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

Recruiting

• Conditions: Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neuron Disease Progressive Spinal Muscle Atrophy; Primary Lateral Sclerosis; Multiple Sclerosis; Postpoliomyelitis Syndrome
• Interventions: Procedure: 232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)

• Registration Number: NCT06320444
• Lead Sponsor: University of Dublin, Trinity College

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2022-12-19
• Study Start: 2023-06-15
• Status Verified: 2024-03
• Study First Submitted QC: 2024-03-12
• Last Update Submitted: 2024-03-12
• Study First Posted: 2024-03-20
• Last Update Posted: 2024-03-20
• Primary Completion: 2024-12-15
• Study Completion: 2025-07-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 240

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.

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Controls	232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)	Individuals from the Irish population with no psychiatric, psychological, neurological or muscular disease diagnosis
Amyotrophic lateral sclerosis Patients	232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)	-
Postpoliomyelitis syndrome patients	232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)	-
Multiple Sclerosis patients	232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)	-
Muscular Atrophy patients	232 Electrode Electrophysiology (EEG-ECG-EMG-EXG)	-

Primary Outcome Measures

Name	Time	Method
Non-invasive recording of the SC functional neuro-electric activity	Baseline	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.
Biomarker of sensorimotor integration	Baseline to 2-years after baseline	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.
Determination of the feasibility of sensorimotor signatures as reliable biomarkers of ALS	Baseline	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.

Trial Locations

Locations (1)

Academic Unit of Neurology, Trinity College Dublin, The University of Dublin; 🇮🇪 Dublin, Leinster, Ireland