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In Essential Tremor (ET), tremor characteristics and the impairment caused by tremor may vary from task to task. A variability of tremor frequency between postural and kinetic tasks has been proposed in ET, suggesting either multiple central oscillating networks, or peripheral or proprioceptive feedback-mechanisms. This electrophysiological study aimed to assess tremor frequencies and amplitudes in tasks involving postural and kinetic tremor, and compare findings within and across tasks, to delineate physiological differences underlying individually affected manual tasks in ET.40 ET patients were included in the study. Tremor was characterized clinically, as well as electrophysiologically using accelerometry and digitizing tablet tasks. Tremor amplitude measures and frequencies were extracted for tasks involving kinetic (digital spiral drawing, handwriting), as well as postural tremor. Tremor was compared between and within tasks.Digital spiral tremor frequencies were significantly higher compared to postural tremor frequencies, as measured by accelerometry, with a mean difference of2 Hz (p 0.001). Within-task variability of repeated digital spirals revealed a significant amplitude reduction over time in both hands (p 0.001), with an up to 32% reduction compared to the first spiral.ET exhibited a frequency variability, which was dependent on activation condition, suggesting neurophysiologically distinct pathways between postural and kinetic tremor. The reduction of tremor amplitudes observed in repeated digital spiral drawing may be explained by a learning effect or adaptation, and should be considered as non-random factor of variability when using spirals in ET to assess effects of interventions.

In the motor system, one specific movement is generated, and, simultaneously, other possible movements are suppressed; a process called surround inhibition. Focal hand dystonia (FHD) is a movement disorder characterized by a loss of surround inhibition. In order to explain the deficit in surround inhibition induced by volitional movement in FHD patients, we examined the inhibitory circuit activated by afferent stimulation at "long latency". We studied 14 patients (age 48.9+/-13.2 years, 3 females, 11 males) with idiopathic task-related FHD. To measure long-latency afferent inhibition (LAI), transcranial magnetic stimulation (TMS) was applied to the affected hemisphere for FHD patients and to the dominant hemisphere for 17 healthy volunteers. Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) and first dorsal interosseous (FDI) during rest and during voluntary phasic flexion of the second digit. Subjects were given electrical stimulation to either their fifth digit (homotopic to ADM, heterotopic to FDI) or their second digit (heterotopic to FDI, homotopic to ADM) at twice sensory perceptual threshold 180 ms prior to TMS application. Additionally, F-waves were recorded from ADM. At rest, we found a significant decrease in ADM MEP amplitudes with both homotopic and heterotopic stimulation compared to the corresponding non-stimulated trials. There was a trend toward less LAI in FHD patients. During movement, LAI was significantly decreased in both patients and controls. There was no significant group effect. The results for LAI in FDI were similar to those from ADM. F-wave area in ADM was greater during movement for both homo- and heterotopic stimulation. We found no difference in F-wave area between patients and healthy volunteers. Our results indicate that LAI is unlikely to be an underlying mechanism that contributes to the generation of normal surround inhibition in healthy volunteers or in the disruption of surround inhibition in FHD.

Kranz et al. used a ninhydrin sweat test (NST) and mouse diaphragm test (MDT) in 14 dystonic patients and 14 controls and reported subclinical neutralizing antibodies (Abs) in patients with “good clinical responses” to BoNT/A. The authors defined the responses based on a three-point decrease on modified-Tsui scale, injected-muscle atrophy, or reported BoNT/A-associated adverse events.1 Only one patient had anti-BoNT/A Abs (1 mU/mL, by MDT) and a marked anhydrotic area reduction (0.26 cm2). Seven other patients had “borderline” titers of either 0.4 or 0.8 mU/mL and reduced anhidrosis area. The study design, small sample size, and subjective clinical-response assessment precludes extension to incidence value (>40%). Mixing Botox- and Dysport-treated patients complicates analysis because these products have different immune-response rates. NST employs area, but neglects color density. NST correlation value was missing, as the anhydrotic area could vary with injection method. Hyperhidrosis effect reproducibility was also overlooked. The Results imply that NST was done with both Botox and Dysport but this contradicts the statement in the Methods that Dysport was the test agent. The observation that patients had different Ab levels after similar toxin doses is expected.2,3 Immune responses mature with time, boosters, and are genetically controlled.2,3 This means that patients responding to treatment would have different Ab levels, even after similar doses and protocols. …

Objective : To investigate cortical regions related to voluntary blinking. Methods : Transcranial magnetic stimulation (TMS) was applied to the facial motor cortex (M1) and the midline frontal region (Fz) in 10 healthy subjects with eyes opened and closed. Motor-evoked potentials were recorded from the orbicularis oculi (OOC), orbicularis oris (OOR), abductor digiti minimi and tibialis anterior using surface and needle electromyography electrodes. Facial M waves and blink reflex were measured using supramaximal electrical stimulation of the facial and supraorbital nerves. Results : TMS at Fz elicited 3 waves in OOC with no response in other tested muscles except for the early wave in OOR. Facial M1 stimulation produced only early and late waves. Because of their latencies, shapes, and relationship to coil position and stimulation intensity, early and late waves appeared to be analogous to the facial M wave and R1 component of the blink reflex. The intermediate wave at 6–8 ms latency was elicited in OOC by Fz stimulation with eyes closed. Conclusions : Since its latency matches the central conduction time of other cranial muscles and it has characteristic of muscle activation-related facilitation, the intermediate wave is presumably related to cortical stimulation. This result provides evidence that the cortical center for the upper facial movements, including blinking, is not principally located in the facial M1, but rather in the mesial frontal region.

We examined whether unilateral exercise creates perception bias in the non-exercised limb and ascertained whether rTMS applied to the primary motor cortex (M1) interferes with this perception. All participants completed 4 interventions: 1) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand (EX), 2) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand whilst receiving rTMS over the contralateral M1 (rTMS+EX); 3) 15-min of rTMS over the ‘trained’ M1 (rTMS) and 4) 15-min rest (Rest). Pre and post-interventions, the error of force output production, the perception of effort (RPE), motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were measured in both hands. EX did not alter the error of force output production in the trained hand (Δ3%; P>0.05); however, the error of force output production was reduced in the untrained hand (Δ12%; P0.05). RPE was significantly higher after rTMS+EX in the trained hand (9.2±0.5 vs. 10.7±0.7; P0.05). The novel finding was that exercise alone reduced the error in force output production by over a third in the untrained hand. Further, when exercise was combined with rTMS the transfer of force perception was attenuated. These data suggest that the contralateral M1 of the trained hand might, in part, play an essential role for the transfer of force perception to the untrained hand.

Background Ataxia has been suggested in the literature to be a symptom of hepatic encephalopathy (HE), but so far has not been objectively quantified. In this study, we wanted to objectively quantify ataxia in patients with liver cirrhosis. Methods One hundred and seven patients with liver cirrhosis were tested for postural control using posturography and compared with 25 controls. For quantification of HE, we used the number connection tests A and B, ammonia levels (NH 3 ), and the partial pressure of ammonia in the arterial blood (pNH 3 ). Results Patients showed an impaired postural control compared with controls. Patients with Child C cirrhosis had lower scores in the posturography than those with Child A or B cirrhosis. Patients with alcohol-induced (AIC) Child B cirrhosis achieved lower scores in the posturography than those with non-alcohol-induced (NAIC) Child B cirrhosis. Patients with AIC Child C had lower scores than the corresponding NAIC patients, although this did not reach statistical significance. In the NAIC group Child C patients, in the AIC group Child B and C patients had lower scores than the controls. Patients with abnormal results in the number connection tests, as well as those with high NH 3 and pNH 3 levels showed worse postural control than those with normal results. Conclusion Patients with cirrhosis have an impaired postural control compared with controls and this impairment deteriorates with progression of liver disease. HE as well as past alcohol abuse contribute to the pathogenesis of ataxia in liver cirrhosis and past alcohol abuse leads to an earlier and more pronounced manifestation of ataxia in the affected patients.

Mouse units used to quantify the activity of botulinum A toxin preparations are not equivalent and issues concerning efficacy and safety remain with regard to their respective potencies and diffusion qualities in human tissue. We compared the effects of Botox (BOT) and Dysport (DYS) in different doses and dilutions in a human skin model. Eighteen (8 women, 10 men) healthy volunteers, aged 28.4 years +/- 5.7 years were injected intradermally with pure saline, BOT and DYS at 16 points in the abdomen in random order and in a double-blind condition, using two conversion ratios (1:3 and 1:4) and three different dilution schemes. For an objective outcome, the Ninhydrin sweat test was used to compare the anhidrotic areas. Both preparations showed a linear dose and dilution relationship with similar variances of responses for anhidrosis and hypohidrosis, indicating the same reliability of response. The dose equivalence conversion ratios (BOT: DYS) were 1:1.3 for anhidrosis and 1:1.6 for hypohidrosis (1:1.1-1.5 and 1:1.4-1.8 95% confidence intervals). The diffusion characteristics of both products were similar. A dose equivalence factor of more than 1:2 (BOT:DYS) is not supported by these objective and reproducible data.

Objective Repetitive transcranial magnetic stimulation (rTMS) is a potential therapeutic tool to rehabilitate chronic stroke patients. In this study, the safety of high-frequency rTMS in stroke was investigated (Phase I). Methods The safety of 20 and 25 Hz rTMS over the motor cortex (MC) of the affected hemisphere, with intensities of 110–130% of the motor threshold (MT), was evaluated using surface electromyography (EMG) of hand and arm muscles. Results Brief EMG bursts, possibly representing peripheral manifestations of after discharges, and spread of excitation to proximal muscles are considered to be associated with a high risk of seizure occurrence. These events were recorded after the rTMS trains. Neither increased MC excitability nor improved pinch force dynamometry was found after rTMS. Conclusions Stimulation parameters for rTMS, which are safe for healthy volunteers, may lead to a higher risk for seizure occurrence in chronic stroke patients. Significance rTMS at rates of 20 and 25 Hz using above threshold stimulation potentially increases the risk of seizures in patients with chronic stroke.

Background Previous studies showed that anodal transcranial DC stimulation (tDCS) applied to the primary motor cortex of the affected hemisphere (M1affected hemisphere) after subcortical stroke transiently improves performance of complex tasks that mimic activities of daily living (ADL). It is not known if relatively simpler motor tasks are similarly affected. Here we tested the effects of tDCS on pinch force (PF) and simple reaction time (RT) tasks in patients with chronic stroke in a double-blind cross-over Sham-controlled experimental design. Results Anodal tDCS shortened reaction times and improved pinch force in the paretic hand relative to Sham stimulation, an effect present in patients with higher impairment. Conclusion tDCS of M1affected hemisphere can modulate performance of motor tasks simpler than those previously studied, a finding that could potentially benefit patients with relatively higher impairment levels.

BACKGROUND Pain sensation associated with injections of botulinum neurotoxin (BoNT) is commonly reported. To date differences in pain sensation between the commercially available products containing BoNT have not been quantified. OBJECTIVES The pain sensations during injection of Dysport, Botox, Neurobloc, and pure saline (control) were compared. In addition, the nociceptive effect of different volumes used for the dilution of the same BoNT dose was investigated. METHODS In a prospective, double-blind, controlled trial, 10 healthy subjects were injected intradermally with Dysport (12 U), Botox (3 and 4 U), Neurobloc (150 and 300 U) reconstituted in 0.9% saline, and pure saline. Pain sensation was quantified during injections. RESULTS Neurobloc injections caused significantly more injection pain than Botox, Dysport, and saline. No significant differences between Dysport, Botox, and saline were found, although there was a trend toward less pain with pure saline injections. Higher pain levels with higher volumes could not be demonstrated significantly. CONCLUSION Our data demonstrate that BoNT type B injections are associated with substantial pain. There is a considerable difference between the commercially available BoNT type B compared to the two BoNT type A preparations. Therefore, considering mitigation of injection pain seems necessary when using BoNT type B.

Objective To test a possible strategy to alleviate somatosensory deficits after stroke. Methods Here, we applied ischemic nerve block to the intact hand of patients with chronic stroke, which in healthy subjects elicits improvements in sensibility of the other hand. Results We found that sensibility in the affected hand improved with intact hand anesthesia, but not with intact foot anesthesia or no anesthesia. Interpretation We conclude that reduction of sensory input from the intact hand leads to site-specific improvements in tactile discriminative skills in the affected hand after the period of anesthesia, a potentially relevant finding in designing neurorehabilitative interventions. Ann Neurol 2006

Stimulation of a peripheral nerve of a hand at rest modulates excitability in the motor cortex and, in particular, leads to inhibition when applied at an interval of ∼200 ms (long-latency afferent inhibition; LAI). Surround inhibition (SI) is the process that inhibits neighboring muscles not involved in a particular task. The neuronal mechanisms of SI are not known, and it is possible that LAI might contribute to it. Using transcranial magnetic stimulation (TMS) with and without movement of the index finger, the motor-evoked potentials (MEPs) were measured of two functionally distinct target muscles of the hand (abductor digiti minimi muscle = ADM, 1st dorsal interosseus muscle = FDI). Electrical stimulation was applied 180 ms before TMS to either the fifth finger or the index finger. Both homotopic and heterotopic finger stimulation resulted in LAI without movement. With index finger movement, motor output further decreased with homo- and heterotopic stimulation in the ADM. In the moving FDI, however, there was no change with either homo- or heterotopic stimulation. Additionally, in the unstimulated movement trials, LAI increased with the amount of unintentional co-activation that occurred despite attempts to maintain the ADM at rest. However, with finger stimulation added, there were almost no increased MEPs despite co-activation. These findings suggest that LAI increases during movement and can enhance SI.

During individual finger movement, two opposite phenomena occur at the level of the central nervous system that could affect other intrinsic hand muscle representations, unintentional co-activation, and surround inhibition (SI). At rest, excitability in the motor cortex (M1) is inhibited at about 20 ms after electric stimulation of a peripheral nerve [short-latency afferent inhibition (SAI)]. We sought to determine whether SAI changes during selective index finger movement. Effects were measured by the response to transcranial magnetic stimulation in two functionally distinct target muscles of the hand [abductor digiti minimi muscle (ADM), first dorsal interosseus muscle (FDI)]. An increase in SAI in the ADM during index finger movement compared to at rest could help explain the genesis of SI. Electrical stimulation was applied to either the little finger (homotopic for ADM, heterotopic for FDI) or the index finger (heterotopic for ADM, homotopic for FDI). During index finger movement, homotopic SAI was present only in the ADM, and the effect of peripheral stimulation was greater when there was less co-activation. Heterotopic SAI found at rest disappeared with movement. We conclude that during movement, homotopic SAI on the muscle in the surround of the intended movement may contribute to SI.

Approximately 5% of patients with cervical dystonia receiving repeated botulinum neurotoxin A (BoNT/A) injections develop secondary loss of treatment benefit. Currently available tests to directly detect neutralizing BoNT/A antibodies (BoNT/A-AB) are either expensive or time consuming. To establish a simple, clinically useful test for antibody detection, we adapted the ninhydrin sweat test (NST). Eighteen dystonic patients with secondary nonresponse and clinically suspected BoNT/A-AB formation were tested for BoNT/A-AB in the mouse diaphragm test (MDT). In addition, the size of the anhidrotic area was determined by the NST 21 days after an intradermal dose of 10 U Dysport into the hypothenar region of the left palm. In nine patients, positive BoNT-AB titers were found in the MDT. There was a significant correlation between the BoNT/A-AB titers and the anhidrotic area (Spearman's rho = -0.9, P0.0001). Both tests provided comparably good results with respect to qualitative antibody detection. In the clinical situation of secondary nonresponse to BoNT/A therapy, the economical NST may be a helpful tool to detect neutralizing BoNT/A-AB.

Objective: Standard coils used in research and the clinic for noninvasive magnetic stimulation of the human brain are not capable of stimulating deep brain regions directly. As the fields induced by these coils decrease rapidly as a function of depth, only very high intensities would allow functional stimulation of deep brain regions and such intensities would lead to undesirable side effects. We have designed a coil based on numerical simulations and phantom brain measurements that allows stimulation of deeper brain regions, termed the Hesed coil (H-coil). In the present study we tested the efficacy and some safety aspects of the H-coil on healthy volunteers. Methods: The H-coil was compared to a regular figure-8 coil in 6 healthy volunteers by measuring thresholds for activation of the abductor pollicis brevis (APB) representation in the motor cortex as a function of distance from each of the coils. Results: The rate of decrease in the coil intensity as a function of distance is markedly slower for the H-coil. The motor cortex could be activated by the H-coil at a distance of 5.5 cm compared to 2 cm with the figure-8 coil. Conclusions: The present study indicate that the H-coil is likely to have the ability of deep brain stimulation and without the need of increasing the intensity to extreme levels that would cause a much greater stimulation in cortical regions. Significance: The ability of non-invasive deep brain stimulation potentially opens a wide range of both research and therapeutic applications.

Objective: Botulinum toxin type A (BTXA) is used to treat neurologic disorders associated with increased muscle tone. Its use is often associated with pain relief. Methods: A possible direct analgesic effect of BTXA on C and Aδ fibers was studied on 16 healthy volunteers receiving 30 U BTXA into one forearm and pure saline into the other. To exclude the secondary effect due to muscular tone reduction, BTXA was injected intradermally. Thermal sensory testing of heat pain (threshold and tolerance) and neuroselective current sensory testing of current pain threshold/tolerance were performed at baseline and 3, 14, and 28 days after treatment. Thereafter, on day 28, capsaicin was administered simultaneously into both forearms to evaluate a possible peripheral effect and central effect on pain processing and on the axon reflex flare. Results: The authors observed no significant difference in any of the perception outcome measures between BTXA and placebo pretreated areas. Flare areas as a result of the release of neuropeptides after capsaicin application showed no differences. Conclusions: The results suggest that pain reduction after BTXA treatment is mediated through its effect on muscle tone rather than a direct analgesic effect.

Background The blocking action of botulinum toxin type A (BTX-A) on cholinergically innervated sweat glands has been used successfully to treat patients with focal hyperhidrosis. Objectives To investigate the long-term efficacy and safety of intradermal injections of BTX-A. Methods We performed an open-label study in 61 patients treated over a period of 3 years for axillary or palmar hyperhidrosis. A total dose of 400 mU BTX-A (Dysport®) was injected into both axillae or 460 mU BTX-A (Dysport®) into both palms. The injections were repeated after relapse. Objective quantification of sweat production was performed using digitized ninhydrin-stained sheets. Results Four weeks after BTX-A treatment the median reduction in sweat production was 71% compared with baseline (P

Clinical quantification of mild traumatic brain injury (MTBI) patients should be based on Glasgow coma scale (GCS) score, duration of loss of consciousness (LOC) and post-traumatic amnesia (PTA). In addition, a short practicable neuropsychological test might be useful in detecting minor memory and attentional deficits. MRI appears to be the most sensitive imaging method for assessing MTBI so far, but information regarding a visualized lesion is not usually utilized in the classification of MTBI. Magnetic resonance imaging (MRI) should, therefore, play a major role in any MTBI classification scheme. An appropriate MRI protocol has to be chosen using at least T1 weighted, T2 weighted, proton density and gradient-echo (GRE) sequence images, all in at least two planes, in order to detect and classify all lesions precisely. Owing to the fact that acute lesions may be missed, it is advisable to perform MRI in the first 2 weeks following trauma. Further research is necessary to clarify the relationship between chronic symptoms after MTBI and MRI abnormalities. It may, thus, be possible to provide optimal strategies for emergency department management, to define a group of patients with a need for acute and rehabilitative intervention after MTBI, and to predict their outcome.

Neuropsychological performance, magnetic resonance imaging (MRI) and electroencephalography (EEG) were investigated in 12 consecutive patients with very mild traumatic brain injury (MTBI) (Glasgow coma score 15) within 24 hours and 6 weeks after injury. The data were compared to 14 control subjects. There was a significant impairment in neuropsychological performance (verbal memory, arithmetic abilities and psychomotor reaction time) at onset and after 6 weeks, whereas verbal fluency and non-verbal memory test revealed no significant differences matching the control values. In MRI scans, three patients showed traumatic lesions (slight epidural haematoma, haemorrhagic contusions and white matter lesions indicating diffuse axonal injury). In the EEG recordings, no generalized slowing or focal changes were found. Structural and functional impairment can be identified using neuroimaging and neuropsychological examination, even in very MTBI patients.