Clinical trial NCT06320444: Non-invasive Spinal, Cortical, and Sensorimotor Biomarkers in Motor Neurone Disease
Official title: Developing Novel Non-invasive Electrophysiological Biomarkers of Dysfunction in Spinal and Cortical Pathways and Sensorimotor Impairments in Motor Neurone Disease
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Motor Neuron Disease, Amyotrophic Lateral Sclerosis
Motor Neuron Disease Progressive Spinal Muscle Atrophy
Primary Lateral Sclerosis
Multiple Sclerosis
Postpoliomyelitis Syndrome
Keywords: Electroencephalography (EEG)
Peripheral Nerve Stimulation
Vibration-Induced Stimulation
Neurodegeneration
Electrophysiology
Biomarkers
Neuromuscular Physiology
Spinal Connectivity
Lead sponsor: University of Dublin, Trinity College
Sponsor class: OTHER
Collaborators: name: Motor Neurone Disease Association, UK
name: Irish Research Council, IE
name: Health Research Board, IE
name: Research Motor Neurone, IE
name: Thierry Latran Foundation, FR
name: ALS Association, USA
First posted: 2024-03-20
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Healthy controls and patients diagnosed with ALS, MS, PLS, PMA, and SMA.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Biomarker of sensorimotor integration
timeFrame: Baseline to 2-years after baseline
measure: Determination of the feasibility of sensorimotor signatures as reliable biomarkers of ALS
timeFrame: Baseline
measure: Non-invasive recording of the SC functional neuro-electric activity
timeFrame: Baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: Academic Unit of Neurology, Trinity College Dublin, The University of Dublin
state: Leinster
Study officials:
affiliation: Academic Unit of Neurology, Trinity College Dublin, The University of Dublin
name: Orla Hardiman, BSc MB BCh BAO MD FRCPI FAAN
role: PRINCIPAL_INVESTIGATOR
References: