Non-invasive Spinal, Cortical, and Sensorimotor Biomarkers in Motor Neurone Disease

Multiple Sclerosis Clinical Trial

Official title:

Developing Novel Non-invasive Electrophysiological Biomarkers of Dysfunction in Spinal and Cortical Pathways and Sensorimotor Impairments in Motor Neurone Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06320444
• Other study ID #: CRFSJ0297
• Status: Recruiting
• Start date: June 15, 2023
• Est. completion date: July 15, 2025

Study information

• Verified date: March 2024
• Source: University of Dublin, Trinity College
• Contact: Orla Hardiman, BSc MB BCh BAO MD FRCPI FAAN
• Phone: +353 1 896 4497
• Email: hardimao[@]tcd.ie
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Substantial variability exists in the onset, and rate of degeneration across individuals with Motor Neurone Disease (MND) or Amyotrophic Lateral Sclerosis (ALS). This variability requires biomarkers that accurately classify and reliably track clinical subtypes as the disease progresses. Degeneration occurs in the brain and spinal cord, however, non-invasive diagnosis of spinal cord function remains highly challenging due to its unique alignment in spine. Disruption of complex spinal and cortical circuits that transmit and process neural signals for position sense and movement has not been adequately captured in the neurophysiological profiling of ALS patients. The overarching aim of this study is to reveal and quantify the extent of change in the sensorimotor integration and its potential contribution to network disruption in ALS.

Description:

Background:

Substantial variability exists in the onset, and rate of degeneration across individuals with Motor Neurone Disease (MND) or Amyotrophic Lateral Sclerosis (ALS). This variability requires biomarkers that accurately classify and reliably track clinical subtypes as the disease progresses. Degeneration occurs in the brain and spinal cord, however, non-invasive diagnosis of spinal cord function remains highly challenging due its unique alignment in the spine. Disruption of complex spinal and cortical circuits that transmit and process neural signals for position sense and movement has not been adequately captured in the neurophysiological profiling of ALS patients.

Aim:

To develop, test, and employ non-invasive techniques to explore (dys)function between motor, sensory brain, and spinal networks in ALS. The project will address if the electrical activity of the cortical-spinal network by the of use peripheral stimulation (vibration, electrical nerve stimulation) to probe and reveal the normal or abnormal communication between brain and spinal networks. It is expected to reveal novel neurophysiological signatures in ALS patients compared to healthy controls.

Study Design & Data Analysis:

Surface electrodes will be mounted over the targeted regions in conjunction with High-Density EEG and High-density Electromyography (EMG). A physical and mathematical model of the underlying sources of electric activity (source localization) will be carried out at rest, during task, and with non-invasive peripheral nerve stimulation (PNS) and TMS. A separate paradigm will augment sensorimotor communication between the primary motor cortex (M1) and the somatosensory cortex (S1). Mild vibration (5N/< 500 grams) will be applied to the wrist and/or bicep tendon transcutaneously. Vibration in conjunction with non-invasive peripheral nerve stimulation will induce transient changes (30 seconds maximum) in the intrinsic excitability of motor neurons in the spinal cord. Surface EMG will capture altered MN activity at the spinal level and the anticipated augmented communication in cortical networks (S1-M1) will be captured with EEG through connectivity analysis. Non-invasive transcranial magnetic stimulation in conjunction with vibration/nerve stimulation will be recorded to explore upper motor neurone influences on the altered intrinsic excitability of spinal motor neurons.

Data collection:

EXG-EEG-EMG and TMS/Peripheral Stimulation recordings will be conducted using a BioSemi® ActiveTwo system with 128 active sintered Ag-AgCl electrodes and headcaps (BioSemi B.V., Amsterdam, The Netherlands). The TMS system is a Brainbox DuoMAG (Brainbox Ltd., Cardif, Wales, UK) which can be used with a Digitimer peripheral stimulator.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 240
• Est. completion date: July 15, 2025
• Est. primary completion date: December 15, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

-

Healthy Volunteers:

• age and gender matched to patient groups

• intact physical ability to take part in the experiment.

Patients:

• Diagnosis of ALS, PLS, PMA, SMA, Polio or MS

• capable of providing informed consent.

Exclusion Criteria:

-

Healthy Controls:

• History of neuromuscular

• neurological or active psychiatric disease disease

• history of reaction or allergy to recording environments, equipment and the recording gels.

Patients:

• presence of active psychiatric disease

• any medical condition associated with severe neuropathy (e.g. poorly controlled diabetes).

• History of reaction or allergy to recording environments, equipment and the recording gels.

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Motor Neuron Disease, Amyotrophic Lateral Sclerosis
• Multiple Sclerosis
• Muscular Atrophy
• Postpoliomyelitis Syndrome
• Primary Lateral Sclerosis
• Sclerosis

Intervention

Procedure:
• 232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)
Noninvasive 232 Channel Electrode Electrophysiological signals (EEG-ECG-EMG-EXG) will be recorded from electrodes placed in a montage over the scalp, neck,and upper back along with muscles located on the hand. These signals will be recorded while resting or performing voluntary task. Other Intervention: The 232 electrode noninvasive electrophysiological data will be recorded in response to non-invasive peripheral nerve stimulation or vibration induced stimulation. These sessions are designed to engage specific cortical motor networks of interest for evaluating sensorimotor networks. (Cognitive, behavioural, motor, spinal, and sensory)

Locations

Country	Name	City	State
Ireland	Academic Unit of Neurology, Trinity College Dublin, The University of Dublin	Dublin	Leinster

Sponsors (7)

Lead Sponsor	Collaborator
University of Dublin, Trinity College	ALS Association, USA, Health Research Board, IE, Irish Research Council, IE, Motor Neurone Disease Association, UK, Research Motor Neurone, IE, Thierry Latran Foundation, FR

Country where clinical trial is conducted

Ireland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Biomarker of sensorimotor integration	A viable biomarker of sensorimotor integration for reliable and early distinction between healthy people and Motor Neuron Disease patient sub-phenotypes.; This will be achieved by comparing connectivity measures between EEG, Non-cortical CNS, and EMG electrophysiological signals. The integration will also be seen in spectral analysis measures.	Baseline to 2-years after baseline
Primary	Determination of the feasibility of sensorimotor signatures as reliable biomarkers of ALS	The sensorimotor integration and signature biomarkers achieved during outcome 1 will be correlated with the clinical scores and will be statistically tested for reliability and robustness. The effect sizes of these statistical and correlation matrices will be used to evaluate the feasibility of the signatures as reliable biomarkers for motor neuron conditions like ALS.	Baseline
Primary	Non-invasive recording of the SC functional neuro-electric activity	Understanding the role of spinal cord (SC) in neuromuscular physiology (in both impaired and healthy individuals) and will also assist in discovering biomarkers in Brain-SC Peripheral connections. This is a perspective outcome that will be future based upon the inferences gained by the first two outcomes.	Baseline