James A. Bashford and colleagues aimed to identify a novel quantitative biomarker related to fasciculations that could monitor patients with amyotrophic lateral sclerosis over time.
Fasciculations are a hallmark of amyotrophic lateral sclerosis. Their presence precedes the onset of muscle weakness. However benign fasciculation syndrome is not considered a prodrome of amyotrophic lateral sclerosis.
The authors have recently developed Surface Potential Quantification Engine (SPiQE), which is an automated analytical tool designed to detect and characterize fasciculation potentials from resting high-density surface electromyography. SPiQE is capable of analysing 30-min recordings, producing simple outputs related to fasciculation frequency, amplitude, inter-fasciculation intervals and data quality. SPiQE’s analytical pipeline achieved a classification accuracy of 88% when applied to 5318 fasciculation potentials that had been identified manually.
A motor unit comprises the motor neuron cell body, axon, terminal branches and connecting muscle fibres. Amyotrophic lateral sclerosis leads to a process called chronic partial denervation. This means that as motor units succumb to the disease and die, surviving motor units are instructed to sprout and branch to reinnervate orphaned muscles fibres.
This is an evolutionary, compensatory mechanism designed to maintain muscle power in the face of a reduced motor unit pool. In amyotrophic lateral sclerosis, a reinnervating motor unit steadily acquires new muscle fibres and consequently produces motor unit action potentials of larger amplitude, longer duration and greater complexity.
However, due to the relentless loss of motor units in amyotrophic lateral sclerosis, this process of reinnervation cannot maintain muscle strength indefinitely. A saturation point is reached and muscle fibres consequently atrophy, leading swiftly to clinical weakness. By assessing fasciculation amplitude serially as a surrogate of this reinnervation process, the scientists hoped to gain insight into this process.
It had been suggested that motor unit firing pattern is evidence for motoneuronal or axonal fasciculations; namely interspike intervals of approximately 5 ms (doublet intervals) provide evidence for the axonal firing. Fasciculation doublets have been shown to occur in biceps brachii, vastus lateralis and tibialis anterior from patients with amyotrophic lateral sclerosis, as well as the gastrocnemius (along with the soleus muscle, the gastrocnemius forms half of the calf muscle) from both patients with amyotrophic lateral sclerosis and benign fasciculation syndrome.
Fasciculation doublets are defined as the occurrence of two almost identical motor unit potentials, presumed to both arise from the same motor unit, with a very short IFI of <100 ms. Shorter inter-fasciculation intervals (5–10 ms) are likely to arise distally in the terminal branches, whereas longer inter-fasciculation intervals (40–80 ms) are thought to originate proximally at the soma.
Faced with the low occurrence rate of doublets during electrical stimulation, the scientists hypothesized that collection of vast numbers of fasciculations would be required to observe IFI peaks in these ranges. In turn, this might help to elucidate the origin of fasciculations in amyotrophic lateral sclerosis.
So in this study, Bashford and colleagues compared amyotrophic lateral sclerosis patients with control subjects who have benign fasciculation syndrome, a condition that is defined by the isolated presence of fasciculations, particularly in muscles of the lower limbs, without evidence of underlying motor neuron degeneration
Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome each underwent up to seven assessments at intervals of 2 months A total of 420 (210 biceps, 210 gastrocnemius) amyotrophic lateral sclerosis and 116 (58 biceps, 58 gastrocnemius) benign fasciculation syndrome recordings were analyzed. Ten biceps recordings from two patients with amyotrophic lateral sclerosis were excluded due to contamination from a Parkinsonian resting tremor
The scientists tested whether the presence of muscle weakness in patients with amyotrophic lateral sclerosis influenced the change in fasciculation frequency over time. The scientists divided the data into strong and weak muscles. The scientists divided each muscle into pre-weakness, peri-weakness and post-weakness groups. This allowed them to assess the chronology of disease by equating these groups to early, middle and late stages of disease, respectively. This was only possible due to the anatomical specificity of the high-density surface electromyography technique, which is a major strength in this setting.
For biceps, fasciculation frequency in strong amyotrophic lateral sclerosis muscles was 10× greater than the benign fasciculation syndrome baseline, while fasciculation frequency in weak muscles started at levels 40× greater than the benign fasciculation syndrome baseline. Over the 14 months of the study, fasciculation frequency decreased in weak muscles at a rate three times faster than average. This supported the suspicion of the authors that biceps fasciculation frequency was non-linear, first rising steadily from a pre-morbid baseline in strong muscles and subsequently falling as weakness ensued.
Given that there was no significant change in biceps fasciculation frequency over the 14 months of the study in strong amyotrophic lateral sclerosis muscles, Bashford and colleagues hypothesize that the rising phase is slow, perhaps starting many years before clinical weakness. In contrast to biceps, gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles, but plateaued in weak muscles.
The most striking implication from these results was the rise and subsequent fall of fasciculation frequency in amyotrophic lateral sclerosis biceps muscles. This non-linear pattern had been previously suggested after statistically modelling fasciculation counts using muscle ultrasound and might explain why a previous surface EMG study of fasciculation frequency did not show a significant linear change over time.
The scientists hypothesize that the two main contributing factors to fasciculation frequency are the size of the affected motor unit pool and the relative degree of hyperexcitability. The size of the viable motor unit pool declines over time in biceps muscles, even while muscles remained strong (albeit at a slower rate than weak muscles). However, it remains unknown what proportion of motor units are affected (and therefore hyperexcitable) at a given stage of the disease.
The decline in fasciculation frequency can be attributed to the relentlessly shrinking motor unit pool. The picture above highlight the proposed model of the interactions between muscle power, size of viable motor unit pool (as assessed by MUNIX) and fasciculation frequency in benign fasciculation syndrome and three stages of disease in amyotrophic lateral sclerosis.
The diagrams depict the dynamic changes in motor unit architecture and relative hyperexcitability (depicted by electric bolts) as a consequence of motor neuron degeneration and motor unit loss.
In benign fasciculation syndrome, there is global hyperexcitability affecting all motor units to a similar degree in the absence of motor neuron degeneration.
In early amyotrophic lateral sclerosis, a subset of motor units are hyperexcitable, motor unit loss has begun and mild–moderate compensatory reinnervation has occurred. Due to the stability of biceps fasciculation frequency in strong muscles over 14 months (at a firing rate ~10 greater than the benign fasciculation syndrome baseline), the rising phase is hypothesized to begin many years before muscle weakness first appears.
It is postulated that towards the latter end of the rising phase, the rate of increase in fasciculation frequency speeds up, so that by the onset of weakness, fasciculation frequency is ~40 the benign fasciculation syndrome baseline.
In the middle stage, the ongoing loss of motor units has promoted extensive re-innervation of surviving motor units, which then become hyperexcitable themselves. This compensatory mechanism leads to fasciculations of greater amplitude and allows muscles to remain strong by staving off muscular atrophy.
However, as a tipping point is reached, these compensatory mechanisms saturate, leading to the onset of muscle atrophy and weakness.
In late amyotrophic lateral sclerosis, the death of the most re-innervated motor units leads to worsening muscle atrophy and weakness. The relentless loss of motor units drives the falling fasciculation frequency. Evidence of doublets with inter-fasciculation intervals in the 20–80 ms range is consistent with the period of motor unit subtypes (fast-slow), supporting a proximal origin of fasciculations at the soma. Throughout all stages of amyotrophic lateral sclerosis and in benign fasciculation syndrome, the degree of hyperexcitability of the lower motor neuron is likely to be driven and/or influenced by descending corticospinal inputs.
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