Assessing Motor Neuron Disease Mechanisms by Threshold Tracking Transcranial Magnetic Stimulation and Magnetic Resonance Spectroscopy

Study Overview
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Brief Summary
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Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which cases the death of neurons controlling the voluntary muscles. The death of motor neurons leads eventually to muscle weakness and muscle atrophy and as a consequence thereof, ALS patients die in average within three years after symptom onset due to respiratory failure. No cure for ALS is currently known, and the medical diagnosis and clinical treatment are impeded by the lack of reliable diagnostic tools for objective disease assessment, and by the limited insight in disease pathophysiology since the underlying disease mechanisms still have not been fully elucidated. An unbalance in the concentrations of GABA and glutamate, the most important inhibitory and excitatory brain metabolites, is suggested to play a role in the disease mechanisms of ALS. By applying Magnetic Resonance Spectroscopy (MRS), a magnetic resonance method which allows for quantification of brain metabolites, GABA and glutamate concentration can be quantified and thus hopefully elucidate their role in ALS disease mechanism. Threshold Tracking Transcranial Magnetic Stimulation (TT-TMS) studies carried out by a single research group have demonstrated cortical hyperexcitability (a physiology state in which neurons in the cerebral cortex are easier activated) as an early feature in ALS patients. For this reason, TT-TMS was suggested as a biomarker of ALS by the research group. However, to be able to suggest a test as a biomarker, one must show the test is reliable and reproducible. The objectives of this study are therefore: to explore the pathophysiology of ALS by investigating the interaction between neuronal networks as assessed by TT-TMS and conventional TMS and MRS, and to investigate the reliability and reproducibility of TT-TMS. The aim is to examine the utility of TT-TMS and MRS as diagnostic tools for objective detection of ALS in the early disease stage. The study will include 60 participants in total, subdivided into two groups: 30 healthy participants and 30 patients with clinical suspicion of motor neuron disease or ALS. Each participant will undergo examination with TMS and MRS, the primary outcomes will be compared between the two groups and the results from the TMS examinations and the MRS-scans will be correlated.

Official Title
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Assessing Motor Neuron Disease Pathophysiology by Two Novel Methods - Threshold Tracking Transcranial Magnetic Stimulation and Magnetic Resonance Spectroscopy

Conditions
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Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Cortical Excitability

Intervention / Treatment
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* Diagnostic Test: MRS, conventional TMS and treshold tracking TMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with possible, probable or definite ALS according to international criteria; progressive muscular atrophy; clinical suspicion of motor neuron disease or ALS Healthy participants: no younger than 45 years of age Exclusion Criteria: Patients and healthy participants: ealier central or peripheral nervous system disease pacemaker or other implants pregnancy use of medications known to affect central nervous system

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>MRS, conventional TMS and treshold tracking TMS The participants will be told not to consume coffee or alcohol or do exhausting exercise 12, 24 and 48 hours, respectively, prior to the examinations | Diagnostic Test: MRS, conventional TMS and treshold tracking TMS<br>* Using two MagStim 200 magnetic stimulator and a figure-of-eightc double 70 mm coil SPECIAL MR Spectroscopy sequence In addition, each group will undergo neurological examination<br>|
| Healthy subjects<br>MRS, conventional TMS and treshold tracking TMS The participants will be told not to consume coffee or alcohol or do exhausting exercise 12, 24 and 48 hours, respectively, prior to the examinations | Diagnostic Test: MRS, conventional TMS and treshold tracking TMS<br>* Using two MagStim 200 magnetic stimulator and a figure-of-eightc double 70 mm coil SPECIAL MR Spectroscopy sequence In addition, each group will undergo neurological examination<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| short interval intracortical inhibition (SICI) measured by threshold tracking TMS | Measurement of the relative change in resting motor threshold during different interstimulus intervals and stimulus intensities | 8 hours | 
| short interval intracortical inihibition (SICI) measured by conventional TMS | Measurement of the size of motor evoked potentials (MEP) during different interstimulus intervals and a predetermined stimulus intensity | 8 hours | 
| Concentration of GABA and glutamate | Concentration of GABA and glutamate quantified as a ratio of creatine or tissue water content | 1 hour | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treshold Tracking Transcranial Magnetic Stimulation, Magnetic Resonance Spectroscopy, Inter-rater agreement, Reproducibililty of Results, Case-control Studies, Biomarkers, Intra-rater agreement