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

Withdrawn

• Conditions: Motor Neuron Disease; Cortical Excitability; Amyotrophic Lateral Sclerosis
• Interventions: Diagnostic Test: MRS, conventional TMS and treshold tracking TMS

• Registration Number: NCT03664206
• Lead Sponsor: Sándor Beniczky

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2018-02-16
• Study First Submitted: 2018-09-07
• Study First Submitted QC: 2018-09-07
• Study First Posted: 2018-09-10
• Primary Completion: 2023-12-31
• Status Verified: 2024-02
• Study Completion: 2024-02-01
• Last Update Submitted: 2024-02-01
• Last Update Posted: 2024-02-02

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Healthy subjects	MRS, conventional TMS and treshold tracking TMS	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
Patients	MRS, conventional TMS and treshold tracking TMS	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

Primary Outcome Measures

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

Trial Locations

Locations (1)

Department of Clinical Neurophysiology, Aarhus University Hospital; 🇩🇰 Aarhus, Denmark