Cervical Electrical Stimulation for ALS

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:

• 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.
• 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.

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