The purpose of this study is to examine how neuromuscular electrical stimulation (NMES), may synergistically enhance corticospinal excitability in people with relapsing form multiple sclerosis (MS). This is an important intermediate step to evaluate the potential of AIH + NMES as a plasticity-priming strategy for more efficacious interventions for persons with MS. This study will measure ankle torque generation and amplitude of motor evoked potentials (MEPs) using a repeated measures study design in order to better understand the effects of AIH combined with NMES, as compared to only receiving NMES, and only receiving AIH.

NMES: NMES refers to the application of mild electrical stimulation and is often used as an assistive technology for foot drop in MS and other neurologic conditions. The NMES-induced improvement in motor performance appears to be mediated primarily by an increase in corticomotoneuronal excitability. A single session of NMES applied over a peripheral nerve, has been shown to transiently increase net corticospinal excitability (increased MEP amplitude) in both able-bodied individuals and in people with neurological conditions.

AIH: AIH involves breathing brief bouts of low levels of oxygen. Research has found AIH to be a safe and effective intervention resulting in increased ankle strength in people with MS. While AIH has shown potential in enhancing neuroplasticity in people with spinal cord injury (SCI), it has yet to be studied extensively in MS. Preliminary research in the MS population demonstrates that a single session of AIH enhances motor output, increasing voluntary muscle strength by as much as 15-20% within 60 minutes. Over the past decade, studies have found AIH can rapidly enhance neural plasticity in persons with incomplete SCI. AIH activates the serotonergic pathway, leading to increased activity of serotonin receptors and the synthesis of plasticity-related proteins. This plasticity is manifested by a rapid increase in voluntary muscle strength, emerging within 60-90 minutes.

In this study, the investigators will examine how NMES, which has been shown to affect cortical excitability, and AIH, which has been shown to affect corticospinal plasticity, may synergistically enhance corticospinal excitability in people with relapsing form of MS. Foot drop is a common symptom in the diagnosis of MS where the inability to maintain active dorsiflexion during the swing phase of the gait cycle affects walking efficiency, instability, and falls. Seminal studies show that individuals with MS retain the ability to express plasticity even at higher levels of disease burden. This indicates that strategies targeting neuroplasticity can be used to enhance functional recovery and limit the impact of MS disability. The investigators will conduct a randomized, blinded, placebo-controlled, cross-over study in 20 MS patients with established motor deficits and controlled relapse activity and 20 control subjects with no neurological diagnosis.

Inclusion Criteria for persons with MS:

• Diagnosis of relapsing form of MS
• Expanded Disability Status Scale (EDSS) score of at least 3 and no more than 6.5
• Relapse free for at least 1 year
• Age ≥18 years and ≤75 years
• No change in Dalfampridine dose at least 2 months prior to enrollment

Exclusion Criteria for persons with MS:

• Uncontrolled hypertension or hypotension (outside 140/90 and 90/60 mmHg)
• History of epilepsy or seizures

Inclusion Criteria for uninjured controls:

• Age ≥18 years and ≤75 years
• Safe to participate in TMS (TMS questionnaire)

Exclusion Criteria for uninjured controls:

• Uncontrolled hypertension or hypotension (outside 140/90 and 90/60 mmHg)
• History of epilepsy or seizures

Exclusion criteria to TMS participation for persons with MS and uninjured controls:

• Uncontrolled medical problems affecting the lungs (pulmonary diseases including chronic obstructive pulmonary disease), the heart (cardiovascular diseases) or the musculoskeletal system (orthopedic diseases)
• Premorbid, ongoing major depression or psychosis, altered cognitive status
• History of stroke
• Metal in head (e.g., surgical clips, shrapnel)
• History of seizures or epilepsy diagnosis
• Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold such as antipsychotic drugs (chlorpromazine, clozapine) or tricyclic antidepressants
• Surgery to the head
• Any non-MS related neurological diseases
• Illnesses that may have caused brain injury
• Unexplained frequent or severe headaches
• Pregnancy in females
• Implanted devices (e.g., pacemakers, medical pumps, brain stimulators)
• Unable to participate in TMS

The investigators do not currently have a plan to share IPD.