Cross-frequency cortex-muscle interactions are abnormal in young people with dystonia.

Sensory processing and sensorimotor integration are abnormal in dystonia, including impaired modulation of beta-corticomuscular coherence. However, cortex-muscle interactions in either direction are rarely described, with reports limited predominantly to investigation of linear coupling, using corticomuscular coherence or Granger causality. Information-theoretic tools such as transfer entropy detect both linear and non-linear interactions between processes. This observational case-control study applies transfer entropy to determine intra- and cross-frequency cortex-muscle coupling in young people with dystonia/dystonic cerebral palsy. Fifteen children with dystonia/dystonic cerebral palsy and 13 controls, aged 12-18 years, performed a grasp task with their dominant hand. Mechanical perturbations were provided by an electromechanical tapper. Bipolar scalp EEG over contralateral sensorimotor cortex and surface EMG over first dorsal interosseous were recorded. Multi-scale wavelet transfer entropy was applied to decompose signals into functional frequency bands of oscillatory activity and to quantify intra- and cross-frequency coupling between brain and muscle. Statistical significance against the null hypothesis of zero transfer entropy was established, setting individual 95% confidence thresholds. The proportion of individuals in each group showing significant transfer entropy for each frequency combination/direction was compared using Fisher's exact test, correcting for multiple comparisons. Intra-frequency transfer entropy was detected in all participants bidirectionally in the beta (16-32 Hz) range and in most participants from EEG to EMG in the alpha (8-16 Hz) range. Cross-frequency transfer entropy across multiple frequency bands was largely similar between groups, but a specific coupling from low-frequency EMG to beta EEG was significantly reduced in dystonia [P = 0.0061 (corrected)]. The demonstration of bidirectional cortex-muscle communication in dystonia emphasizes the value of transfer entropy for exploring neural communications in neurological disorders. The novel finding of diminished coupling from low-frequency EMG to beta EEG in dystonia suggests impaired cortical feedback of proprioceptive information with a specific frequency signature that could be relevant to the origin of the excessive low-frequency drive to muscle.

Multiscale Wavelet Transfer Entropy With Application to Corticomuscular Coupling Analysis.

OBJECTIVE: Functional coupling between the motor cortex and muscle activity is commonly detected and quantified by cortico-muscular coherence (CMC) or Granger causality (GC) analysis, which are applicable only to linear couplings and are not sufficiently sensitive: some healthy subjects show no significant CMC and GC, and yet have good motor skills. The objective of this work is to develop measures of functional cortico-muscular coupling that have improved sensitivity and are capable of detecting both linear and non-linear interactions. METHODS: A multiscale wavelet transfer entropy (TE) methodology is proposed. The methodology relies on a dyadic stationary wavelet transform to decompose electroencephalogram (EEG) and electromyogram (EMG) signals into functional bands of neural oscillations. Then, it applies TE analysis based on a range of embedding delay vectors to detect and quantify intra- and cross-frequency band cortico-muscular coupling at different time scales. RESULTS: Our experiments with neurophysiological signals substantiate the potential of the developed methodologies for detecting and quantifying information flow between EEG and EMG signals for subjects with and without significant CMC or GC, including non-linear cross-frequency interactions, and interactions across different temporal scales. The obtained results are in agreement with the underlying sensorimotor neurophysiology. CONCLUSION: These findings suggest that the concept of multiscale wavelet TE provides a comprehensive framework for analyzing cortex-muscle interactions. SIGNIFICANCE: The proposed methodologies will enable developing novel insights into movement control and neurophysiological processes more generally.

The rise and fall of fasciculations in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a median survival of 3 years from symptom onset. Accessible and reliable biomarkers of motor neuron decline are urgently needed to quicken the pace of drug discovery. Fasciculations represent an early pathophysiological hallmark of amyotrophic lateral sclerosis and can be reliably detected by high-density surface electromyography. We set out to quantify fasciculation potentials prospectively over 14 months, seeking comparisons with established markers of disease progression. Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome underwent up to seven assessments each. At each assessment, we performed the amyotrophic lateral sclerosis-functional rating scale, sum power score, slow vital capacity, 30-min high-density surface electromyography recordings from biceps and gastrocnemius and the motor unit number index. We employed the Surface Potential Quantification Engine, which is an automated analytical tool to detect and characterize fasciculations. Linear mixed-effect models were employed to account for the pseudoreplication of serial measurements. The amyotrophic lateral sclerosis-functional rating scale declined by 0.65 points per month (P < 0.0001), 35% slower than average. A total of 526 recordings were analysed. Compared with benign fasciculation syndrome, biceps fasciculation frequency in amyotrophic lateral sclerosis was 10 times greater in strong muscles and 40 times greater in weak muscles. This was coupled with a decline in fasciculation frequency among weak muscles of -7.6/min per month (P = 0.003), demonstrating the rise and fall of fasciculation frequency in biceps muscles. Gastrocnemius behaved differently, whereby strong muscles in amyotrophic lateral sclerosis had fasciculation frequencies five times greater than patients with benign fasciculation syndrome while weak muscles were increased by only 1.5 times. Gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles (2.4/min per month, P < 0.0001), which levelled off in weak muscles. Fasciculation amplitude, an easily quantifiable surrogate of the reinnervation process, was highest in the biceps muscles that transitioned from strong to weak during the study. Pooled analysis of >900 000 fasciculations revealed inter-fasciculation intervals <100 ms in the biceps of patients with amyotrophic lateral sclerosis, particularly in strong muscles, consistent with the occurrence of doublets. We hereby present the most comprehensive longitudinal quantification of fasciculation parameters in amyotrophic lateral sclerosis, proposing a unifying model of the interactions between motor unit loss, muscle power and fasciculation frequency. The latter showed promise as a disease biomarker with linear rates of decline in strong gastrocnemius and weak biceps muscles, reflecting the motor unit loss that drives clinical progression.

Abnormal patterns of corticomuscular and intermuscular coherence in childhood dystonia.

OBJECTIVE: Sensorimotor processing is abnormal in Idiopathic/Genetic dystonias, but poorly studied in Acquired dystonias. Beta-Corticomuscular coherence (CMC) quantifies coupling between oscillatory electroencephalogram (EEG) and electromyogram (EMG) activity and is modulated by sensory stimuli. We test the hypothesis that sensory modulation of CMC and intermuscular coherence (IMC) is abnormal in Idiopathic/Genetic and Acquired dystonias. METHODS: Participants: 11 children with Acquired dystonia, 5 with Idiopathic/Genetic dystonia, 13 controls (12-18 years). CMC and IMC were recorded during a grasp task, with mechanical perturbations provided by an electromechanical tapper. Coherence patterns pre- and post-stimulus were compared across groups. RESULTS: Beta-CMC increased post-stimulus in Controls and Acquired dystonia (p = 0.001 and p = 0.010, respectively), but not in Idiopathic/Genetic dystonia (p = 0.799). The modulation differed between groups, being larger in both Controls and Acquired dystonia compared with Idiopathic/Genetic dystonia (p = 0.003 and p = 0.022). Beta-IMC increased significantly post-stimulus in Controls (p = 0.004), but not in dystonia. Prominent 4-12 Hz IMC was seen in all dystonia patients and correlated with severity (rho = 0.618). CONCLUSION: Idiopathic/Genetic and Acquired dystonia share an abnormal low-frequency IMC. In contrast, sensory modulation of beta-CMC differed between the two groups. SIGNIFICANCE: The findings suggest that sensorimotor processing is abnormal in Acquired as well as Idiopathic/Genetic dystonia, but that the nature of the abnormality differs.

Cortico-muscular coherence enhancement via coherent Wavelet enhanced Independent Component Analysis.

Functional coupling between the motor cortex and muscle activity is usually detected and characterized using the spectral method of cortico-muscular coherence (CMC) between surface electromyogram (sEMG) and electroencephalogram (EEG) recorded synchronously under motor control task. However, CMC is often weak and not easily detectable in all individuals. One of the reasons for the low levels of CMC is the presence of noise and components unrelated to the considered tasks in recorded sEMG and EEG signals. In this paper we propose a method for enhancing relative levels of sEMG components coherent with synchronous EEG signals via a variant of Wavelet Independent Component Analysis combined with a novel component selection algorithm. The effectiveness of the proposed algorithm is demonstrated using data collected in neurophysiologcal experiments.

Corticomuscular Coherence With Time Lag With Application to Delay Estimation.

Functional coupling between the motor cortex and muscle activity is usually detected and characterized using the spectral method of corticomuscular coherence (CMC). This functional coupling occurs with a time delay, which, if not properly accounted for, may decrease the coherence and make the synchrony difficult to detect. In this paper, we introduce the concept of CMC with time lag (CMCTL), that is the coherence between segments of motor cortex electroencephalogram (EEG) and electromyography (EMG) signals displaced from a central observation point. This concept is motivated by the need to compensate for the unknown delay between coupled cortex and muscle processes. We demonstrate using simulated data that under certain conditions the time lag between EEG and EMG segments at points of local maxima of CMCTL corresponds to the average delay along the involved corticomuscular conduction pathways. Using neurophysiological data, we then show that CMCTL with appropriate time lag enhances the coherence between cortical and muscle signals, and that time lags which correspond to local maxima of CMCTL provide estimates of delays involved in corticomuscular coupling that are consistent with the underlying physiology.

Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain.

We report an English kindred affected across 4 generations with a hereditary neuropathy associated with debilitating neuropathic pain as the main clinical feature. The principal finding on clinical examination was sensory loss, and there was variable motor dysfunction. Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range. There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero. This is predicted to lead to premature termination of translation. Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity. Chronic pain is an increasingly recognised sequela of certain hereditary neuropathies and may be musculoskeletal or neuropathic in origin. In this kindred, the neuropathy was relatively mild in severity, however, neuropathic pain was an important and disabling outcome.

Modulation of corticomuscular coherence by peripheral stimuli.

The purpose of this study was to investigate the effects of peripheral afferent stimuli on the synchrony between brain and muscle activity as estimated by corticomuscular coherence (CMC). Electroencephalogram (EEG) from sensorimotor cortex and electromyogram (EMG) from two intrinsic hand muscles were recorded during a key grip motor task, and the modulation of CMC caused by afferent electrical and mechanical stimulation was measured. The particular stimuli used were graded single-pulse electrical stimuli, above threshold for perception and activating cutaneous afferents, applied to the dominant or non-dominant index finger, and a pulsed mechanical displacement of the gripped object causing the subject to feel as if the object may be dropped. Following electrical stimulation of the dominant index finger, the level of ß-range (14-36 Hz) CMC was reduced in a stimulus intensity-dependent fashion for up to 400 ms post-stimulus, then returned with greater magnitude before falling to baseline levels over 2.5 s, outlasting the reflex and evoked changes in EMG and EEG. Subjects showing no baseline ß-range CMC nevertheless showed post-stimulus increases in ß-range CMC with the same time course as those with baseline ß-range CMC. The mechanical stimuli produced similar modulation of ß-range CMC. Electrical stimuli to the non-dominant index finger produced no significant increase in ß-range CMC. The results suggest that both cutaneous and proprioceptive afferents have access to circuits generating CMC, but that only a functionally relevant stimulus produces significant modulation of the background ß-range CMC, providing further evidence that ß-range CMC has an important role in sensorimotor integration.

Hand-held nerve conduction device in carpal tunnel syndrome: a prospective study.

INTRODUCTION: We assessed the clinical impact of replacing standard neurophysiologic testing with a hand-held device (Mediracer) for diagnosis of carpal tunnel syndrome (CTS). METHODS: One hundred patients (200 hands) with suspected CTS were studied by blinded assessors [Hand-therapist (HT)1 and Consultant Neurophysiologist] using the Mediracer, followed by standard neurophysiologic testing. To simulate testing by personnel without neurological training, Mediracer recordings were analyzed separately by an assessor who had not seen the patients (HT2). RESULTS: Correlation of the CTS grades was 0.94 for the results obtained by HT1, and 0.87 for HT2. The sensitivity and specificity of the Mediracer was 0.85 and 0.9, respectively, by HT1, and 0.84 and 0.89 for HT2. Nine patients had conditions other than CTS, and 35 patients were judged to require further investigation. CONCLUSIONS: The Mediracer should only be used in patients with typical CTS symptoms and signs and no muscle wasting who have had careful neurological assessment.

Rectification of the EMG is an unnecessary and inappropriate step in the calculation of Corticomuscular coherence.

Corticomuscular coherence (CMC) estimation is a frequency domain method used to detect a linear coupling between rhythmic activity recorded from sensorimotor cortex (EEG or MEG) and the electromyogram (EMG) of active muscles. In motor neuroscience, rectification of the surface EMG is a common pre-processing step prior to calculating CMC, intended to maximize information about action potential timing, whilst suppressing information relating to motor unit action potential (MUAP) shape. Rectification is believed to produce a general shift in the EMG spectrum towards lower frequencies, including those around the mean motor unit discharge rate. However, there are no published data to support the claim that EMG rectification enhances the detection of CMC. Furthermore, performing coherence analysis after the non-linear procedure of rectification, which results in a significant distortion of the EMG spectrum, is considered fundamentally flawed in engineering and digital signal processing. We calculated CMC between sensorimotor cortex EEG and EMG of two hand muscles during a key grip task in 14 healthy subjects. CMC calculated using unrectified and rectified EMG was compared. The use of rectified EMG did not enhance the detection of CMC, nor was there any evidence that MUAP shape information had an adverse effect on the CMC estimation. EMG rectification had inconsistent effects on the power and coherence spectra and obscured the detection of CMC in some cases. We also provide a comprehensive theoretical analysis, which, along with our empirical data, demonstrates that rectification is neither necessary nor appropriate in the calculation of CMC.

Canomad presenting without ophthalmoplegia and responding to intravenous immunoglobulin.

The acronym CANOMAD encompasses chronic ataxic neuropathy combined with ophthalmoplegia, M protein, cold agglutinins, and anti-disialosyl antibodies.Herein we describe 2 patients presenting with progressive ataxic neuropathy who only developed ophthalmoplegia after a significant delay post-presentation, which in 1 case had features indicative of brainstem dysfunction. Both patients were found to have an IgM paraprotein and anti-disialosyl antibodies. They responded to treatment with intravenous immunoglobulin, thus illustrating the importance of diagnosing this condition.

Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies.

Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.

Detecting fasciculations in amyotrophic lateral sclerosis: duration of observation required.

A practical issue in the diagnosis of amyotrophic lateral sclerosis (ALS) is how long the EMG must be observed before a muscle can be declared free of fasciculations with some degree of certainty. To answer this question, the intervals between fasciculation potentials (FPs) were recorded from 53 muscles of 19 ALS patients. The distribution of the FP intervals found across the sample showed that to record a single fasciculation with a probability approaching unity, observation for up to 90 s may be required.

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.

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.