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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Cortical Excitability
• Intervention / Treatment: Diagnostic test: MRS, conventional TMS and treshold tracking TMS

• Study Type: Observational

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Department of Clinical Neurophysiology, Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited among patients examined at the Department of Neurophysiology who are referred for diagnostic neurophysiological examinations without any relation to the proposed project and at the Department of Neurology who are being examining for routine controls.

The healthy participants will be recruited by announcement at the homepage www.forsoegsperson.dk/ and by announcement at Aarhus University and Aarhus University Hospital

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients; 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; 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
Healthy subjects; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sándor Beniczky
• Collaborators: Aarhus University Hospital; Central Denmark Region; Lundbeck Foundation; Danish Council for Independent Research; Aage og Johanne Louis-Hansens Fond; The A.P Moeller Foundation for Advancement of Medical Science
• Investigators: Study Chair: Hatice Tankisi, MD, PhD, Department of Clinical Neuropysiology, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2018
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): February 1, 2024

Study Registration Dates

• First Submitted: September 7, 2018
• First Submitted That Met QC Criteria: September 7, 2018
• First Posted (Actual): September 10, 2018

Study Record Updates

• Last Update Posted (Estimated): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Biomarkers; Magnetic Resonance Spectroscopy; Treshold Tracking Transcranial Magnetic Stimulation; Inter-rater agreement; Reproducibililty of Results; Case-control Studies; Intra-rater agreement
• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: AMND; 7025-00066B (Other Grant/Funding Number: Independent Research Fund Denmark); 18-2B-2454 (Other Grant/Funding Number: Aage og Johanne Louis-Hansens Fond); 17-L-0365 (Other Grant/Funding Number: The A.P. Møller Foundation); 3530 (Other Grant/Funding Number: Lundbeck Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No