Neuromuscular Magnetic Stimulation in ALS Patients

Study Overview
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Brief Summary
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Aim of the study is to verify whether neuromuscular magnetic stimulation can improve muscle function in spinal-onset Amyotrophic Lateral Sclerosis (ALS) patients.

Detailed Description
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Background: Amyotrophic lateral sclerosis (ALS) is a multi-factorial and multi-systemic pathology associated with motor neuron degeneration, muscle atrophy and paralysis. Mounting evidence suggests that the earliest presymptomatic functional and pathological changes are occurring distally in axons and at the neuromuscular junction (NMJ). These changes precede, and can be independent of the loss of cell bodies or alterations in other cell types already linked to the ALS disease process. In line with these studies, we found that in human ALS muscles the acetylcholine receptors (AChRs) are less sensitive to ACh than denervated non-ALS muscles. It has been also reported that muscle specific expression of mutant superoxide dismutase (SOD1) gene induces muscle atrophy, significant reduction in muscle strength, mitochondrial dysfunction, microgliosis, and neuronal degeneration, suggesting that retrograde signals from muscle to nerve may contribute to synapse and axon damage. This suggests that skeletal muscle is an important target for therapeutic intervention. Neuromuscular system may be artificially stimulated either by an electrical stimulation (ES) or by time-varying electromagnetic fields. Neuromuscular magnetic stimulation (NMMS) has been proposed as an alternative, non-invasive, stimulation technique. Objective: aim of the study is to verify whether neuromuscular magnetic stimulation can improve muscle function in spinal-onset Amyotrophic Lateral Sclerosis (ALS) patients. We will study if neuromuscular magnetic stimulation can counteract muscle atrophy by promoting the modulation of factors associated with muscle catabolism and/or increasing the efficacy of nicotinic acetylcholine receptors. Methods: At the baseline visit, ALS patients will be randomized in two groups to receive daily real neuromuscular magnetic stimulation in one arm and sham neuromuscular magnetic stimulation in the opposite arm for two weeks. All patients will undergo median nerve conduction study and a clinical examination, including handgrip strength test and evaluation of upper limbs muscle strength by Medical Research Council Muscle Scale. At the end of the stimulation procedures, a needle muscle biopsy will be performed bilaterally from flexor carpi radialis muscle. Muscle samples will be used to perform histomorphometric and molecular analysis and electrophysiological recordings of acetylcholine evoked currents.

Official Title
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Neuromuscular Magnetic Stimulation Counteracts Muscle Decline in ALS Patients

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Device: Neuromuscular magnetic stimulation (NMMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of probable or definite ALS with spinal-onset right-handed patients a bilateral symmetric muscular deficit in flexor carpi radialis muscle or flexor digitorum profundus muscle (defined by a MRC Muscle Scale score of 3-4/5) Exclusion Criteria: history of epilepsy or severe headaches, pregnancy or breast-feeding patients with implanted cardiac pacemaker, neurostimulators, surgical clips or medical pumps presenting any other comorbid condition affecting the possibility of completing the study
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized in two groups by receiving a sequential number according to a from a computer-generated random list. A first group will receive a real stimulation (rNMMS) of the right arm and a sham stimulation (sNMMS) of the left arm; a second group received a rNMMS of the left arm and a sNMMS of the right arm. Every cycle of stimulation will last two weeks. All patients will undergo a medial nerve conduction study (NCS) and a clinical evaluation before and at the end of the treatment and another evaluation after two weeks after the end of treatment. Clinical examination will include i) handgrip strength test for the measure of maximal isometric strength of hand and flexor forearm muscles; ii) MRC Muscle Scale for manual muscular testing of the upper limbs. At the end of the stimulation procedure, a needle muscle biopsy under a local anesthetic will be performed bilaterally from flexor carpi radialis muscle for histological, physiological and molecular studies.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Right-real NMMS Group<br>It will receive a real stimulation (rNMMS) of the right arm and a sham stimulation (sNMMS) of the left arm | Device: Neuromuscular magnetic stimulation (NMMS)<br>* It is a non-invasive, stimulation technique that does not induce high-intensity cutaneous electric fields and does not activate skin nociceptors, thus resulting in a painless and better-tolerated procedure. rNMMS is delivered through a high-frequency magnetic stimulator connected to a conventional circular cooled coil. Magnetic stimulator is placed above the flexor muscles of the forearm. rNMMS is delivered at a 5-Hz frequency and with a 100% stimulation intensity of 100% of the maximum intensity in 140 trains of 50 stimuli. sNMMS is delivered with a sham coil producing similar acoustic sensations and mechanical skin perceptions.<br>|
| Active Comparator: Left-real NMMS Group<br>It will receive a rNMMS of the left arm and a sNMMS of the right arm | Device: Neuromuscular magnetic stimulation (NMMS)<br>* It is a non-invasive, stimulation technique that does not induce high-intensity cutaneous electric fields and does not activate skin nociceptors, thus resulting in a painless and better-tolerated procedure. rNMMS is delivered through a high-frequency magnetic stimulator connected to a conventional circular cooled coil. Magnetic stimulator is placed above the flexor muscles of the forearm. rNMMS is delivered at a 5-Hz frequency and with a 100% stimulation intensity of 100% of the maximum intensity in 140 trains of 50 stimuli. sNMMS is delivered with a sham coil producing similar acoustic sensations and mechanical skin perceptions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Week 2 in the muscle strength measured by Medical Research Council Muscle Scale (MRC). | Evaluation of the efficacy of NMMS in improving the muscular strength in ALS patients as measured by MRC-score (numeric scale, normal value: 35 for upper limbs, 40 for lower limbs). | Baseline to Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Week 2 in the muscle strength measured by handgrip dynamometry | Evaluation of the efficacy of NMMS in improving the muscular strength in ALS patients as measured by handgrip dynamometry (numeric scale, normal value: >35 for female, >45 for male) | Baseline to Week 2 | 
| Change from baseline to Week 2 in the Compound Muscle Action Potential (CMAP) amplitude from flexor carpi radialis | Evaluation of the effect of NMMS on the electrophysiological parameter (CMAP) to analyse the physiological mechanisms of the applied neurophysiological technique (milliVolt, mV, normal value 10.2 mV). | Baseline to Week 2 | 
| Change from baseline to Week 2 in the amplitude of the ACh-evoked currents (IACh) for nicotinic acetylcholine receptors | Evaluation of the effect of NMMS on the nicotinic acetylcholine receptor in patients with ALS (nanoAmpere, nA) | Baseline to Week 2 | 
| Change from baseline to Week 2 on levels of insulin-like growth factor-1 (IGF-1) and Myostatin | Evaluation of the effect of NMMS on the adaptation changes of gene expression due to rNMMS quantifying shifts in messenger ribonucleic acid (mRNA) levels of a selected panel of genes involved in muscle growth (numeric value) | Baseline to Week 2 | 
| Change from baseline to Week 2 on the diameter size of muscle fibers | Evaluation of the effect of NMMS on histomorphometric analysis in ALS muscle fibers (micrometer, μm). | Baseline to Week 2 | 
| Change from baseline to Week 2 on levels of Muscle Atrophy F-box (MAFbx)/Atrogin-1 and Muscle Ring-Finger Protein 1 (MuRF-1) | Evaluation of the effect of NMMS on the adaptation changes of gene expression due to rNMMS quantifying shifts in mRNA levels of a selected panel of genes involved in downregulation of atrophy-related genes (numeric value) | Baseline to Week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic lateral sclerosis, Muscle disease, Neuromuscular magnetic stimulation