Preconditioning repetitive transcranial magnetic stimulation of premotor cortex can reduce but not enhance short-term facilitation of primary motor cortex.

Short trains of suprathreshold 5-Hz repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) evoke motor potentials (MEPs) in hand muscles that progressively increase in amplitude via a mechanism that is thought to be similar to short-term potentiation described in animal preparations. Long trains of subthreshold rTMS over dorsal premotor cortex (PMd) are known to affect the amplitude of single-pulse MEPs evoked from M1. We tested whether PMd-rTMS affects short-term facilitation in M1. We also explored the effect of PMd-rTMS on M1 responses evoked by single-pulse TMS of different polarities. We tested in 15 healthy subjects short-term facilitation in left M1 (10 suprathreshold TMS pulses at 5 Hz) after applying rTMS to left PMd (1,500 subthreshold pulses at 1 and 5 Hz). In a sample of subjects we delivered single-pulse TMS with different polarities and paired-pulse TMS at short intervals (SICI) after PMd-rTMS. Short-term facilitation in M1 was reduced after applying 1 Hz to PMd, but was unaffected after 5-Hz PMd-rTMS. PMd-rTMS with 1 Hz reduced the amplitude of MEPs evoked by monophasic posteroanterior (PA) or biphasic anteroposterior (AP)-PA but had little effect on MEPs by monophasic AP or biphasic PA-AP single-pulse TMS. PMd-rTMS left SICI unchanged. PMd-rTMS (1 Hz) reduces short-term facilitation in M1 induced by short 5-Hz trains. This effect is likely to be caused by reduced facilitation of I-wave inputs to corticospinal neurons.

Motor cortical excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington's disease.

OBJECTIVE: TMS techniques have provided controversial information on motor cortical function in Huntington's disease (HD). We investigated the excitability of motor cortex in patients with HD using repetitive transcranial magnetic stimulation (rTMS). METHODS: Eleven patients with HD, and 11 age-matched healthy subjects participated in the study. The clinical features of patients with HD were evaluated with the United Huntington's Disease Rating Scale (UHDRS). rTMS was delivered with a Magstim Repetitive Magnetic Stimulator through a figure-of-8 coil placed over the motor area of the first dorsal interosseus (FDI) muscle. Trains of 10 stimuli were delivered at 5 Hz frequency and suprathreshold intensity (120% resting motor threshold) with the subjects at rest and during voluntary contraction of the target muscle. RESULTS: In healthy subjects at rest, rTMS produced motor evoked potentials (MEPs) that increased in amplitude over the course of the trains. Conversely in patients, rTMS left the MEP size almost unchanged. In both groups, during voluntary contraction rTMS increased the silent period (SP) duration. CONCLUSIONS: Because rTMS modulates motor cortical excitability by activating cortical excitatory and inhibitory interneurons these findings suggest that in patients with HD the excitability of facilitatory intracortical interneurones is decreased. SIGNIFICANCE: We suggest that depressed excitability of the motor cortex in patients with HD reflects a disease-related weakening of cortical facilitatory mechanisms.

No clinical or neurophysiological evidence of botulinum toxin diffusion to non-injected muscles in patients with hemifacial spasm.

Botulinum toxin injected into a muscle may diffuse to nearby muscles thus producing unwanted effects. In patients with hemifacial spasm, we evaluated clinically and neurophysiologically, whether botulinum toxin type A (BoNT-A) diffuses from the injection site (orbicularis oculi) to untreated muscles (orbicularis oris from the affected side and orbicularis oculi and oris from the unaffected side). We studied 38 patients with idiopathic hemifacial spasm. Botulinum toxin was injected into the affected orbicularis oculi muscle alone (at 3 standardized sites) at a clinically effective dose. Patients were studied before (T0) and 3-4 weeks after treatment (T1). We evaluated the clinical effects of botulinum toxin and muscle strength in the affected and unaffected muscles. We also assessed the peak-to-peak amplitude compound muscle action potential (CMAP) recorded from the orbicularis oculi and orbicularis oris muscles on both sides after supramaximal electrical stimulation of the facial nerve at the stylomastoid foramen. In all patients, botulinum toxin treatment reduced muscle spasms in the injected orbicularis oculi muscle and induced no muscle weakness in the other facial muscles. The CMAP amplitude significantly decreased in the injected orbicularis oculi muscle, but remained unchanged in the other facial muscles (orbicularis oris muscle on the affected side and contra-lateral unaffected muscles). In conclusion, in patients with hemifacial spasm, botulinum toxin, at a clinically effective dose, induces no clinical signs of diffusion and does not reduce the CMAP size in the nearby untreated orbicularis oris or contralateral facial muscles.

Synaptic potentiation induced by rTMS: effect of lidocaine infusion.

Repetitive transcranial magnetic stimulation (rTMS) delivered at various intensities and frequencies excites cortical motor areas. Trains of stimuli (at 5-Hz frequency, and suprathreshold intensity) progressively increase the size of motor evoked potentials (MEPs) and the duration of the cortical silent period (CSP) in normal subjects. Because antiepileptic drugs, acting mainly on sodium channels, depress MEP facilitation during rTMS, we suggested that rTMS trains facilitate the MEP size by inducing synaptic potentiation primarily involving voltage-gated sodium channels. The aim of this study was to evaluate the effect of lidocaine-a drug that acts selectively on sodium channels-on the rTMS-induced changes in cortical excitability. We tested the changes in motor threshold, MEP size, CSP duration evoked by focal rTMS and the M-wave amplitude in healthy subjects before and after lidocaine infusion. Lidocaine abolished the normal rTMS-induced facilitation of MEPs but left the other rTMS variables and the M-wave unchanged. Our results suggest that the MEP facilitation related to rTMS-induced synaptic potentiation results from an increase in cortical excitatory interneuron excitability that involves voltage-gated sodium channels.

Ovarian hormones and cortical excitability. An rTMS study in humans.

OBJECTIVE: Ovarian steroids influence neural excitability. Using repetitive transcranial magnetic stimulation (rTMS) we investigated changes in cortical excitability during the menstrual cycle. METHODS: Eight women underwent rTMS on Days 1 and 14 of the menstrual cycle. As a control group, 8 age-matched men were also tested twice, with a 14-day interval between the two experimental sessions. Repetitive magnetic pulses were delivered in trains of 10 stimuli (5 Hz frequency and 120% of the motor threshold calculated at rest) to the left motor area of the first dorsal interosseous muscle. RESULTS: In women, the motor evoked potential (MEP) size did not increase on Day 1, but it increased progressively during the train on Day 14. The duration of the silent period progressively lengthened during the train on both days. In men the MEP increased in size, and the silent period lengthened to a similar extent on both days. CONCLUSIONS: In women, hormone changes related to the menstrual cycle alter cortical excitability. SIGNIFICANCE: Low estrogen levels probably reduce cortical excitability because their diminished action on sodium channels reduces recruitment of excitatory interneurons during rTMS thus abolishing the MEP facilitation.

Abnormalities of motor cortex excitability preceding movement in patients with dystonia.

In patients with dystonia, abnormal movements are commonly triggered or made worse by voluntary action. By means of transcranial magnetic stimulation (TMS), we investigated changes in motor cortex excitability before the execution of wrist voluntary movements in patients with upper limb dystonia and normal control subjects. Magnetic stimulation was delivered by two Magstim 200 stimulators connected through a Bistim module to a figure-of-eight coil placed over the motor area of the forearm extensor muscles. A subthreshold (80% of the rest motor threshold) conditioning stimulus was delivered 3 ms before the suprathreshold (120% of the rest motor threshold) test stimulus and the degree of inhibition of the conditioned motor evoked potentials (MEPs) was taken as an indicator of intracortical inhibition. MEPs were recorded over the forearm extensor muscles of the right arm. To study MEP amplitudes and intracortical inhibition before the onset of wrist extension in the pre-movement condition, TMS pulses were delivered from 0 ms to 100 ms after the go-signal. Besides the pre-movement condition, intracortical inhibition and the unconditioned MEP size were also investigated at rest and during tonic wrist extension. In healthy subjects studied before the wrist movement, the unconditioned MEP amplitude increased progressively and intracortical inhibition decreased significantly. Before movement in dystonic patients, the unconditioned MEP amplitude remained significantly unchanged from resting values and intracortical inhibition decreased less than it did in healthy subjects. In both groups studied during contraction, the unconditioned MEP amplitude increased and intracortical inhibition decreased from values at rest. In conclusion, these findings from reaction time tasks in patients with primary dystonia provide evidence of abnormal pre-movement motor cortex excitability. This abnormality is due to an altered release or running of motor programmes.

Effects of transcranial magnetic stimulation on the H reflex and F wave in the hand muscles.

OBJECTIVE: In 14 healthy subjects, we studied the effects of transcranial magnetic stimulation (TMS) on the excitability of spinal motoneurons in the abductor pollicis brevis muscle (ABP), by testing the F wave and H reflex. METHODS: TMS pulses were delivered with the subjects at rest and at various motor threshold (Mth) intensities. Electrical stimuli were delivered to the median nerve at the wrist at two different intensities. High-intensity pulse was used to evoke an F wave and low-intensity paired pulse to evoke an H reflex in the ABP muscle. The effects of TMS were studied using a conditioning-test paradigm. The tests F wave and H reflex were conditioned by TMS (120% Mth) at various interstimulus intervals (ISIs) (30-100ms) and intensities (90-200% Mth). RESULTS: At 30ms but not at ISIs from 40 to 100ms, conditioning TMS (120% Mth) significantly increased the F-wave area. At the 30ms ISI, conditioning TMS at 120% Mth intensity significantly increased the F-wave area whereas higher intensities (140-180% Mth) did not. At 200% Mth intensity, the F-wave area decreased significantly. At 30 and 40ms ISIs, conditioning TMS at 120% Mth significantly reduced the H-reflex area. At 50-100ms ISIs, the H-reflex area almost matched the control value. At the 30ms ISI, conditioning TMS at >or=100% Mth intensity significantly decreased the H-reflex area. CONCLUSIONS: In conclusion, our findings suggest that the distinct changes in the TMS-conditioned F wave and H reflex reflect changing excitability in the motoneuronal populations activated by the cortical input.

Spread of electrical activity at cortical level after repetitive magnetic stimulation in normal subjects.

In normal subjects, focal repetitive transcranial magnetic stimulation (rTMS) of the hand motor area evokes muscle potentials (MEPs) from muscles in the hand (target muscles) and the arm (non-target muscles). In this study we investigated the mechanisms underlying the spread of MEPs induced by focal rTMS in non-target muscles. rTMS was delivered with a Magstim stimulator and a figure-of-eight coil placed over the first dorsal interosseus (FDI) motor area of the left hemisphere. Trains of 10 stimuli were given at a suprathreshold intensity (120% of motor threshold) and at frequencies of 5, 10 and 20 Hz at rest. Electromyographic (EMG) activity was recorded simultaneously from the FDI (target muscle) and the contralateral biceps muscle and from the FDI muscle ipsilateral to the side of stimulation (non-target muscle). rTMS delivered in trains to the FDI motor area of the left hemisphere elicited MEPs in the contralateral FDI (target muscle) that gradually increased in amplitude over the course of the train. Focal rTMS trains also induced MEPs in the contralateral biceps (non-target muscle) but did so only after the second or third stimulus; like target-muscle MEPs, in non-target muscle MEPs progressively increased in amplitude during the train. At no frequency did rTMS elicit MEPs in the FDI muscle ipsilateral to the site of stimulation. rTMS left the latency of EMG responses in the FDI and biceps muscles unchanged during the trains of stimuli. The latency of biceps MEPs was longer after rTMS than after a single TMS pulse. In conditioning-test experiments designed to investigate the cortical origin of the spread, a single TMS pulse delivered over the left hemisphere at an interstimulus interval (ISI) of 50, 100 and 150 ms reduced the amplitude of the test MEP evoked by a single TMS pulse delivered over the right hemisphere; and a conditioning rTMS train delivered over the left hemisphere increased the amplitude of the test MEP evoked by a single TMS pulse over the right hemisphere. A conditioning rTMS train delivered over the left hemisphere and paired magnetic shocks (test stimulus) at 3 and 13 ms ISIs over the right hemisphere reduced MEP inhibition at the 3-ms ISI but left the MEP facilitation at 13 ms unchanged. Using a control MEP size matched with that observed after a conditioning contralateral rTMS, we found that paired-pulse inhibition remained unchanged. Yet a single TMS conditioning pulse sufficiently strong to evoke a MEP in the contralateral FDI and biceps muscles simultaneously (as rTMS did) left paired-pulse inhibition unchanged. We conclude that the spread of EMG activity to non-target muscles depends on cortical mechanisms, mainly including changes in the excitability of the interneurones mediating intracortical inhibition.

Repetitive magnetic stimulation of cortical motor areas in Parkinson's disease: implications for the pathophysiology of cortical function.

We investigated the neurophysiological and clinical effects of repetitive magnetic stimulation (rTMS) delivered to the cortical motor areas in healthy subjects and patients with Parkinson's disease. rTMS was delivered with a high speed magnetic stimulator (Cadwell, Kennewick, WA) through a figure-eight coil centred on the primary motor area at a stimulus intensity of 120% motor threshold. Trains of 10 stimuli were delivered at frequencies of 5 Hz while subjects were at rest and during a voluntary contraction of the contralateral first dorsal interosseous muscle. In normal subjects at rest, the muscle evoked responses (MEPs) to each stimulus in a train of magnetic stimuli progressively increased in size during the train. rTMS left the MEPs unchanged in patients off therapy and had a small facilitatory effect in those on therapy. In normal subjects and patients, 5-Hz rTMS trains delivered during a voluntary contraction of the target muscle left the MEP unchanged in size. MEPs were followed by a silent period that increased in duration during the course of the train. The silent period duration increased to a similar extent in patients and controls. The reduced rTMS-induced facilitation of MEPs in patients with Parkinson's disease reflects a decreased facilitation of the excitatory cells in the cortical motor areas.

Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia.

To find out whether botulinum toxin alters the excitability of cortical motor areas, we studied intracortical inhibition with transcranial magnetic stimulation in patients with upper limb dystonia before, 1 month after, and 3 months after the injection of botulinum toxin type A in the affected muscles. Eleven normal subjects and 12 patients with dystonia involving the upper limbs (7 with generalized dystonia, 2 with segmental dystonia, and 3 with focal dystonia) were studied. Patients were assessed clinically with the Dystonia Movement Scale. Paired magnetic stimuli were delivered by two Magstim 200 magnetic stimulators connected through a Bistim module to a figure-of-eight coil placed over the motor area of the forearm muscles. Paired stimulation was given at rest. A subthreshold (80% of motor threshold) conditioning stimulus was delivered 3 and 5 msec before the suprathreshold (120% of motor threshold) test stimulus. Electromyographic signals were recorded over the flexor or extensor muscles of the forearm on the affected side. We measured the amplitude of the test motor evoked potential (expressed as a percentage of the unconditioned motor evoked potential). All results were compared using ANOVA. In all patients, a botulinum toxin type A injection (50-100 mouse units) reduced dystonic movements in the arm. In normal subjects, electromyographic recordings showed significant inhibition of the test response. Before botulinum toxin injection, patients had less test response inhibition than normal subjects. One month after injection, patients had test response inhibition similar to that of normal subjects. At 3 months after injection, they again had less inhibition than normal subjects or patients at 1 month after injection. In conclusion, our data suggest that botulinum toxin can transiently alter the excitability of the cortical motor areas by reorganizing the inhibitory and excitatory intracortical circuits. The cortical changes probably originate through peripheral mechanisms.

Ia presynaptic inhibition after muscle twitch in the arm.

Contraction of upper limb muscles in healthy subjects was used to investigate presynaptic inhibition at spinal level. The H reflex recorded in the forearm flexor muscles in response to median nerve stimulation was depressed in amplitude from 400 ms to 1 s after a muscle twitch induced by transcranial stimulation, root stimulation, direct biceps stimulation, and triceps tendon tap. Stimulation of the cutaneous branch of musculocutaneous nerve, ipsilateral triceps and contralateral biceps, and biceps tendon tap did not alter H-reflex size. Forearm flexor H-reflex amplitude is therefore related to changes in proprioceptive inflow secondary to the biceps muscle twitch. Root and direct muscle stimulation both failed to reduce the size of the motor evoked potential (MEP) after transcranial magnetic stimulation, suggesting that the inhibition acts at presynaptic level. Attenuation of H-reflex amplitude was related to the size of the muscle twitch and was less pronounced during an isometric twitch than during free joint movement. Our results suggest that the biceps muscle twitch produces long-lasting inhibition of the Ia afferents from forearm flexor muscles. This is an important and a simple mechanism for suppressing proprioceptive input during movement.

Impaired EMG inhibition elicited by tendon stimulation in dystonia.

OBJECTIVE: to test the effects of tendon stimulation on isometric voluntary contraction. METHODS: Twenty patients with dystonia (12 patients with generalized and eight with task-specific dystonia) and 10 normal healthy subjects participated in the study. The tendon of the extensor carpi radialis muscle was stimulated with electrical stimuli at the wrist, and the electromyogram (EMG) signal was recorded during an isometric voluntary contraction. RESULTS: In normal subjects, tendon stimulation elicited an excitatory phase (TE1), followed by a pronounced inhibitory phase (TI1) and a second excitatory phase (TE2). The three phases had similar perceptive thresholds, latencies, and durations in patients and control subjects. In patients with generalized dystonia, the TI1 area exceeded the control values (controls [mean +/- SE], 40.3 +/- 5.4; patients, 66.9 +/- 5.5; p = 0.0048, Mann-Whitney U: test). In the patients with task-specific dystonia, the TI1 area was similar to control values (controls [mean +/- SE], 40.3 +/- 5.4; patients, 54.2 +/- 4.8; p = 0.7396, Mann-Whitney U: test). CONCLUSIONS: The EMG suppression (TI1) after tendon stimulation is reduced in generalized dystonia, indicating a decreased group III-elicited presynaptic inhibition of Ia fibers. The impaired group III presynaptic inhibitory action from tendon afferents could contribute to the motor abnormalities present in dystonia. Dystonia causes widespread dysfunction of presynaptic inhibitory mechanisms in the spinal cord, involving Group I and III afferents.