Alfredo Berardelli

Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee

P.M. Rossini (Chairman) (Rome, Baly), A.T. Barker (Sheffield, UK), A. Berardelli (Rome, Italy), M.D. Caramia (Rome, Italy), G. Caruso (Naples, Italy), R.Q. Cracco (Brooklyn, NY;, USA), M.R. Dimitrijevid (Houston, TX, USA), M. Hallett ( Bethesda, MD, USA), Y. Katayama (Tokyo, Japan), C.H. Liicking ( Freiburg, Germany), A.L. Maertens de Noordhout (Liege, Belgium), C.D. Marsden (London, UK), N.M.F. Murray (London, UK), J.C. Rothwell (London, UK), M. Swash (London, UK) and C. Tomberg (Brussels, Belgium)

Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction.

1. The silent period evoked in the first dorsal interosseous (FDI) muscle after electrical and magnetic transcranial stimulation (TCS), electrical stimulation of the cervicomedullary junction and ulnar nerve stimulation was studied in ten healthy subjects. 2. With maximum‐intensity shocks, the average duration of the silent period was 200 ms after electrical TCS, 300 ms after magnetic TCS, 43 ms after stimulation at the cervicomedullary junction and 100 ms after peripheral nerve stimulation. 3. The duration of the silent period, the amplitude of the motor‐evoked potential, and the twitch force produced in the muscle were compared at increasing intensities of magnetic TCS. When the stimulus strength was increased from 30 to 70% of the stimulator output, the duration of the silent period lengthened as the amplitude of the motor potential and force of the muscle twitch increased. At 70 to 100% of the output, the amplitude of the motor potential and force of the muscle twitch saturated, whereas the duration of the silent period continued to increase. 4. Proximal arm muscle twitches induced by direct electrical stimulation of the biceps and extensor wrist muscles produced no inhibition of voluntary activity in the contracting FDI muscle. 5. The level of background activation had no effect on the duration of the silent period recorded in the FDI muscle after magnetic TCS. 6. Corticomotoneurone excitability after TCS was studied by means of a single magnetic conditioning shock and a test stimulus consisting either of one single magnetic shock or single and double electrical shocks (interstimulus interval 1.8 ms) in the relaxed muscle. A conditioning magnetic shock completely suppressed the response evoked by a second magnetic shock, reduced the size of the response evoked by a single electrical shock but did not affect the response evoked by double electrical shocks. Inhibition of the test magnetic shock was also present during muscle contraction. 7. Our findings indicate that the first 50 ms of the silent period after TCS are produced mainly by spinal mechanisms such as after‐hyperpolarization and recurrent inhibition of the spinal motoneurones. If descending inhibitory fibres contribute, their contribution is small. Changes in proprioceptive input probably have a minor influence. From 50 ms onwards the silent period is produced mainly by cortical inhibitory mechanisms.

Consensus: Motor cortex plasticity protocols

Noninvasive transcranial stimulation is being increasingly used by clinicians and neuroscientists to alter deliberately the status of the human brain. Important applications are the induction of virtual lesions (for example, transient dysfunction) to identify the importance of the stimulated brain network for a certain sensorimotor or cognitive task, and the induction of changes in neuronal excitability, synaptic plasticity or behavioral function outlasting the stimulation, for example, for therapeutic purposes. The aim of this article is to review critically the properties of the different currently used stimulation protocols, including a focus on their particular strengths and weaknesses, to facilitate their appropriate and conscientious application.

Facilitation of muscle evoked responses after repetitive cortical stimulation in man

Abstract The technique of repetitive transcranial magnetic stimulation (rTMS) allows cortical motor areas to be activated by trains of magnetic stimuli at different frequencies and intensities. In this paper, we studied long-term neurophysiological effects of rTMS delivered to the motor cortex at 5 Hz with an intensity of 120% of motor threshold. Each stimulus of the train produced muscle-evoked potentials (MEPs) in hand and forearm muscles, which gradually increased in size from the first to the last shock. After the end of the train, the response to a single-test stimulus remained enhanced for 600–900 ms. In contrast, the train had no effect on the size of the MEPs evoked by transcranial electrical stimulation, while it suppressed H-reflexes in forearm muscles for 900 ms. We conclude that rTMS of these parameters increases the excitability of the motor cortex and that this effect outlasts the train for almost 1 s. At the spinal level, rTMS may increase presynaptic inhibition of Ia afferent fibers responsible for the H-reflex.

Scaling of the size of the first agonist EMG burst during rapid wrist movements in patients with Parkinson's disease.

Rapid wrist flexion movements were studied in a group of 10 patients with Parkinsons disease both on and off their normal drug therapy, and were compared with the same movements made by a group of eight normal individuals. When normal subjects made movements through 60 degrees, the first agonist burst of EMG activity in the wrist flexor muscles was longer and larger than that seen in movements of 15 degrees. If a large opposing load of 2.2 Nm was added, this also increased the size and duration of the first agonist EMG burst. Although the movements made by the patients were slower than those of normals, the size and duration of the first agonist EMG burst changed with movement size and added load in the normal way. This shows that patients can produce large, long bursts of EMG activity, but that there is a failure to match these parameters appropriately to the size of movement required. The effect of levodopa therapy on the movements was not dramatic. Although patients produced faster wrist movements when on medication than when off, the change was relatively small compared with the change seen in their overall clinical rating. Changes in the velocity of movements at a single joint are not a good reflection of the overall clinical state of patients with Parkinsons disease.

A prevalence study of primary dystonia in eight European countries

There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorders (and botulinum toxin) clinics. The crude annual period prevalence rate (1996–1997) for primary dystonia was 152 per million (95% confidence interval 142–162), with focal dystonia having the highest rate of 117 per million (108–126). Prevalence rates for cervical dystonia, blepharospasm and writers cramp were as follows: 57 (95% confidence interval 51–63), 36 (31–41), and 14 (11–17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focus dystonias with the exception of writers cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writers cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.Abstract There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorders (and botulinum toxin) clinics. The crude annual period prevalence rate (1996–1997) for primary dystonia was 152 per million (95% confidence interval 142–162), with focal dystonia having the highest rate of 117 per million (108–126). Prevalence rates for cervical dystonia, blepharospasm and writers cramp were as follows: 57 (95% confidence interval 51–63), 36 (31–41), and 14 (11–17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focus dystonias with the exception of writers cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writers cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.

ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease

Objective: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). Methods: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. Results: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. Conclusions: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.

EFNS/MDS‐ES recommendations for the diagnosis of Parkinson's disease

A Task Force was convened by the EFNS/MDS‐ES Scientist Panel on Parkinsons disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD.

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

Effects of diazepam, baclofen and thiopental on the silent period evoked by transcranial magnetic stimulation in humans

The cortical silent period evoked by magnetic transcranial stimulation and the peripheral silent period were studied in healthy subjects after intravenous injection of diazepam, baclofen or thiopental. None of the drugs tested changed the peripheral silent period. But, unexpectedly, diazepam significantly shortened the cortical silent period, the inhibitory effect lasting about 30 min. In experiments using paired transcranial stimuli, the conditioning shock inhibited the test response to a similar extent with and without diazepam. Although baclofen did not change the cortical silent period, it reduced the size of the H reflex in the forearm muscles. Thiopental also left the duration of the cortical silent period unchanged. These findings show that the cortical silent period can be modified pharmacologically. Diazepam possibly shortens the silent period by modulating GABA A receptors at a subcortical site.