor‐mediated intracortical inhibition, as measured by the duration of the CSP, does not contribute to the generation of surround inhibition in hand muscles.     

Cortical mechanisms mediating the inhibitory period after magnetic stimulation of the facial motor area

We studied the silent period (SP) that interrupts voluntary electromyographic activity (EMG) in facial muscles, after transcranial magnetic stimulation (TMS), in normal subjects. High-intensity magnetic stimulation with a 12-cm round coil centered at the vertex induced a long-lasting SP (215 ms), whereas supramaximal stimulation of the facial nerve only induced a short (< 20 ms) and incomplete EMG suppression, and cutaneous stimuli had no inhibitory effect at all. Cutaneous trigeminal stimulation delivered after TMS evoked blink-like reflexes, showing that facial motoneurons were not inhibited during the SP. Simultaneous recordings from perioral muscles (large cortical representation) and from orbicularis oculi and masseter muscles (small cortical representation) showed SPs of identical duration. Focal stimuli with a figure-of-eight coil showed that positioning of the coil was critical and that the optimal scalp sites for evoking the largest motor potentials and longest SPs coincided. Low-intensity stimulation occasionally elicited short SPs without a preceding motor potential. We conclude that the SP induced in facial muscles by TMS results from the excitation of cortical inhibitory interneurons surrounding the upper motoneurons. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 418–424, 1997.     

Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia

We observed a marked prolongation of the transcranially evoked silent period during continuous intrathecal administration of high doses of the gamma-aminobutyric acid (GABA)_B receptor agonist baclofen in a patient with generalized dystonia. Size of motor evoked potentials and central conduction time remained unchanged during intrathecal baclofen administration. The selective prolongation of the silent period during high-dose continuous intrathecal baclofen therapy supports the notion that GABA_B-ergic intracortical interneurons play a part in the generation of the transcranially evoked silent period. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1209–1212, 1998.     

Facilitation of magnetic motor evoked potentials during the mixed nerve silent period

We studied motor nueron excitability during the mixed nerve silent period (MNSP) in a hand muscle using magnetic motor evoked potentials (MEPs) and F-waves. MEPs elicited between the V₁ and V₂ potentials of the MNSP were much larger than control MEPs elicited at rest, and were even comparable in size to control MEPs occured without shortening of MEP latency, suggesting a supraspinal mechanism. MEPs were facilitated during the MNSP when elicited with a figure-8-shaped coil in a posterior–anterior orientation, but not when MEPs of the same size were elicited with the coil held in a lateral–medial orientation. F-waves elicited during the MNSP were variable between subjects, and not consistently different from control F-waves elicited at rest. Our findings may reflect increased cortical motor excitability during the MNSP, possibly related to activation of muscle afferents by mixed nerve stimulation. © John Wiley & Sons, Inc.     

The use of transcranial magnetic stimulation in the clinical evaluation of suspected myelopathy

Central motor conduction time (CMCT) and motor evoked potential (MEP) latencies measured by using transcranial magnetic stimulation (TMS) are parameters used to evaluate electrophysiologic function of the corticospinal motor tract. We present 5 cases to illustrate how the use of TMS had contributed to clinical management. CMCT and MEP latency measurements were found to be useful in determining the significance of lesions seen on neuroimaging and helped clinical decisions in the presence of multiple lesions or multiple clinical conditions that cause similar clinical manifestations. TMS study is particularly useful in localizing levels of conduction defect.     

Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex

Stimulation with weak electrical direct currents has been shown to be capable of inducing stimulation-polarity-dependent prolonged diminutions or elevations of cortical excitability, most probably elicited by a hyper- or depolarization of resting membrane potentials. The aim of the present study was to test if cognitive task and motor exercise practiced during the stimulation are able to modify transcranial direct current stimulation-induced plasticity in the left primary motor cortex in 12 healthy subjects. Motor evoked potentials were recorded before and after 10 min of anodal and cathodal transcranial direct current stimulation. In Experiment 1, subjects were required to sit passively during the stimulation, in Experiment 2 the subject's attention was directed towards a cognitive test and in Experiment 3 subjects were instructed to push a ball in their right hand. Both the cognitive task and motor exercise modified transcranial direct current stimulation-induced plasticity; when performing the cognitive task during stimulation the motor cortex excitability was lower after anodal stimulation and higher after cathodal stimulation, compared with the passive condition. When performing the motor exercise, the motor cortex excitability was lower after both anodal and cathodal stimulation, compared with the passive condition. Our results show that transcranial direct current stimulation-induced plasticity is highly dependent on the state of the subject during stimulation.     

Measurements of transcallosally mediated cortical inhibition for differentiating parkinsonian syndromes.

Clinicopathologic evidence suggests differential involvement of cortex and corpus callosum (CC) in various disorders presenting with a parkinsonian syndrome. We tested the hypothesis of whether neurophysiologic and morphometric assessments of CC as surrogate parameters of cortical involvement could be helpful in differential diagnosis of parkinsonian disorders. The integrity of CC was assessed neurophysiologically by measuring the ipsilateral silent period (iSP) evoked by transcranial magnetic stimulation (TMS) in a total of 25 patients with idiopathic parkinsonian syndromes (IPS), corticobasal ganglionic degeneration (CBD), progressive supranuclear palsy (PSP), or multiple system atrophy (MSA). Additionally, morphometric analyses of magnetic resonance imaging (MRI) measurements of CC was carried out in all patients. iSP was abnormal in all 5 CBD and all 5 PSP patients, whereas it was intact in all 10 IPS patients and all 5 MSA patients. Among various MRI parameters of CC, testing between different groups revealed a significant difference only for measurements of the middle part of the truncus. CBD and PSP patients exhibited a significant atrophy as compared with control subjects. These data suggest impairment of callosal integrity in patients with CBD and PSP. iSP measurements may be a useful clinical neurophysiologic test in differential diagnosis of patients with parkinsonian syndromes.     

Modulation of interhemispheric interactions across symmetric and asymmetric bimanual force regulations

The corpus callosum is essential for neural communication between the left and right hemispheres. Although spatiotemporal coordination of bimanual movements is mediated by the activity of the transcallosal circuit, it remains to be addressed how transcallosal neural activity is involved in the dynamic control of bimanual force execution in human. To address this issue, we investigated transcallosal inhibition (TCI) elicited by single‐pulse transcranial magnetic stimulation (TMS) in association with the coordination condition of bimanual force regulation. During a visually‐guided bimanual force tracking task, both thumbs were abducted either in‐phase (symmetric condition) or 180° out‐of‐phase (asymmetric condition). TMS was applied to the left primary motor cortex to elicit the disturbance of ipsilateral left force tracking due to TCI. The tracking accuracy was equivalent between the two conditions, but the synchrony of the left and right tracking trajectories was higher in the symmetric condition than in the asymmetric condition. The magnitude of force disturbance and TCI were larger during the symmetric condition than during the asymmetric condition. Right unimanual force tracking influenced neither the force disturbance nor TCI during tonic left thumb abduction. Additionally, these TMS‐induced ipsilateral motor disturbances only appeared when the TMS intensity was strong enough to excite the transcallosal circuit, irrespective of whether the crossed corticospinal tract was activated. These findings support the hypotheses that interhemispheric interactions between the motor cortices play an important role in modulating bimanual force coordination tasks, and that TCI is finely tuned depending on the coordination condition of bimanual force regulation.     

Afferent-induced facilitation of primary motor cortex excitability in the region controlling hand muscles in humans

Sensory inputs from cutaneous and limb receptors are known to influence motor cortex network excitability. Although most recent studies have focused on the inhibitory influences of afferent inputs on arm motor responses evoked by transcranial magnetic stimulation (TMS), facilitatory effects are rarely considered. In the present work, we sought to establish how proprioceptive sensory inputs modulate the excitability of the primary motor cortex region controlling certain hand and wrist muscles. Suprathreshold TMS pulses were preceded either by median nerve stimulation (MNS) or index finger stimulation with interstimulus intervals (ISIs) ranging from 20 to 200 ms (with particular focus on 40–80 ms). Motor-evoked potentials recorded in the abductor pollicis brevis (APB), first dorsalis interosseus and extensor carpi radialis muscles were strongly facilitated (by up to 150%) by MNS with ISIs of around 60 ms, whereas digit stimulation had only a weak effect. When MNS was delivered at the interval that evoked the optimal facilitatory effect, the H-reflex amplitude remained unchanged and APB motor responses evoked with transcranial electric stimulation were not increased as compared with TMS. Afferent-induced facilitation and short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) mechanisms are likely to interact in cortical circuits, as suggested by the strong facilitation observed when MNS was delivered concurrently with ICF and the reduction of SICI following MNS. We conclude that afferent-induced facilitation is a mechanism which probably involves muscle spindle afferents and should be considered when studying sensorimotor integration mechanisms in healthy and disease situations.