C. Lorenzano

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. Ann Neurol 2000;48:20–26

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.

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 Parkinsons 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 Parkinsons disease reflects a decreased facilitation of the excitatory cells in the cortical motor areas.

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.

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, the affected side; and orbicularis oculi and oris; 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.

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.

Short-term cortical plasticity in patients with dystonia: a study with repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) delivered at 5 Hz frequency and suprathreshold (RMT) intensity produces a progressive facilitation of motor‐evoked potential (MEP) amplitude that outlasts the end of stimulation. This phenomenon is related to a short‐term enhancement of cortical excitatory interneurones. In this study, we investigated whether 5 Hz‐rTMS elicits similar MEP facilitation during stimulation and similar facilitatory after‐effects in patients with upper limb dystonia and healthy subjects. Trains of 5, 10, and 20 stimuli were delivered at 120% RMT over the primary motor cortex with the subjects at rest. rTMS‐trains were followed by single test stimuli delivered at various interstimulus intervals (0.5–10 s) at 120% RMT using a conditioning‐test paradigm. Single conditioning stimuli were also delivered. The effects of suprathreshold 1 Hz‐rTMS were also tested. The MEP amplitude during the course of the trains and of the test stimuli was measured. In control experiments, we investigated the role of the afferent inputs elicited by muscle twitches after ulnar nerve stimulation on the MEP amplitude. In patients and healthy subjects, MEP amplitude increased significantly during the course of 5 Hz‐trains. In both groups the MEP facilitation outlasted the end of 5 Hz‐rTMS, however the facilitatory after‐effects were more pronounced and lasted longer in patients than in healthy subjects. MEP amplitudes during and after 1 Hz‐rTMS remained unchanged. Ulnar nerve stimulation did not change the test MEP amplitude. We conclude that in patients with upper limb dystonia there is an abnormal recovery from MEP facilitation after suprathreshold 5 Hz‐rTMS suggesting an abnormal pattern of short‐term cortical plasticity.

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.

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.