Stephan Wischer

Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation

1 Transcranial magnetic stimulation (TMS) of the human motor cortex results in multiple discharges (D and I waves) in the corticospinal tract. We tested whether these volleys can be explored non‐invasively with paired TMS. The intensity of the first stimulus (S1) was set to produce a motor‐evoked potential (MEP) of 1 mV in the resting contralateral abductor digiti minimi (ADM) muscle; the second stimulus (S2) was set to 90 % of the resting motor threshold. At interstimulus intervals of 1·1‐1·5, 2·3‐2·9 and 4·1‐4·4 ms the MEP elicited by S1 plus S2 was larger than that produced by S1 alone. 2 Varying the S1 intensity between 70 and 130 % resting motor threshold with S2 held constant at 90 % resting motor threshold showed that the threshold for the first MEP peak was <= 70 % resting motor threshold. The second and third MEP peaks appeared only at higher S1 intensities. The latency of all peaks decreased with increasing S1 intensity. 3 Varying the S2 intensity with S1 held constant to produce a MEP of 1 mV on its own showed that the amplitude of all MEP peaks increased with S2 intensity, but that their timing remained unchanged. 4 Paired TMS in the active ADM (S1 clearly suprathreshold, S2 just above threshold; interstimulus interval, 1 ms) produced strong MEP facilitation. The onset of this facilitation occurred later by about 1·5 ms than the onset of the MEP evoked by S2 alone. No MEP facilitation was seen if the magnetic S2 was replaced by anodal or cathodal transcranial electrical stimulation. 5 It is concluded that the MEP facilitation after paired TMS, at least for the first MEP peak, is due to facilitatory interaction between I waves, and takes place in the motor cortex at or upstream from the corticospinal neurone.

Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study

A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed.

Motor system excitability in patients with restless legs syndrome

Article abstract In 18 patients with idiopathic restless legs syndrome (RLS), intracortical inhibition by paired transcranial magnetic stimulation (TMS) was significantly reduced for both foot and hand muscles, suggesting that the entire motor cortex is disinhibited in RLS. Decreased intracortical facilitation in the foot muscle but not in the hand muscle may be due to subliminal activation of the symptomatic lower limbs. Motor excitability measurements of single TMS were not altered. These results support a subcortical origin of RLS.

Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation.

Abstract To evaluate changes in the motor system during the silent period (SP) induced by transcranial magnetic stimulation (TMS) of the motor cortex, we investigated motor thresholds as parameters of the excitability of the cortico-muscular pathway after a suprathreshold conditioning stimulus in the abductor digiti minimi muscle (ADM) of normal humans. Since the unconditioned motor threshold was lower during voluntary tonic contraction than at rest (31.9±5.4% vs. 45.6±7.5%), it is suggested that the difference between active and resting motor threshold indicates the magnitude of the voluntary drive on the cortico-muscular pathway. Therefore, we compared conditioned resting and active motor threshold (cRMT and cAMT) during the SP. cRMT showed an intensity-dependent period of elevation of more than 200 ms in duration and approximately 17% of the maximum stimulator output above the unconditioned threshold, due to decreased excitability of the cortico-muscular pathway after the conditioning stimulus. Some 30–40 ms after the conditioning stimulus, cAMT approximated cRMT, indicating complete suppression of the voluntary motor drive. This suppression did not start directly after the conditioning stimulus since cAMT was still significantly lower than the cRMT within the first 30–40 ms. Threshold elevation was significantly longer than the SP (220±41 vs. 151±28 ms). Recovery of the voluntary motor drive started late in the SP and was nearly complete at the end of the SP, although thresholds were still significantly elevated. We conclude that the SP is largely due to a suppression of voluntary motor drive, while the threshold elevation is a different inhibitory phenomenon that is of less importance for the generation of the SP, at least in its late part. It is argued that the pathway of fast cortico-spinal fibers activated by TMS is partially different from the pathway involved in the maintenance of tonic voluntary muscle activation.

Deficient motor control in children with tic disorder: evidence from transcranial magnetic stimulation.

Decreased motor inhibition was reported in adult patients with tic disorder (TD) using the technique of transcranial magnetic stimulation. Since tics usually begin during childhood, motor threshold, cortical silent period (CSP) and intracortical inhibition/facilitation were measured in 21 TD children and 25 healthy children aged 10-16 years. In TD children motor threshold was normal. The CSP was significantly shortened compared to healthy controls but did not depend on tic localization. Intracortical inhibition and facilitation did not differ between the two groups. This study confirms that the finding of decreased motor control in adult patients also holds true for children wherever the tics in the latter group were located.

Relationship between lamotrigine oral dose, serum level and its inhibitory effect on CNS: insights from transcranial magnetic stimulation

The antiepileptic drug lamotrigine (LTG) is known to reduce cortical excitability evaluated by transcranial magnetic stimulation (TMS). We investigated the relationship between LTG oral dosages, serum levels and inhibitory effects on resting motor threshold (RMT), a parameter of motor system excitability assessed by TMS. In a randomized, placebo-controlled crossover study 16 male volunteers received 325 mg LTG as a single dose, as bi-hourly graded cumulative dose, or placebo. RMT and serum levels were measured before and after 2-8 h. With single dose, RMT elevation showed a poor but significant correlation to serum levels. With graded dose, serum levels as well as RMT increased dose-dependently with significant (P<0.0001) linear correlation. However, detailed comparison showed a high inter-individual variability in the relationship resembling a sigmoid correlation. Different mechanisms besides the sodium-channel blockage as the main mode of action of LTG are discussed to explain the diversity of individual dose-response relationships. Provided that the RMT elevation reflects the antiepileptic potential of LTG, TMS may be developed as a tool to monitor interindividual response of epilepsy patients to LTG treatment as well as to explore efficacy of other antiepileptic drugs with similar mode of action.

Differential inhibition of chromatic and achromatic perception by transcranial magnetic stimulation of the human visual cortex.

The magnocellular visual pathway is devoted to low-contrast achromatic and motion perception whereas the parvocellular pathway deals with chromatic and high resolution spatial vision. To specifically separate perception mediated by these pathways we have used low-contrast Gaussian filtered black-white or coloured visual stimuli. By use of transcranial magnetic stimulation (TMS) over the visual cortex inhibition of magnocellular stimuli was achieved distinctly earlier by about 40 ms compared with parvocellular information. A nonspecific inhibition of all stimuli could be seen peaking at 75-90 ms, significantly higher for magnocellular stimuli. The particular vulnerability of magnocellular stimuli to TMS is correlated with distinct physiological properties of this pathway such as faster conduction velocity and non-linear stimulus encoding.

Riluzole does not have an acute effect on motor thresholds and the intracortical excitability in amyotrophic lateral sclerosis

Intracortical excitability in amyotrophic lateral sclerosis (ALS) is impaired. The effectiveness of the glutamate antagonist riluzole (Rilutek®, Rhône-Poulenc Rorer) in ALS has been shown in clinical studies. In healthy subjects it modifies intracortical excitability in a frequently used double-stimulus paradigm of transcranial magnetic stimulation (TMS). Under riluzole intracortical inhibition is enhanced in healthy individuals, although not always significantly, whereas intracortical facilitation has been described as reduced [10, 11]. We wanted to find out whether riluzole affects and potentially rebalances impaired intracortical excitability in ALS. We, therefore, enrolled 13 patients with clinically and electromyographically confirmed ALS into this study. Five patients had to be excluded because motor thresholds were too high to get reliable motor evoked potentials (MEPs). In the remaining 8 patients, mean age was 59.9±11.9 years (± standard deviation) and mean symptom duration 9.6±2.5 months. Intracortical excitability was assessed before and 1.5 hours after the first intake of a loading dose of 100 mg of riluzole using a conventional paired-pulse TMS paradigm with interstimulus intervals (ISI) ranging from 1–30 ms and intensities adjusted to yield MEPs of 1.0 mV for test pulses and of 90% active motor threshold for conditioning pulses. Patients’ baseline results were compared to those of 9 age-matched, healthy control subjects. Before drug intake, motor thresholds did not differ between groups, but there was significantly less intracortical inhibition in the ALS patient group. Riluzole intake did not significantly alter motor thresholds or intacortical excitability in the ALS patients. We conclude that riluzole does not immediately influence intracortical excitability in ALS. Our results are in contrast to the findings of Stefan et al (1998) [14] where a partial normalization of intracortical inhibition in ALS was observed after at least 5 days of drug intake. The difference between that study and our result may indicate a delayed onset of riluzole’s influence on intracortical excitability.

Normal intracortical excitability in developmental stuttering.

Persistent developmental stuttering (PDS) shares clinical features with task‐specific dystonias. In these dystonias, intracortical inhibition is abnormally weak. We therefore sought to determine intracortical inhibition and intracortical facilitation in PDS. In 18 subjects with PDS since childhood (mean age, 39.4 [SD 13.0] years) and 18 speech‐fluent controls (43.6 [14.3] years), we investigated resting and active motor thresholds as well as intracortical inhibition and facilitation of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation. In PDS, the resting and active motor thresholds were increased, whereas intracortical inhibition and facilitation were normal. Normal intracortical excitability makes a pathophysiological analogy between focal dystonia and PDS less likely. The enhanced motor threshold suggests reduced motor cortical neuronal membrane excitability in PDS.

Treatment of restless legs syndrome with the dopamine agonist alpha-dihydroergocryptine

An open pilot study with the dopamine agonist α‐dihydroergocryptine (DHEC) was conducted in 16 patients with idiopathic restless legs syndrome (RLS) over a period of 5 weeks. Following a drug‐free interval of 1 week, the patients were treated with daily doses of 10 to 40 mg DHEC. As compared to baseline values, treatment led to a statistically significant reduction of subjective RLS symptoms. Overall complaints at night decreased significantly by 63.9 ± 38.1% as measured by a visual analogue scale. Detailed evaluation of sensory discomfort, motor restlessness, involuntary movements, as well as sleep quality also showed significant improvement. Side effects were mostly mild and affected mainly the gastrointestinal tract. Five patients needed domperidone for treatment of concomitant nausea. One patient stopped the study due to nausea. In conclusion, the results of this open study suggest a role for DHEC in the treatment of RLS.