Cervical Electrical Stimulation for ALS

• ClinicalTrials.gov Identifier: NCT03411863
• Recruitment Status: Completed
• First Posted: January 26, 2018
• Results First Posted: October 25, 2022
• Last Update Posted: October 25, 2022
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Device: CES at rest; Device: CES plus active hand or wrist movements	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Noninvasive Cervical Electrical Stimulation for ALS: Mechanistic and Safety Study
• Actual Study Start Date: January 4, 2018
• Actual Primary Completion Date: June 1, 2021
• Actual Study Completion Date: June 1, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Electromyographic (EMG) Responses (Rest) [ Time Frame: up to 1 day ]
   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).
2. Electromyographic Responses (Active) [ Time Frame: up to 1 day ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, New York

James J. Peters VA Medical Center, Bronx, NY

Bronx, New York, United States, 10468

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Principal Investigator: Noam Y. Harel, MD PhD; James J. Peters Veterans Affairs Medical Center

  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:

Study Protocol and Statistical Analysis Plan  [PDF] May 5, 2019

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT03411863
• Other Study ID Numbers: B2527-P
• First Posted: January 26, 2018
• Results First Posted: October 25, 2022
• Last Update Posted: October 25, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: At time of publication.
• 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.

• 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

Keywords provided by VA Office of Research and Development:

Transcutaneous Electric Nerve Stimulation; transcranial magnetic stimulation

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases