Multiple SclerosisNCT06413602
The Synergistic Effects of AIH and FES in Persons With MS
A study testing Acute Intermittent Hypoxia and Neuromuscular Electrical Stimulation in people with Multiple Sclerosis and Multiple Sclerosis, Relapsing-Remitting, run by Shirley Ryan AbilityLab at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Secondary Progressive
- What is being tested?
- Acute Intermittent Hypoxia and Neuromuscular Electrical Stimulation
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Nov 2024to Aug 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
- Age ≥18 years and ≤75 years
- Safe to participate in TMS (TMS questionnaire)
Who cannot join
- Uncontrolled hypertension or hypotension (outside 140/90 and 90/60 mmHg)
- History of epilepsy or seizures
- 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)
Show all 18Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Exploring the Synergistic Effects of AIH and FES in Persons With MS
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.
Read the detailed description
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.
- Conditions
- Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Secondary Progressive
- Being tested
- Acute Intermittent Hypoxia, Neuromuscular Electrical Stimulation
- Keywords
- multiple sclerosis, plasticity, electrical stimulation, NMES, modalities, neuroplasticity, motoneuron, aih, hypoxia, acute intermittent hypoxia, control, control group
- Medical subject headings
- Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Chronic Progressive, Hypoxia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Acute Intermittent HypoxiaOther
Also called AIH
During AIH, the participant will be equipped with a non-rebreathing face mask, and provided with the AIH intervention. The AIH intervention involves alternating breathing cycles. One cycle involves breathing air with lower oxygen concentration (9-10% oxygen) for 30 and 90 seconds, followed by breathing normal room air (21% oxygen) for a similar duration. This cycle is repeated 15 times in one session. Blood oxygen and heart rate are monitored throughout.
Neuromuscular Electrical StimulationOther
Also called NMES
During NMES, participants will receive electrical stimulation to the common peroneal nerve. Stimulation will be done with a 50% duty cycle, duration of 0.5-1ms for each pulse and a frequency 25-40 Hz. The stimulus intensity will be adjusted to produce approximately 50% of the maximum M-wave (compound muscle action potential) for each participant.
| Study group | Role | What they receive |
|---|---|---|
| AIH alone | Experimental | Participants will undergo 30 minutes of AIH. Receives: Other: Acute Intermittent Hypoxia |
| NMES alone | Experimental | Participants will undergo repetitive common peroneal nerve stimulation for up to 30 minutes. Receives: Other: Neuromuscular Electrical Stimulation |
| Combined AIH and NMES | Experimental | Participants will undergo 30 minutes of AIH. Immediately following, participants will undergo NMES for up to 30 minutes. Receives: Other: Acute Intermittent Hypoxia; Other: Neuromuscular Electrical Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Motor Evoked Potentials (MEPs) in Ankle Dorsiflexors
The MEPs will be elicited by Transcranial Magnetic Stimulation (TMS), a procedure that uses magnetic fields to stimulate nerve cells in the brain.
Measured: Immediately prior to and within 60 minutes after the intervention.
Secondary outcomes (3)
Ankle Dorsiflexion Torque
Maximal volitional ankle dorsiflexion flexion torque will be measured using a strength testing dynamometer (Biodex System 4).
Measured: Immediately prior to and within 60 minutes after the intervention.
Ankle Dorsiflexion EMG
While measuring ankle dorsiflexion torque, the investigators will also record surface electromyography (EMG) from the tibialis anterior muscle during each contraction. Average peak EMG amplitude will be calculated.
Measured: Immediately prior to and within 60 minutes after the intervention.
Symbol Digit Modalities Test
A neurocognitive test that requires individuals to pair specific numbers with given geometric figures within 90 seconds. Both written and oral format will be administered, and scores will be calculated by totaling the number of correct answers for each section.
Measured: Immediately prior to and within 60 minutes after the intervention.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2024
- Study start1 Nov 2024
- Primary completionAug 2026 (estimated)
- Study completionAug 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by Shirley Ryan AbilityLabThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- randomized, blinded, cross-over study
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Shirley Ryan AbilityLab
- Sponsor type
- University, hospital or other
- Collaborators
- Northwestern University
- Responsible party
- Principal investigator, Milap Sandhu, Shirley Ryan AbilityLab
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06413602
- Sponsor's protocol ID
- STU00221027
- Status last verified
- Feb 2026
- First submitted
- 9 May 2024
- Last updated
- 23 Feb 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: The investigators do not currently have a plan to share IPD.
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploring the Synergistic Effects of AIH and FES in Persons With MS
- ClinicalTrials.gov ID
- NCT06413602
- Acronym / sponsor ID
- STU00221027
- Conditions
- Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Secondary Progressive
- Keywords
- multiple sclerosis, plasticity, electrical stimulation, NMES, modalities, neuroplasticity, motoneuron, aih
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Shirley Ryan AbilityLabUniversity, hospital or other
- Collaborators
- Northwestern University
- Study start
- 1 Nov 2024 (actual)
- Primary completion
- Aug 2026 (estimated)
- Study completion
- Aug 2027 (estimated)
- First posted
- 14 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 3
- Model description
- randomized, blinded, cross-over study
| Arm | Type | Receives |
|---|---|---|
| AIH alone | Experimental | Other: Acute Intermittent HypoxiaParticipants will undergo 30 minutes of AIH. |
| NMES alone | Experimental | Other: Neuromuscular Electrical StimulationParticipants will undergo repetitive common peroneal nerve stimulation for up to 30 minutes. |
| Combined AIH and NMES | Experimental | Other: Acute Intermittent Hypoxia, Other: Neuromuscular Electrical StimulationParticipants will undergo 30 minutes of AIH. Immediately following, participants will undergo NMES for up to 30 minutes. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (18 listed)
- Uncontrolled hypertension or hypotension (outside 140/90 and 90/60 mmHg)
- History of epilepsy or seizures
- Uncontrolled hypertension or hypotension (outside 140/90 and 90/60 mmHg)
- History of epilepsy or seizures
- Uncontrolled medical problems affecting the lungs (pulmonary diseases including chronic obstructive pulmonary disease), the heart (cardiovascular diseases) or the musculoskeletal system (orthopedic diseases)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acute Intermittent HypoxiaAlso: AIHDuring AIH, the participant will be equipped with a non-rebreathing face mask, and provided with the AIH intervention. The AIH intervention involves alternating breathing cycles. One cycle involves breathing air with lower oxygen concentration (9-10% oxygen) for 30 and 90 seconds, followed by breathing normal room air (21% oxygen) for a similar duration. This cycle is repeated 15 times in one session. Blood oxygen and heart rate are monitored throughout. | Other | AIH alone, Combined AIH and NMES |
| Neuromuscular Electrical StimulationAlso: NMESDuring NMES, participants will receive electrical stimulation to the common peroneal nerve. Stimulation will be done with a 50% duty cycle, duration of 0.5-1ms for each pulse and a frequency 25-40 Hz. The stimulus intensity will be adjusted to produce approximately 50% of the maximum M-wave (compound muscle action potential) for each participant. | Other | Combined AIH and NMES, NMES alone |
Primary outcome
Motor Evoked Potentials (MEPs) in Ankle Dorsiflexors
Time frame: Immediately prior to and within 60 minutes after the intervention.
The MEPs will be elicited by Transcranial Magnetic Stimulation (TMS), a procedure that uses magnetic fields to stimulate nerve cells in the brain.
3 secondary outcomes
Ankle Dorsiflexion Torque
Time frame: Immediately prior to and within 60 minutes after the intervention.
Ankle Dorsiflexion EMG
Time frame: Immediately prior to and within 60 minutes after the intervention.
Symbol Digit Modalities Test
Time frame: Immediately prior to and within 60 minutes after the intervention.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2026.
- Individual participant dataSharing planned: No. The investigators do not currently have a plan to share IPD.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Acute Intermittent Hypoxia and Neuromuscular Electrical Stimulation in people with Multiple Sclerosis and Multiple Sclerosis, Relapsing-Remitting, run by Shirley Ryan AbilityLab at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 23 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Motor Evoked Potentials (MEPs) in Ankle Dorsiflexors (time frame: Immediately prior to and within 60 minutes after the intervention.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2026.