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| Name | Class |
|---|---|
| National Multiple Sclerosis Society | OTHER |
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Majority of people with multiple sclerosis experience difficulty with balance and mobility, leading to an increased risk of falls. The goal of this clinical trial is to learn about brain activity during walking adaptation in people with multiple sclerosis. Also, this clinical trial will test a form of nerve stimulation to see if it can improve walking performance.
The main questions it aims to answer are:
Participants will walk on a treadmill where each leg will go a different speed which will create walking adaptation. At the same time, brain scans will occur. There will be two sessions of walking adaptation, one with nerve stimulation, and one without nerve stimulation. Researchers will compare people with multiple sclerosis to healthy young adults to see if there are differences in brain activity.
Most people with MS (PwMS) experience significant gait asymmetries between the two legs leading to an increased risk of falls and musculoskeletal injury. The objective of this study is to investigate the neural mechanisms of gait adaptation and the effects of transcutaneous electrical nerve stimulation (TENS) on adaptability during split-belt treadmill training in PwMS. Our hypothesis is that TENS will strengthen sensorimotor integration via amplified afferent signaling, thereby enhancing adaptation, and further improving gait symmetry chronically. Functional near-infrared spectroscopy (fNIRS) will be used during a split-belt treadmill training paradigm to assess cortical activation during gait adaptation. Additionally, the effect of split-belt treadmill training coupled with TENS on gait adaptability in PwMS will be tested with experimental and a sham TENS split-belt treadmill sessions. Cortical activation and the effect of TENS on gait adaptability will be compared between young neurotypical adults and PwMS to assess differences that can be attributed to multiple sclerosis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Split-belt Treadmill Training without TENS | Sham Comparator | During this arm, participants will perform split-belt treadmill training with sensory stimulation equipment outfitted but not active during all adaptation sessions. |
|
| Split-belt Treadmill Training with TENS | Experimental | During this arm, participants will perform split-belt treadmill training with active sensory stimulation occuring simultaneously during all adaptation sessions. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Split-belt Treadmill | Behavioral | Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Cortical Activation | Cortical activation is measured using functional near-infrared spectroscopy (fNIRS) during split-belt treadmill walking. Hemodynamic responses are modeled using a general linear model (GLM) applied to the oxyhemoglobin (HbO) signal. The model includes regressors for distinct phases of walking, with the primary contrast comparing early adaptation (strides 6-30 after split-belt onset) to a baseline walking period. The outcome is defined as the difference in this HbO beta weight contrast with TENS ON compared to TENS OFF. Activation is averaged across all fNIRS channels to provide a whole-brain estimate of cortical activity. A larger value indicates a greater increase in activation from baseline walking to early adaptation. This was measured on both training session 1 and training session 2 to account for the crossover design (i.e. participants are receiving TENS on different days). | Training session 1 (day 1), training session 2 (day 28) |
| Change in Adaptation Savings | Adaptation savings is defined as the difference in early adaptation performance between training session 1 (Day 1) and training session 2 (Day 28) during split-belt treadmill walking. Early adaptation is quantified using relative step length asymmetry (SLA), calculated from strides 6 to 30 following split-belt onset. SLA is computed from three-dimensional motion capture and force data as the difference between step lengths of the legs, normalized to total stride length: SLA = (Step Length_fast - Step Length_slow) / (Step Length_fast + Step Length_slow). This yields a unitless measure of asymmetry. The outcome measure is the difference in SLA between visits (training session 2 - training session 1). Larger values reflect faster adaptation at training session 2, consistent with retention of prior learning. | Training session 1 (day 1), training session 2 (day 28) |
| Rate of Step Length Asymmetry Adaptation | Step length asymmetry during early adaptation, representing the rate of adaptation. Early adaptation is quantified using relative step length asymmetry (SLA), calculated from strides 6 to 30 following split-belt onset. SLA is computed from three-dimensional motion capture and force data as the difference between step lengths of the legs, normalized to total stride length: SLA = (Step Length_fast - Step Length_slow) / (Step Length_fast + Step Length_slow). This yields a unitless measure of asymmetry. The outcome measure is the difference in early adaptation SLA during TENS ON compared to TENS OFF. Values closer to zero reflect faster adaptation.This analysis was performed only on data from each participant's first visit to avoid known effects of increased adaptation rate (learning) during subsequent exposures. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Brett W Fling, Ph.D. | Colorado State University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Sensorimotor Neuroimaging Laboratory | Fort Collins | Colorado | 80523 | United States |
The data will not publicly available due to participant privacy.
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A total of 55 participants consented to be screened for eligibility, and 51 participants (31 people with multiple sclerosis and 20 healthy controls) were enrolled.
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| ID | Title | Description |
|---|---|---|
| FG000 | Split-belt Treadmill Training With TENS First | During this arm, participants will perform split-belt treadmill training with sensory stimulation equipment outfitted and active for the first training session but not active during the second session. |
| FG001 | Split-belt Treadmill Training With TENS Second | During this arm, participants will perform split-belt treadmill training with active sensory stimulation equipment outfitted but not active during the first training session, and active during the second training session. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
This population contained 28 people with multiple sclerosis and 20 healthy controls.
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| ID | Title | Description |
|---|---|---|
| BG000 | Split-belt Treadmill Training With TENS First | During this arm, participants will perform split-belt treadmill training with sensory stimulation equipment outfitted and active for the first training session but not active during the second session. |
| BG001 | Split-belt Treadmill Training With TENS Second |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Rows are split between people with multiple sclerosis and healthy controls. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Cortical Activation | Cortical activation is measured using functional near-infrared spectroscopy (fNIRS) during split-belt treadmill walking. Hemodynamic responses are modeled using a general linear model (GLM) applied to the oxyhemoglobin (HbO) signal. The model includes regressors for distinct phases of walking, with the primary contrast comparing early adaptation (strides 6-30 after split-belt onset) to a baseline walking period. The outcome is defined as the difference in this HbO beta weight contrast with TENS ON compared to TENS OFF. Activation is averaged across all fNIRS channels to provide a whole-brain estimate of cortical activity. A larger value indicates a greater increase in activation from baseline walking to early adaptation. This was measured on both training session 1 and training session 2 to account for the crossover design (i.e. participants are receiving TENS on different days). | The sample included 28 individuals with multiple sclerosis and 20 healthy controls. A randomized crossover design was used, with each participant receiving TENS ON during one training session and TENS OFF during the other. | Posted | Least Squares Mean | Standard Error | Unitless GLM beta weight (HbO) | Training session 1 (day 1), training session 2 (day 28) |
Adverse events were monitored during each study visit (visit 1 at day 1 and visit 2 at day 28) and between visits. Participants were not followed after study completion.
Adverse event data were collected through participant self-report and investigator observation during each study visit. No adverse events occurred. Definitions of adverse and serious adverse events followed ClinicalTrials.gov guidance. No alternative definitions were used.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Split-belt Treadmill Training With TENS: People With Multiple Sclerosis | During this arm, participants with multiple sclerosis will perform split-belt treadmill training with active sensory stimulation occuring simultaneously during adaptation. Split-belt Treadmill: Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Brett Fling | Colorado State University | (970) 491-3451 | brett.fling@colostate.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 25, 2023 | May 28, 2025 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 31, 2023 | May 28, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| D004561 | Transcutaneous Electric Nerve Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D026741 | Physical Therapy Modalities |
| D012046 | Rehabilitation |
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|
| Transcutaneous Electrical Nerve Stimulation (TENS) | Device | TENS is a form of nerve stimulation that stimulates at a frequency below motor threshold, targeting activation of sensory receptors, such as muscle spindles. Electrodes that create this stimulation will be placed on the skin superficial to the muscle bellies of the tibialis anterior and rectus femoris. |
|
| Training session 1 (day 1) |
During this arm, participants will perform split-belt treadmill training with active sensory stimulation equipment outfitted but not active during the first training session, and active during the second training session. |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Rows are split between people with multiple sclerosis and healthy controls. | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Rows are split between people with multiple sclerosis and healthy controls. | Count of Participants | Participants |
|
| Race (NIH/OMB) | Rows are split between people with multiple sclerosis and healthy controls. | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Split-belt Treadmill Training Without TENS | During this arm, participants will perform split-belt treadmill training with sensory stimulation equipment outfitted but not active during adaptation. Split-belt Treadmill: Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. |
| OG001 | Split-belt Treadmill Training With TENS | During this arm, participants will perform split-belt treadmill training with active sensory stimulation occuring simultaneously during adaptation. Split-belt Treadmill: Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. Transcutaneous Electrical Nerve Stimulation (TENS): TENS is a form of nerve stimulation that stimulates at a frequency below motor threshold, targeting activation of sensory receptors, such as muscle spindles. Electrodes that create this stimulation will be placed on the skin superficial to the muscle bellies of the tibialis anterior and rectus femoris. |
|
|
|
| Primary | Change in Adaptation Savings | Adaptation savings is defined as the difference in early adaptation performance between training session 1 (Day 1) and training session 2 (Day 28) during split-belt treadmill walking. Early adaptation is quantified using relative step length asymmetry (SLA), calculated from strides 6 to 30 following split-belt onset. SLA is computed from three-dimensional motion capture and force data as the difference between step lengths of the legs, normalized to total stride length: SLA = (Step Length_fast - Step Length_slow) / (Step Length_fast + Step Length_slow). This yields a unitless measure of asymmetry. The outcome measure is the difference in SLA between visits (training session 2 - training session 1). Larger values reflect faster adaptation at training session 2, consistent with retention of prior learning. | The sample included 28 individuals with multiple sclerosis and 20 healthy controls. A randomized crossover design was used, with each participant receiving TENS ON during one training session and TENS OFF during the other. | Posted | Least Squares Mean | Standard Error | Unitless Relative Step Length Asymmetry | Training session 1 (day 1), training session 2 (day 28) |
|
|
|
|
| Primary | Rate of Step Length Asymmetry Adaptation | Step length asymmetry during early adaptation, representing the rate of adaptation. Early adaptation is quantified using relative step length asymmetry (SLA), calculated from strides 6 to 30 following split-belt onset. SLA is computed from three-dimensional motion capture and force data as the difference between step lengths of the legs, normalized to total stride length: SLA = (Step Length_fast - Step Length_slow) / (Step Length_fast + Step Length_slow). This yields a unitless measure of asymmetry. The outcome measure is the difference in early adaptation SLA during TENS ON compared to TENS OFF. Values closer to zero reflect faster adaptation.This analysis was performed only on data from each participant's first visit to avoid known effects of increased adaptation rate (learning) during subsequent exposures. | The sample included 28 individuals with multiple sclerosis and 20 healthy controls. A randomized crossover design was used, with each participant receiving TENS ON during one training session and TENS OFF during the other. | Posted | Least Squares Mean | Standard Error | Unitless Relative Step Length Asymmetry | Training session 1 (day 1) |
|
|
|
|
| 0 |
| 29 |
| 0 |
| 29 |
| 0 |
| 29 |
| EG001 | Split-belt Treadmill Training Without TENS: People With Multiple Sclerosis | During this arm, participants with multiple sclerosis will perform split-belt treadmill training with sensory stimulation equipment outfitted but not active during adaptation. Split-belt Treadmill: Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. | 0 | 29 | 0 | 29 | 0 | 29 |
| EG002 | Split-belt Treadmill Training With TENS: Healthy Controls | During this arm, healthy control participants will perform split-belt treadmill training with active sensory stimulation occuring simultaneously during adaptation. Split-belt Treadmill: Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. | 0 | 20 | 0 | 20 | 0 | 20 |
| EG003 | Split-belt Treadmill Training Without TENS: Healthy Controls | During this arm, healthy control participants will perform split-belt treadmill training with sensory stimulation equipment outfitted but not active during adaptation. Split-belt Treadmill: Split-belt treadmill training, where the speed of each leg is controlled independently has been shown to create gait adaptation where the coordination of each leg is altered, creating improved gait symmetry for people with walking impairments. | 0 | 20 | 0 | 20 | 0 | 20 |
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D000698 |
| Analgesia |
| D000760 | Anesthesia and Analgesia |
| Male |
|
| Unknown or Not Reported |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Healthy Controls |
|
|
| Statistical analysis comparing savings between TENS ON and TENS OFF conditions in healthy controls. | Mixed Models Analysis | Degrees of freedom = 44 | 0.878 | This value was corrected with false discovery rate. | Mean Difference (Net) | -0.0058 | Standard Error of the Mean | 0.167 | 2-Sided | The estimate calculation is TENS ON - TENS OFF at Visit 2 | Other |
| Healthy Controls |
|
|
| Statistical analysis comparing rate of adaptation between TENS ON and TENS OFF conditions in healthy controls. | Mixed Models Analysis | Degrees of freedom = 44 | 0.698 | This value was corrected using false discovery rate. | Mean Difference (Final Values) | -0.008 | Standard Error of the Mean | 0.021 | 2-Sided | The estimate calculation is TENS ON - TENS OFF | Other |