Amyotrophic Lateral Sclerosis
Conditions
Keywords
Transcutaneous Electric Nerve Stimulation, transcranial magnetic stimulation
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.
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.
Interventions
DEVICECES 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.
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.
Sponsors
VA Office of Research and Development
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Electromyographic (EMG) Responses (Rest) | 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). |
| Electromyographic Responses (Active) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participants Without Neurological Disease All subjects undergo same full protocol.
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.
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. | 8 |
| Participants With ALS All subjects undergo same full protocol.
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.
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. | 11 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Participants With ALS | Total | Participants Without Neurological Disease |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 17 Participants | 7 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 11 Participants | 19 Participants | 8 Participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Male | 6 Participants | 11 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 5 / 11 |
| other Total, other adverse events | 2 / 8 | 5 / 11 |
| serious Total, serious adverse events | 0 / 8 | 1 / 11 |
Outcome results
Primary
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).
Time frame: up to 1 day
Population: Participants who completed at least one session of resting conditioned/non-conditioned stimuli were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES -10 ms | 8.4 % change compared to TMS alone | Standard Deviation 25.5 |
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES +2 ms | -5.9 % change compared to TMS alone | Standard Deviation 23.6 |
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES -25 ms | 6.8 % change compared to TMS alone | Standard Deviation 29 |
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES +5 ms | 14.1 % change compared to TMS alone | Standard Deviation 38.7 |
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES -2 ms | 8.0 % change compared to TMS alone | Standard Deviation 24.9 |
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES +10 ms | 14.0 % change compared to TMS alone | Standard Deviation 30.4 |
| Participants Without Neurological Disease | Electromyographic (EMG) Responses (Rest) | TMS+CES 0 ms | 2.7 % change compared to TMS alone | Standard Deviation 53.2 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES +10 ms | 45.8 % change compared to TMS alone | Standard Deviation 77 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES -25 ms | 21.6 % change compared to TMS alone | Standard Deviation 44.7 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES -10 ms | -6.1 % change compared to TMS alone | Standard Deviation 17.9 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES 0 ms | 38.5 % change compared to TMS alone | Standard Deviation 38.6 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES +2 ms | 48.3 % change compared to TMS alone | Standard Deviation 67.2 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES +5 ms | 11.2 % change compared to TMS alone | Standard Deviation 39 |
| Participants With Amyotrophic Lateral Sclerosis (ALS) | Electromyographic (EMG) Responses (Rest) | TMS+CES -2 ms | 3.4 % change compared to TMS alone | Standard Deviation 42 |
Primary
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.
Time frame: up to 1 day
Population: Unfortunately, this data is uninterpretable due to technically mis-timed synchronization between muscle action and spinal stimulation.