Spinal Interneuron Excitability in ALS

NCT ID: NCT02429492

Last Updated: 2026-01-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-16
• Study Completion Date: 2021-09-07

Brief Summary

Amyotrophic lateral sclerosis (ALS) is due to neurodegeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis and death. However, there is growing evidence that interneurons involved in the gain regulation of spinal motoneuron (lower motor neurons) and in sensorimotor integration may participate in the pathogenesis of ALS. While sensory afferents in the peripheral nerve are traditionally thought to be unaffected at the beginning of the disease, diffusion MRI has revealed degeneration and demyelination of the posterior columns in the spinal cord of patients recently diagnosed with ALS, and there are sporadic reports of sensory involvement. Early alteration of the sensorimotor integration could participate to the degeneration of motor neurons and interneurons. The goal of the project is to further investigate sensorimotor integration at spinal level in human patients recently diagnosed with ALS, and to study whether an interneuron pathology could participate in ALS pathogenesis.

Our project has first an interest for the fundamental research aiming at increasing basic knowledge of pathophysiology of ALS, and specifically on the functional effects of the underlying neurodegenerative mechanisms. By testing the excitability of spinal interneurons in patients recently diagnosed, and by doing so for clinically uninvolved muscles, we will be able to evaluate whether an interneuron pathology could be involved in ALS. Our results will help to understand better the chain reactions in the neurodegenerative processes that dramatically evolve until the death of all motor neurons. Our project has also an interest for the development of therapeutic approaches for ALS. Indeed, our methods will help to determine specific electrophysiological biomarkers that will help to evaluate quantitatively spinal and corticospinal neural processes: their changes during the course of the disease (follow-up study), the effect of therapeutic agents and/or rehabilitation methods on their excitability, and their repercussions on motor neuron activity (evaluation of therapeutics). Lastly, our methods could be tested in other neuromuscular diseases to determine possible differences in spinal neural activity. Indeed, the motor dysfunction common to several neuromuscular diseases can make it difficult to make a definitive diagnosis. The development of specific biomarkers is crucial for an early diagnosis, and to evaluate the best treatment for the patients as rapidly as possible.

Detailed Description

Given the all-or-none properties of neuromuscular junctions, the electromyogram (EMG) reflects the activity of spinal motoneurons. These neurons are the last order neurons in all neural pathways involved in motor control. Modification of the afferent neural activity, whatever its level (spinal or supraspinal), will affect the excitability of spinal motoneurons and thus EMG activity. Combined with electrical and/or magnetic stimulation of peripheral nerve and/or cortical structures, it is possible to test indirectly the excitability of corticospinal and spinal reflex pathways involved in human motor control. One of the novelties is that we will investigate the interneurons that are activated by motor axons or afferents inputs from affected muscles (distal musculature: hand/wrist or foot/ankle muscles), which control clinically unaffected muscles (proximal musculature: elbow or knee muscles). This has a threefold interest i) functional exploration of clinically unaffected muscles that are never evaluated in ALS patients, ii) to better interpret the EMG signal and to better elucidate the pathophysiological mechanisms underlying the change in EMG activity, and iii) to determine if interneuron pathology manifests before detectable change in the motoneuron. The conditioned EMG and threshold tracking methods will be used to evaluate the excitability of spinal interneurons in ALS patients, as compared to sex and age-matched healthy subjects.

Conditions

ALS

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

ALS patients

Patients with amyotrophy lateral sclerosis (ALS)

Group Type: EXPERIMENTAL

Electrophysiology

Intervention Type: DEVICE

EMG recordings conditioned by electrical peripheral nerve stimulation and/or transcranial magnetic stimulation

Control subjetcs

Neurologically intact subjects sex and age-matched to ALS patients

Group Type: EXPERIMENTAL

Electrophysiology

Intervention Type: DEVICE

EMG recordings conditioned by electrical peripheral nerve stimulation and/or transcranial magnetic stimulation

Interventions

Electrophysiology

EMG recordings conditioned by electrical peripheral nerve stimulation and/or transcranial magnetic stimulation

Intervention Type: DEVICE

Other Intervention Names

EMG

Eligibility Criteria

Inclusion Criteria

• speaking french
• signature of the written consent
• patients with ALS and no other motor neuron disease (ALS group)
• neurologically intact subjects (Control group)

Exclusion Criteria

• pregnancy
• contraindication to TMS

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pierre-François Pradat, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Hopital Pitie Salpetriere

Paris, , France

Countries

France

References

Turner MR, Kiernan MC. Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis? Amyotroph Lateral Scler. 2012 May;13(3):245-50. doi: 10.3109/17482968.2011.636050. Epub 2012 Mar 16.

Reference Type: BACKGROUND

PMID: 22424125 (View on PubMed)

Sangari S, Peyre I, Lackmy-Vallee A, Bayen E, Pradat PF, Marchand-Pauvert V. Transient increase in recurrent inhibition in amyotrophic lateral sclerosis as a putative protection from neurodegeneration. Acta Physiol (Oxf). 2022 Apr;234(4):e13758. doi: 10.1111/apha.13758. Epub 2022 Jan 23.

Reference Type: RESULT

PMID: 34981890 (View on PubMed)

Marchand-Pauvert V, Peyre I, Lackmy-Vallee A, Querin G, Bede P, Lacomblez L, Debs R, Pradat PF. Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis. J Physiol. 2019 Nov;597(22):5445-5467. doi: 10.1113/JP278117. Epub 2019 Oct 26.

Reference Type: RESULT

PMID: 31523813 (View on PubMed)

Related Links

https://www.lib.upmc.fr/?page_id=81

research team web site

Other Identifiers

2014-A01240-47

Identifier Type: OTHER

Identifier Source: secondary_id

C14-21

Identifier Type: -

Identifier Source: org_study_id