Effects of Acute Intermittent Hypoxia on Neuroplasticity in MS

Investigating the Effects of Acute Intermittent Hypoxia on Neuroplasticity in Persons With Multiple Sclerosis

This study seeks to explore changes in the neural pathways and arm function following a breathing intervention in the multiple sclerosis (MS) population. The breathing intervention, known as Acute Intermittent Hypoxia (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. Here, the study examines arm and hand function before and after AIH. In order to better understand the brain and spinal cord response to AIH, the investigators will measure muscle response, and signals sent from the brain to the arm muscles before and after AIH.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Secondary Progressive
• Intervention / Treatment: Other: Acute Intermittent Hypoxia; Other: Sham Acute Intermittent Hypoxia

Detailed Description

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. This study will explore potential mechanisms of AIH in MS using measurements of arm function, as well as examination of corticospinal and spinal motoneuron excitability.

Over the past decade, studies have found that brief episodes of modest oxygen reduction (termed 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 both lower- and upper-limb muscles. The actions of AIH appear to be biologically linked to systems designed to preserve breathing systems that are impaired by damage to the central nervous system (CNS).

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rachel Kalvakota, OTD, OTR/L; Phone Number: 3122383947; Email: rkalvakota@sralab.org

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Shirley Ryan AbilityLab
      • Principal Investigator: Milap Sandhu, PT, PhD
      • Contact: Rachel Kravitt, OTD, OTR/L; Phone Number: (312)238-3947; Email: rkravitt@sralab.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of relapsing-remitting MS according to the McDonald criteria, over 5 years ago
• Relapse free for at least 6 months
• Expanded Disability Status Scale (EDSS) ≤7
• Index finger abduction strength <5 according to Medical Research Council Scale, or 9-Hole Peg Test score >20 seconds in at least one hand
• Stable disease modifying therapies for at least 6 months
• Individuals taking dalfampridine will be eligible if taking the same daily dose for at least 2 months prior to screening

Exclusion Criteria:

• Another diagnosis (e.g., peripheral neuropathies or orthopedic) affecting upper limb function
• Mini-Mental State Examination (MMSE) score <24
• Modified Ashworth Scale score >3 on elbow joint
• Uncontrolled hypertension or hypotension (outside 140/90 and 85/55 mmHg)
• History of epilepsy, chronic obstructive pulmonary disease, or sleep apnea
• Unstable medical conditions, ongoing upper limb therapy, or musculoskeletal pain
• Pregnancy as confirmed by urine test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AIH first; Participants in the first arm will undergo 2 sessions of AIH each separated by a 1-week washout period. 1 week later, participants will undergo 2 sessions of Sham AIH also separated by a 1-week washout period.	Other: Acute Intermittent Hypoxia; 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.; Other Names: AIH; Other: Sham Acute Intermittent Hypoxia; During Sham AIH, the participant will be equipped with a non-rebreathing face mask, and provided with the AIH intervention. The Sham AIH intervention involves alternating breathing cycles. One cycle involves breathing air closely resembling room air (~21% 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 Names: Sham AIH
Experimental: Sham First; Participants in the this arm will undergo 2 sessions of Sham AIH each separated by a 1-week washout period. 1 week later, participants will undergo 2 sessions of AIH also separated by a 1-week washout period.	Other: Acute Intermittent Hypoxia; 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.; Other Names: AIH; Other: Sham Acute Intermittent Hypoxia; During Sham AIH, the participant will be equipped with a non-rebreathing face mask, and provided with the AIH intervention. The Sham AIH intervention involves alternating breathing cycles. One cycle involves breathing air closely resembling room air (~21% 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 Names: Sham AIH

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor Evoked Potentials (MEPs) in First Dorsal Interosseous (FDI)	The MEPs will be elicited by Transcranial Magnetic Stimulation (TMS), a procedure that uses magnetic fields to stimulate nerve cells in the brain.	Immediately before, immediately after, and 60 minutes after the intervention.
Changes in Spinal Reflex Threshold	Spinal reflect threshold will be measured by calculating the average change in threshold length recorded from the biceps tendon's indentation. A linear motor will be used to impose precise tendon indentations of the biceps brachii.	Immediately before the intervention and immediately after the intervention.
Threshold For Detecting Passive Joint Movement	An assisted movement with enhanced sensation (AMES) will be used to rotate the participant's joint. The difference between the reference and matching joint angles is used to measure joint position sense. The investigators will present three target positions, and subjects will perform ipsilateral matching for each target 5 times.	Immediately before the intervention and immediately after the intervention.
Accuracy of Direction Estimation of Passive Joint Movement	An AMES will be used to rotate the participant's joint. The difference between the reference and matching joint angles is used to measure joint position sense. The investigators will present three target positions, and subjects will perform ipsilateral matching for each target 5 times.	Immediately before the intervention and immediately after the intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grip Strength	The participant will squeeze a calibrated dynamometer to measure grip strength.	Immediately before the intervention and immediately after the intervention.
Pinch Strength	The participant will pinch a calibrated pinch gauge to measure pinch strength.	Immediately before the intervention and immediately after the intervention.
Index Finger Abduction Force	Index finger abduction force will be measured using a load cell. We will also record surface EMG activity from the FDI muscle.	Immediately before the intervention and immediately after the intervention.
Nine-Hole Peg Test	A dexterity measurement involving placing 9 pegs in corresponding holes. Time to complete is measured.	Immediately before the intervention and immediately after the intervention.
Symbol Digit Modalities Test	A cognition assessment. Using a key, the participant has 90 seconds to match numbers to given geometric figures.	Immediately before the intervention and immediately after the intervention.
Box and Block Test	A 60 second dexterity measurement involving translating small wooden blocks from one box to another box separated by a partition.	Immediately before the intervention and immediately after the intervention.
Modified Ashworth Scale	A grading system is applied to the amount of tone felt during a rapid high velocity stretch. The minimal value is 0, and the maximum value is 4. A higher score indicates a higher degree of spasticity.	Immediately before the intervention and immediately after the intervention.
Ipsilateral Joint Position Matching Task	The participant's hand will be passively moved to a target joint position and then returned to a base position. Participants are then asked to recreate the target joint angle with the same hand. The difference between the reference and matching joint angles is used to measure joint position sense.	Immediately before the intervention and immediately after the intervention.
Visual Analog Pain Scale	This is used to measure any changes in pain. It is a one-dimensional scale where the patient marks their pain on a 10-cm ruler. The minimal value is 0, and the maximum value is 10. The higher the score, the greater the pain is.	Immediately before the intervention and immediately after the intervention.

Collaborators and Investigators

• Sponsor: Shirley Ryan AbilityLab
• Collaborators: National Multiple Sclerosis Society
• Investigators: Principal Investigator: Milap Sandhu, Shirley Ryan Ability Lab

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: April 24, 2024
• First Submitted That Met QC Criteria: April 25, 2024
• First Posted (Actual): April 30, 2024

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: multiple sclerosis; neuroplasticity; hypoxia; upper extremity; plasticity; Acute Intermittent Hypoxia; arm; motoneuron; aih
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Signs and Symptoms, Respiratory; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Multiple Sclerosis; Hypoxia; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive; Investigative Techniques; Therapeutics; Reproductive Techniques, Assisted; Reproductive Techniques; Reproduction; Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena; Insemination, Artificial; Insemination; Insemination, Artificial, Homologous
• Other Study ID Numbers: STU00221436

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We do not currently have a plan to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No