Cervical Electrical Stimulation for ALS

Noninvasive Cervical Electrical Stimulation for ALS: Mechanistic and Safety Study

Veterans are at higher risk than non-Veterans of falling ill with amyotrophic lateral sclerosis (ALS). ALS causes degeneration of motor neurons in both the brain and the spinal cord. Evidence from studies in people with spinal cord injury suggests that activating spared nerve circuits with electromagnetic stimulation improves nerve transmission.

With this goal, the investigators have developed a novel method of noninvasive cervical (neck) electrical stimulation (CES). In this study, the investigators will investigate CES for its potential to strengthen nerve circuits to the hands in ALS.

To the investigators' knowledge, electrical spinal stimulation for ALS has never been tested previously. This study will be performed in two stages: First, basic experiments will be performed to better understand how CES interacts with other types of electrical and magnetic stimulations over the brain and peripheral nerves. Second, experiments will be performed to determine the types of CES that can facilitate active arm and hand movements.

These experiments will improve understanding of electrical stimulation in ALS, and may set the table for future treatments.

Both United States Veterans and non-Veterans are eligible to participate in this study.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Device: CES at rest; Device: CES plus active hand or wrist movements

Detailed Description

Amyotrophic lateral sclerosis (ALS) reduces connections between the cortical motor neurons that initiate movement and the spinal motor neurons that direct muscles to execute movement. This situation shares many key features with incomplete spinal cord injury (SCI). Accumulating evidence in SCI suggests that externally activating spared nerve circuits with electromagnetic stimulation augments neural transmission.

With this goal, the investigators developed a novel method of noninvasive cervical electrical stimulation (CES). CES activates multiple muscles on both upper limbs by triggering afferent sensory or efferent motor nerve roots depending on stimulus intensity. This study will investigate CES for its potential to strengthen residual circuits to the hands in ALS.

To the investigators' knowledge, electrical spinal stimulation for ALS has never been tested or applied previously. Therefore, a pilot study is essential. This study will be performed in two stages:

1. Map CES circuit and synaptic targets: The experiments share a common structure comprising conditioning and test stimuli delivered at a range of intensities, sites, and interstimulus intervals.
2. Determine parameters for combining CES with volitional movement: volitional limb movements depend on the same corticospinal and motor neuron circuits as those activated by TMS and F-waves. Since preliminary data shows that subthreshold CES facilitates transcranial magnetic stimulation (TMS) responses, CES may also be able to facilitate volitional limb movements.

Successful completion of these experiments will: mechanistically elucidate CES circuit interactions; investigate the potential for CES to enhance concurrent volitional muscle activation; and establish CES as safe and feasible in the ALS population. Given the limited treatment options for ALS, any amount of progress would represent a meaningful step forward. Moreover, results of this pilot study could lead to direct translation for lasting clinical benefit by combining repetitive subthreshold CES with repetitive task-oriented physical exercise training in subsequent studies. CES would be compatible with other interventions, including medications and cell-based treatments.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10468
      • James J. Peters VA Medical Center, Bronx, NY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (ALS):

• Age between 21 and 75 years
• Diagnosis of probable or definite ALS (or non-disabled volunteer)

• Incomplete weakness of left or right wrist or hand muscles:

  • score of 2, 3, or 4 (out of 5) on manual muscle testing of:
  • wrist flexion
  • finger extension
  • finger flexion
  • or finger abduction
• Detectable F-wave responses of the left or right abductor pollicis brevis (APB) to median nerve stimulation and/or adductor digiti minimi (ADM) to ulnar nerve stimulation
• US Veteran or non-Veteran

Inclusion Criteria (Participants without neurological disease):

• Age between 21 and 75 years
• No history of significant neurological disease
• Detectable F-wave responses of the left or right APB to median nerve stimulation and/or ADM to ulnar nerve stimulation
• US Veteran or non-Veteran

Exclusion Criteria (ALS):

• History of other serious injury or disease of central or peripheral nervous system
• History of seizures
• Ventilator dependence or patent tracheostomy site
• Use of medications that significantly lower seizure threshold
• History of head trauma with evidence of brain contusion or hemorrhage or depressed skull fracture on prior imaging

• History of implanted:

  • brain/spine/nerve stimulators
  • aneurysm clips
  • ferromagnetic metallic implants
  • or cardiac pacemaker/defibrillator
• Significant coronary artery or cardiac conduction disease
• History of bipolar disorder or suicide attempt or active psychosis
• Heavy alcohol consumption (> equivalent of 5 oz of liquor) within previous 48 hours
• Open skin lesions over the face, neck, shoulders, or arms
• Pregnancy
• Unsuitable for study participation as determined by study physician

Exclusion Criteria: (Participants without neurological disease)

• History of other serious injury or disease of central or peripheral nervous system
• History of seizures
• Ventilator dependence or patent tracheostomy site
• Use of medications that significantly lower seizure threshold
• History of head trauma with evidence of brain contusion or hemorrhage or depressed skull fracture on prior imaging

• History of implanted:

  • brain/spine/nerve stimulators
  • aneurysm clips
  • ferromagnetic metallic implants
  • or cardiac pacemaker/defibrillator
• Significant coronary artery or cardiac conduction disease
• History of bipolar disorder or suicide attempt or active psychosis
• Heavy alcohol consumption (> equivalent of 5 oz of liquor) within previous 48 hours
• Open skin lesions over the face, neck, shoulders, or arms
• Pregnancy
• Unsuitable for study participation as determined by study physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Participants without neurological disease; Participants without neurological disease. All subjects undergo the same full protocol.	Device: CES at rest; CES will be delivered at rest at various intensities, in combination with either electrical stimulation over peripheral nerves or magnetic stimulation over the motor cortex. This is an experiment designed to measure CES interactions with other central and peripheral nerve circuits.; Device: CES plus active hand or wrist movements; CES will be delivered while the participant performs specific finger or wrist tasks at different degrees of effort. This is an experiment designed to detect momentary changes in muscle function.
Experimental: Participants with ALS; Participants with ALS. All subjects undergo the same full protocol.	Device: CES at rest; CES will be delivered at rest at various intensities, in combination with either electrical stimulation over peripheral nerves or magnetic stimulation over the motor cortex. This is an experiment designed to measure CES interactions with other central and peripheral nerve circuits.; Device: CES plus active hand or wrist movements; CES will be delivered while the participant performs specific finger or wrist tasks at different degrees of effort. This is an experiment designed to detect momentary changes in muscle function.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electromyographic (EMG) Responses (Rest)	These results are derived from peak-to-peak EMG amplitude in the abductor pollicis brevis (APB) muscle in response to transcranial magnetic stimulation (TMS). Values represent the ratio of peak-to-peak APB amplitude when TMS is paired with cervical electrical stimulation (CES) at the indicated timing (in milliseconds) normalized to the response to TMS alone (control).	up to 1 day
Electromyographic Responses (Active)	Effect of CES on concurrent finger or wrist active movements will be measured via root-mean-square of ongoing muscle activity in various hand and forearm muscles.	up to 1 day

Collaborators and Investigators

• Sponsor: VA Office of Research and Development

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2018
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): June 1, 2021

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: January 19, 2018
• First Posted (Actual): January 26, 2018

Study Record Updates

• Last Update Posted (Actual): October 25, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Transcutaneous Electric Nerve Stimulation; transcranial magnetic stimulation
• 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: B2527-P

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: A Limited Dataset (LDS), with individual electrophysiological and physiological outcome measures, will be shared in electronic format pursuant to a VA-approved Data Use Agreement. Individually Identifiable Data will be shared pursuant to valid HIPAA Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions as described in the authorization and consent, and a written assurance from the recipient that the information will be maintained in accordance with the security requirements of 38 Code of Federal Regulations (CFR) Part 1.466.
• IPD Sharing Time Frame: At time of publication.
• IPD Sharing Access Criteria: A Limited Dataset (LDS) will be shared in electronic format pursuant to a VA-approved Data Use Agreement. Individually Identifiable Data will be shared pursuant to valid HIPAA Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions as described in the authorization and consent, and a written assurance from the recipient that the information will be maintained in accordance with the security requirements of 38 CFR Part 1.466.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No