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Question In transcranial magnetic stimulation (TMS), two pulse waveforms are mainly used to study cortical function. While monophasic stimuli are optimal to measure cortical excitability, the biphasic pulse waveform is increasingly used to induce cortical plasticity and to treat neurological as well as psychiatric illnesses. Methods We used a novel stimulation device (flexTMS) to study variable pulse configurations in young healthy volunteers. Primary outcome measure was cortical resting motor threshold (RMT). We determined the strength-duration relationship for single-pulse biphasic TMS using pulse durations between 120 and 400 μs. To further characterize the biphasic stimulus, we systematically varied amplitude and current direction of the first and second part of the stimulus waveform. Results The strength-duration relation has a parabolic shape for biphasic stimulation with a minimum at a pulse length of approximately 240 μs. Varying the amplitude of the part inducing a posterior-anterior oriented current considerably raised RMT, while changes of the part which induces an anterior-posterior current had little effect. Conclusion Our results clarify the role of pulse duration in biphasic TMS. The part inducing a posterior-anterior current in the brain contributes most to the effect of biphasic stimulation. These findings have important methodological implications and contribute to the understanding of the physiology of TMS.

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to evaluate the integrity and maturation of the corticospinal tract. TMS was used in this study to compare intracortical inhibition (ICI) in children, adolescents, and adults. The paired-pulse technique of TMS with interstimulus intervals of 2 ms was used to determine the ratio of conditioned (cMEP) and unconditioned amplitudes (ucMEP) that measures ICI. In experiment 1 (Exp 1) stimulus intensity was adapted to motor threshold (50 healthy subjects; 24 male, 26 female, median age 13.5 years, range 6.3 - 34 years) and in experiment 2 (Exp 2) stimulus intensity was adapted to the ucMEP (200 - 400 microV). Children (quotient of cMEP and ucMEP: Exp. 1: 0.71 +/- 0.41, Exp. 2: 0.82 +/- 0.25) had significantly less ICI compared to adults (Exp. 1: 0.21 +/- 0.19, mean +/- STD, Exp. 2: 0.35 +/- 0.22, in both experiments p < 0.001). Recently, ICI has been linked to the regulating function of GABAergic cortical interneurons on practice-dependent neuronal plasticity. Therefore, the lower ICI in children points to maturation processes that may have implications for the greater capacity of practice-dependent neuronal plasticity in children.

We studied the clinical impact of neutralizing antibodies to botulinum toxin A that occurred during long-term treatment of children between 1993 and 2001. Antibodies were found in high titers in 35 of 110 (31.8%) samples from individual patients. Antibody formation correlated with secondary nonresponse (p0.001). The most significant risk factors for antibody formation were the frequency of treatments (p = 0.0001) and the injection of a higher weight-adapted maximum dose per treatment (p = 0.001).

Transcranial magnetic stimulation was used to investigate the effect of the psychostimulant drug methylphenidate (MPH) on motor cortex excitability in healthy adults (n = 12) in a placebo-controlled, crossover design study. MPH caused an enhancement of intracortical inhibition as well as intracortical facilitation. Enhancement of both of these TMS parameters was unexpected and suggests that MPH exerts its action on the motor cortex not only through the dopaminergic neurotransmitter system.

Objective : To study the mechanisms of amplitude attenuation caused by a transcranial magnetic conditioning stimulus. Both conventional MEPs and the recently described triple stimulation technique (TST) were applied; the latter to improve the quantification of the response size decrease. Methods : TST uses a peripheral collision method to eliminate the effects of desynchronization of the transcranial magnetic stimulation (TMS) induced spinal motor neuron discharges. The attenuation of motor evoked potentials (MEPs) and responses to TST was studied in 10 healthy volunteers using the conditioning-test paradigm with 2 ms interstimulus intervals. Results : Conventional MEPs and responses to TST demonstrated a marked attenuation by the preceding conditioning stimulus in all subjects. The ratio of MEP to TST amplitudes was the same in conditioned and unconditioned responses. Conclusions : Our findings suggest that the transcranial conditioning stimulus does not change the degrees of desynchronization of spinal motor neuron discharges, but results in a reduced number of excited alpha motor neurons. This reduction can be estimated by both MEPs and TST.

Bereits der Name Botulinum Toxin A verrat viel uber die Historie einer Substanz, die in den letzten Jahren eine sprunghafte Karriere vom Gift zum Arzneimittel erfahren hat. Bekannt geworden ist das Toxin als Verursacher des Botulismus, einer Lebensmittelvergiftung, die durch verdorbene Wurst- und Konservenwaren (Botulus lat. fur Wurst) hervorgerufen wird. Im Jahr 1895 konnte das Bakterium Clostridium botulinum vom Mikrobiologen von Ermengem als Verursacher des Botulismus und Erzeuger des Botulinum Toxins identifiziert werden. Die wissenschaftliche Erstbeschreibung der Erkrankung geht 1817 auf den Arzt und Dichter Julius Kerner zuruck, der erstaunlicherweise schon damals uber einen therapeutischen Nutzen der Substanz spekulierte (Kerner 1817).

Epidermal nevus syndrome (ENS) is a congenital neurocutaneous disorder characterized by linear nevus with a significant involvement of the nervous, ophthalmological and skeletal systems. Clinical manifestations of ENS include neurological features such as mental retardation, seizures, and movement disorders which are caused by a wide range of neuropathological lesions. We describe three patients with ENS, all of whom had in addition to the characteristic features of ENS intracranial and/or intraspinal lipomas. In one patient the lipoma extended from the thoracal vertebra 8 to the 4th ventricle; in the second patient it was localized on T9, and in the third patient an intracranial lipoma was located at the right cerebellopontine angle. The intraspinal lipomas caused a significant spastic movement disorder. So far, CNS lipomas have not been described as typical neuropathological findings in ENS. The differential diagnosis to encephalocraniocutaneous lipomatosis with the typical finding of CNS lipoma is discussed.

The role of intracortical organization in the pathophysiology of cerebral palsy (CP) is not clear. We used transcranial magnetic stimulation to investigate the paradigm of transcallosal inhibition (TI) in a group of adolescent patients with diplegic CP (n = 4), hereditary spastic paraplegia (n = 2), and healthy control adolescents (n = 4). None of the patients with CP showed TI, whereas all other subjects had normal TI. These findings indicate a lack of inhibitory control of the motor cortex in CP.

Therapeutic effect of botulinum toxin A was studied in a group of pediatric patients (n = 28) aged between 6 months and 18 years. The patients were diagnosed with cervical dystonia (n = 6), adductor spasm of the hip (n = 8), spastic drop foot (n = 7) and various other focal motor problems associated with spastic muscular hyperactivity (n = 7). The mean dose of botulinum toxin A (Dysport®) used to inject into the affected muscle was 22 U/kg body weight. Reduced muscular hyperactivity with a significant increase in joint mobility was achieved for dystonic (p < 0.0001) as well as for spastic conditions in patients with adductor spasm (p < 0.0002). For these patients the improved joint mobility represented a significant benefit for both daily activities and nursing care. Local paresis and local hematoma were observed in 1/28 and 1/28 patients, respectively; 1/28 patients developed a secondary non-response. However, apart from these side effects, no other adverse reactions to botulinum toxin A treatment were recorded during the treatment and observation period (12-64 months). Our results suggest that botulinum toxin A represents an effective and safe therapeutic substance for the treatment of pediatric patients suffering of focal motor problems due to dystonic or spastic muscular hyperactivity.

Question Long-term potentiation (LTP) and long-term depression (LTD) are forms of cortical plasticity and are considered to be synaptic processes underlying learning and memory. Transcranial magnetic stimulation (TMS) with monophasic quadro-pulses (QPS) demonstrated to be effective to induce LTD-and LTP-like plasticity in human motor cortex (M1). Here, we aimed to study whether biphasic QPS at different inter-stimulus-and inter-burst-intervals induces plastic changes in human M1. Methods We investigated healthy volunteers ( n = 10 per protocol) with quadro-pulse stimulation (QPS) consisting of repeated bursts of four biphasic TMS pulses (duration: 160 μs) separated by inter-stimulus intervals of 1.5 ms and 50 ms and inter-burst intervals of 200 ms, 1 s and 5 s resulting in 6 different protocols (QPS 1.5−200 , QPS 1.5−1 , QPS 1.5−5 , QPS 50−200 , QPS 50−1 , QPS 50−5 ; 1440 total stimulus counts per protocol). TMS was applied by a custom-made magnetic stimulator (IMETUM, Munich). Resting motor threshold (rMT), and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1mv and 0.4 mV (SI 1mV and SI 0.4mV ) were measured before (Pre) QPS directly after (Post1), after 15 min (Post2), after 30 min (Post3) and after 60 min (Post4). Results We found a significant increase of MEPs after QPS 1.5−5 at SI 0.4mV and a significant decrease after QPS 50−200 , QPS 50−5 and QPS 1.5−200 at SI 1 mV . QPS 1.5−1 and QPS 50−1 had no significant effect on MEPs, respectively. Significant changes in rMT, referring to a model of intrinsic plasticity, were observed for QPS 50−200 but not for QPS 50−5 . Conclusion Biphasic QPS demonstrated to induce intensity and frequency dependent LTP-or LTD-like effects displayed by an increase or decrease in MEP amplitudes. This form of stimulation might offer new opportunities in investigations of cortical plasticity in humans.

Background Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. Methods In NF1 patients (n = 11; 19–44 years) and healthy controls (HC; n = 11; 19–31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. Results In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. Conclusions This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

Adductor spasticity in children with cerebral palsy (CP) impairs motor function and development. In a placebo-controlled, double-blind, randomized multicentre study, we evaluated the effects of botulinum toxin A(BTX-A) in 61 children (37 males, 24 females; mean age 6 years 1 month [SD 3y 1mo]) with CP (leg-dominated tetraparesis, n=39; tetraparesis, n=22; GMFCS level I, n=3; II, n=6; III, n=17; IV, n=29; V, n=6). Four weeks after treatment, a significant superiority of BTX-A was observed in the primary outcome measure (knee-knee distance 'fast catch', p=0.002), the Ashworth scale (p=0.001), and the Goal Attainment Scale (p=0.037).

Received: 8 September 1998 /Accepted in revised form:16 September 1998Sir: Intramuscular injection of botulinum toxin A is an e•ectivetherapy for children and adults with dystonic and spastic move-ment disorders as well as with achalasia [2, 3, 4]. We report on theuse of botulinum toxin in two infants with hypertrophic pyloricstenosis, neither of whom responded to this treatment. Our resultssuggest that: (1) botulinum toxin A is not a treatment option inhypertrophic pyloric stenosis in infants and (2) the release ofacetylcholine does not play a major role in the pathophysiology ofthis condition.Two unrelated infants (a 3-week-old male and a 5-week-oldfemale) were diagnosed with hypertrophic pyloric stenosis, con-firmed by ultrasound. Following approval by the Ethics committee(Freiburg University) and by the parents who were informed aboutthe experimental nature of this therapy, botulinum toxin A wasdelivered into the pyloric muscle using a flexible, upper gastro-intestinal, endoscopically-guided injection. The dose of botulinumtoxin A was adapted from previous experience in patients withdystonic conditions for the first patient (5 U Dysport/kg bodyweight; total 20 U) and patients with spasticity for the secondpatient (12 U Botox/kg body weight, total 44 U).Neither patient showed either clinical or sonographic responseto treatment during the following 4 days, although this periodshould have been su†cient to achieve a detectable e•ect. Correctadministration application was confirmed by reviewing videorecordings of the procedure. The given dose used for our secondpatient was the same as that used e•ectively for the treatment ofchildren with achalasia [3]. In both of our patients surgicalintervention (Ramstedt procedure) was performed with a successfuloutcome.Acetylcholine is considered to be the primary neurotransmitterwith excitatory e•ects upon smooth muscle [1]. In achalasia the lossor dysfunction of inhibitory neurons which contain vasoactivepolypeptide and nitric oxide results in a predominantly excitatorycholinergic innervation that can be suppressed by botulinum toxinA [4]. In hypertrophic pyloric stenosis the inability to relax thepyloric muscle has been considered to be due to deficiency of nitricoxide synthetase [5]. The lack of e•ect of botulinum toxin Asuggests that the gastric outlet obstruction in hypertrophic pyloricstenosis is not due to a predominantly cholinergic excitatoryinnervation. Instead, hypertrophic pyloric stenosis could be causedby development-related denervation a•ecting both inhibitory andexcitatory pathways.

Intramuscular injections of botulinum toxin type A (BTX-A) have increasingly been used to reduce spasticity in specific muscle groups in children with cerebral palsy. Targets of therapeutic efforts are improvement of gross motor function, alleviation of pain or facilitation of hygienic care. Placebo-controlled studies have shown the local and functional effectiveness of BTX-A for the treatment of dynamic pes equinus. Whether long-term treatment with BTX-A improves motor development and delays contractures is still under investigation.

Three patients with cerebral palsy are described suffering, respectively, of pes equinus, spasm of the m. teres major and flexion spasm of the hand, who were treated with botulinum toxin A. These patients demonstrate not only the local reduction of the muscular hyperactivity following treatment with botulinum toxin A but also the potential functional benefit resulting from such a treatment. Thus, local intramuscular injection of botulinum toxin A in children with cerebral palsy should be considered as part of a multidisciplinary treatment concept, since reduction of the disability and the functional improvements could have high impact on daily living activities.

Intramuscular injection of botulinum neurotoxin A is a relatively new method for treating spastic movement disorders in children. One major goal of any therapy for patients with movement disorders is to improve gross motor function. In this study, 18 patients with adductor spasm were treated with botulinum neurotoxin A. Treatment effect was determined with the Gross Motor Function Measure, a standardized, validated instrument designed to assist in assessment of gross motor function. Spastic muscle hyperactivity and joint mobility were evaluated by the modified Ashworth Scale and by range of motion, respectively. Compared to pretreatment values, significant improvement in gross motor function ( P < .010), decrease in the modified Ashworth Scale, and increase in the range of motion ( P < .010) were achieved. Patients with moderate impairment of gross motor function (classed at level III and level IV in the Gross Motor Function Classification System) benefited most from treatment. In patients with severe handicap (level V), only one of five treated patients showed improvement in gross motor function. Nevertheless, all patients in this subgroup benefited from improved ease in hygienic care. In conclusion, we have demonstrated that for most children with moderate functional impairment, the Gross Motor Function Measure is a useful instrument for objective documentation of improvements of gross motor function following treatment with botulinum neurotoxin A. ( J Child Neurol 2000;15:214-217).

Botulinum toxin type A (BTX-A) has been used successfully to manage spasticity in children with cerebral palsy. Little has been done to evaluate treatment outcome and satisfaction from the patients' and parents' points of view. The aim of this study was to investigate the parents' perceptions of the benefits of BTX-A on movement disorders in children with cerebral palsy. Twenty-six children with adductor spasticity were enrolled into an open-label, prospective study. Patients received intramuscular injections of BTX-A, and assessments of joint mobility (passive range of motion), degree of spasticity (Modified Ashworth Scale) and functional benefit (Gross Motor Function Measure) were made before and 12–18 weeks after treatment. Parents' assessment of treatment outcomes were evaluated using a standardised questionnaire. BTX-A was shown to be effective in reducing muscular hyperactivity and functional limitations. Parents' satisfaction with the treatment outcome was high. For non-ambulatory patients, the reported benefits included facilitation of daily care, ease of positioning and reduction of pain. For patients who were disabled to a lesser extent, improvements in gait and posture included sitting with improved comfort, standing for longer periods of time and/or walking longer distances. The parents' responses supported the impressions of the therapists, demonstrating that BTX-A produced beneficial effects on daily activities, according to both objective measures and parents' observation.