Kerry Mills

Corticomotor threshold to magnetic stimulation: normal values and repeatability.

The threshold for corticomotor excitation by magnetic stimuli is a clinically important parameter in the assessment of central motor conduction. Hitherto, arbitrary criteria have been adopted to define threshold and there are few published data using a figure of eight coil. A new method is described in which the highest stimulus intensity evoking responses in the relaxed first dorsal interosseous muscle with a probability of zero [lower threshold (LT)] and the lowest intensity evoking responses with a probability of one [upper threshold (UT)] have been determined. The method, which utilizes a coil located and optimally oriented over hand motor cortex, minimizes the number of stimuli needed. Both LT and UT are normally distributed and are independent of age, gender, and hemisphere. In 102 healthy hands of 55 control subjects 23–84 years of age, mean ± SD UT was 46.6 ± 9.4% and LT was 38.0 ± 8.6% maximum stimulator output. Repeatability estimates indicated an absolute change of more than 13% or 11% in UT or LT respectively in the same individual over 1–3 months was significant at the 5% level.

Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis

The pathogenesis of idiopathic amyotrophic lateral sclerosis (ALS) remains unknown, but accumulating evidence suggests a neu roexcitotoxic mechanism may have some credence. Glutamate‐induced hyperexcitability of cortical or spinal motoneurons may be expected to manifest itself as a reduced threshold for activation of these structures. We have measured corticomotor threshold to the first dorsal interosseous (FDI) muscles of 48 patients with sporadic ALS using magnetic brain stimulation and have correlated the findings with physical signs of upper and/or lower motor neuron degeneration. We find that if FDI in patients with ALS shows no weakness, wasting, or signs of an upper motor neuron lesion, mean corticomotor threshold is significantly lower than in 102 healthy control FDI muscles (P = 0.02). In contrast, FDI muscles showing signs of lower motor neuron degeneration only or mixed upper and lower motor neuron signs are associated with a raised corticomotor threshold (P = 0.008, P < 0.001, respectively). We conclude that early in ALS, at a time when hand muscle function is normal, corticomotor threshold is reduced and suggest that this may be a manifestation of abnormal excitability of cortical or spinal motoneurons to neurotransmitters, whose action will ultimately lead to cell death.

Muscle activity and acceleration during whole body vibration: Effect of frequency and amplitude

BACKGROUND Whole body vibration may improve muscle and bone strength, power and balance although contradictory findings have been reported. Prolonged exposure may result in adverse effects. We investigated the effects of high (5.5 mm) and low (2.5mm) amplitude whole body vibration at various frequencies (5-30 Hz) on muscle activity and acceleration throughout the body. METHODS Surface electromyographic activity was recorded from 6 leg muscles in 12 healthy adults (aged 31.3 (SD 12.4) years). The average rectified acceleration of the toe, ankle, knee, hip and head was recorded from 15 healthy adults (36 (SD 12.1) years) using 3D motion analysis. FINDINGS Whole body vibration increased muscle activity 5-50% of maximal voluntary contraction with the greatest increase in the lower leg. Activity was greater with high amplitude at all frequencies, however this was not always significant (P<0.05-0.001). Activation tended to increase linearly with frequency in all muscles except gluteus maximus and biceps femoris. Accelerations throughout the body ranged from approximately 0.2 to 9 g and decreased with distance from the platform. Acceleration at the head was always < 0.33 g. The greatest acceleration of the knee and hip occurred at approximately 15 Hz and thereafter decreased with increasing frequency. INTERPRETATION Above the knee at frequencies > 15 Hz acceleration decreased with distance from the platform. This was associated with increased muscle activity, presumably due to postural control and muscle tuning mechanisms. The minimal acceleration at the head reduces the likelihood of adverse reactions. The levels of activation are unlikely to cause hypertrophy in young healthy individuals but may be sufficient in weak and frail people.

Silent period to transcranial magnetic stimulation: construction and properties of stimulus-response curves in healthy volunteers

Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus–response (S–R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900–1800 mg). The S–R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947–0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8±3.31 ms (x±SEM), −11.51±3.31 ms, 11.56±0.65%, and 49.82±0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69±0.72 vs 47.95±0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3±5.8% at baseline to 59.4±10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6±42.4 ms to 143.5±46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5±4.9% to 59.9±7.2% and from 29.1±6.4% to 34.6±6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S–R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

Peripheral and central motor conduction in amyotrophic lateral sclerosis.

Conventional peripheral motor conduction studies and transcranial magnetic stimulation (TMS) studies, to measure central motor conduction time (CMCT), to the first dorsal interosseous muscle (FDI) were performed on 65 patients with amyotrophic lateral sclerosis (ALS). The hands of each patient were classified into one of four groups depending on the presence of physical signs of lower motor neurone (LMN) and/or upper motor neurone (UMN) involvement. Statistical analysis was made of the results from patients compared with previously established normal values and with those from a control group of 53 normal subjects. Results between the four groups of patients were compared in order to assess any correlation between neurophysiological findings and physical signs. A reduction in the amplitude of compound muscle action potentials (CMAP), prolongation of distal motor latency (DML) and F wave latency were found in 36%, 34% and 19% of hands respectively. These abnormalities were more common in hands with LMN signs. In nine hands, prolongation of DML occurred in the absence of muscle wasting or weakness. CMCT abnormalities were present in 17% of patients with ALS but did not appear to correlate with physical signs.

Critical illness myopathy: further evidence from muscle-fiber excitability studies of an acquired channelopathy.

Recent studies have demonstrated acquired muscle inexcitability in critical illness myopathy (CIM) and have used direct muscle stimulation (DMS) techniques to distinguish neuropathy from myopathy as a cause of weakness in the critically ill. The mechanisms underlying weakness in CIM are incompletely understood and DMS is only semiquantitative. We report results from a series of 32 patients with CIM and demonstrate significant slowing of muscle‐fiber conduction velocity (MFCV) and muscle‐fiber conduction block during the acute phase of CIM, which correlates with prolonged compound muscle action potential (CMAP) duration, clinical severity, and course. We also used a paired stimulation technique to explore the excitability of individual muscle fibers in vivo. We demonstrate altered muscle‐fiber excitability in CIM patients. Serial studies help define the course of these pathophysiological changes. Parallels are made between CIM and hypokalemic periodic paralysis. Our findings provide further evidence for muscle membrane dysfunction being the principal underlying abnormality in CIM. Muscle Nerve, 2007

Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder?

Sensory involvement is thought not to be a feature of amyotrophic lateral sclerosis (ALS). However, in the setting of a specialist motor neuron disease clinic, we have identified five patients with sporadic ALS and a sensory neuropathy for which an alternative cause could not be identified. In three individuals, sensory nerve biopsy was performed, demonstrating axonal loss without features of an alternative aetiology. These findings support the hypothesis that ALS is a multisystem neurodegenerative disorder that may occasionally include sensory neuropathy among its non-motor features.

Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer

OBJECTIVES To determine the prognosis in patients with Lambert-Eaton myasthenic syndrome (LEMS) without small cell lung cancer (SCLC), and to analyse longitudinal clinical, electrophysiological, and immunological data on each patient to establish prognostic factors for long term outcome. METHODS The retrospective and part prospective study of 47 patients with LEMS was undertaken from data recorded during visits to a specialist neuromuscular clinic. Serial measurements of muscle strength score in shoulder abduction, elbow extension and hip flexion, compound muscle action potential (CMAP) amplitude, and postcontraction increment in abductor digiti minimi (ADM), and anti-P/Q-type voltage gated calcium channel (VGCC) antibody titre were made at each visit. RESULTS Muscle strength scores were improved in 88% of patients after a median duration of immunosuppressive treatment of 6 years (range 1.3 to 17 years); anti-VGCC antibody titres fell in 52% after treatment; and mean resting CMAP amplitude improved from 2.7 mV initially to 8.8 mV after 2 years of treatment p<0.001). Initial pretreatment anti-VGCC antibody titre did not correlate significantly with either CMAP amplitude, CMAP increment, or clinical score: from serial measurements made during follow up, significant correlation between antibody titre and CMAP amplitude was seen in only two patients. Sustained clinical remission was achieved by 20 (43%) of whom only four remained in remission without the need for immunosuppression. Using a Cox proportional hazards model, the only independent predictor of sustained clinical remission was initial pretreatment clinical score (p=0.03). Lymphoma presented in three patients during the study. CONCLUSIONS The prognosis in patients with LEMS without SCLC is favourable, although patients often need significant doses of immunosuppressive treatment to remain clinically stable. Only initial clinical muscle strength measurements and not anti-VGCC antibody titres or electrophysiological recordings are predictive of long term outcome.

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS

Background: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABAA receptor, and 11C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. Methods: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. 11C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical 11C-flumazenil binding that might explain differences in cortical excitability seen using TMS. Results: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical 11C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. Conclusions: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. 11C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

Characteristics of fasciculations in amyotrophic lateral sclerosis and the benign fasciculation syndrome

The aim of this study was to determine first, if benign fasciculations and those in amyotrophic lateral sclerosis can de distinguished on the basis of their waveforms or firing characteristics, and second to determine how fasciculation parameters evolved with progression of amyotrophic lateral sclerosis. Fasciculation potentials recorded from 63 muscles of 28 patients with definite amyotrophic lateral sclerosis were compared with those from 21 muscles of 11 patients with the benign fasciculation syndrome. In each muscle, at a single site, up to 15 identifiable fasciculation potentials could be recognized. Thus the characteristics of 430 fasciculations from patients with amyotrophic lateral sclerosis and 191 benign fasciculations were analysed. Fasciculation potential amplitude, area, turns, duration, firing interval, indices of waveform variability, evidence of axonal conduction block, evidence of axonal conduction variability and propensity to produce double fasciculations were measured. The waveforms of fasciculations in amyotrophic lateral sclerosis were on average of shorter duration and had a greater number of turns than benign fasciculations, but, although irregular in both conditions, the firing rate in amyotrophic lateral sclerosis was significantly higher. In both conditions, there was evidence of multifocal distal generation of fasciculations, axonal conduction block in the motor unit arborization and of variable axonal conduction. When severe weakness and marked chronic neurogenic change were present on electromyography, the firing rate of fasciculations in amyotrophic lateral sclerosis was higher but fasciculation potential amplitude, area and indices of waveform variability were little changed. Double fasciculations in which the waveforms of the two potentials were the same occurred in both conditions. The intervals were in two bands: an early band with 4-10 ms intervals showed identical waveforms of the two potentials, indicating the region of generation was the same. A second band of double fasciculation occurred in the tibialis anterior at an interval of 30-50 ms. Here, the first fasciculation waveform was variable in shape but the second fasciculation was the same on each occasion, suggesting reactivation of the fasciculation via the F-wave route. Double fasciculations in which the second discharge was different from the first had flat time-interval histograms, indicating no interaction between different fasciculations. In conclusion, benign and malignant fasciculations are not distinguishable on the basis of waveform; highly complex fasciculation potentials can be seen in both conditions. Fasciculation firing rate and the frequency of double fasciculations increases in amyotrophic lateral sclerosis when there is a marked lower motor neuron abnormality.