Multiple Sclerosis
Conditions
Keywords
split-belt treadmill, adaptation, multiple sclerosis, functional near-infrared spectroscopy, cortical activation, gait asymmetry, locomotion, sensorimotor control
Brief summary
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: * What areas of the brain are the most active during walking adaptation? * Can nerve stimulation make walking adaptation more effective? 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.
Detailed description
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.
Interventions
BEHAVIORALSplit-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.
DEVICETranscutaneous 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.
Sponsors
National Multiple Sclerosis Society
Colorado State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 86 Years
Healthy volunteers
Yes
Inclusion criteria
* A diagnosis of relapsing remitting multiple sclerosis OR a neurotypical adult (ages 18-86) * Not experiencing an active relapse * Able to stand and walk without an assistive device * Able to walk for three tenths of a mile without stopping to rest
Exclusion criteria
* Unable to walk for three tenths of a mile without assistance * Musculoskeletal injury in past 6 months * Lower extremity surgery in past 6 months * Unable to abstain from medications that impair balance * Currently pregnant * History of traumatic brain injury * History of vestibular disease * History of any other balance impairment unrelated to multiple sclerosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cortical Activation | Training session 1 (day 1), training session 2 (day 28) | 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). |
| Change in Adaptation Savings | Training session 1 (day 1), training session 2 (day 28) | 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. |
| Rate of Step Length Asymmetry Adaptation | Training session 1 (day 1) | 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 22 |
| 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. | 26 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Split-belt Treadmill Training With TENS First | Split-belt Treadmill Training With TENS Second | Total |
|---|---|---|---|
| Age, Continuous Healthy Controls | 57.3 years STANDARD_DEVIATION 11.9 | 50.9 years STANDARD_DEVIATION 15.5 | 53.8 years STANDARD_DEVIATION 14 |
| Age, Continuous People with Multiple Sclerosis | 55.5 years STANDARD_DEVIATION 9.1 | 52.2 years STANDARD_DEVIATION 11.6 | 53.7 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Healthy Controls Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Healthy Controls Not Hispanic or Latino | 9 Participants | 11 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Healthy Controls Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) People with Multiple Sclerosis Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) People with Multiple Sclerosis Not Hispanic or Latino | 12 Participants | 15 Participants | 27 Participants |
| Ethnicity (NIH/OMB) People with Multiple Sclerosis Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Healthy Controls White | 9 Participants | 11 Participants | 20 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) People with Multiple Sclerosis White | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Healthy Controls Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Healthy Controls Male | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male People with Multiple Sclerosis Female | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male People with Multiple Sclerosis Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 29 | 0 / 29 | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 | 0 / 20 | 0 / 20 |
Outcome results
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.
Time frame: Training session 1 (day 1), training session 2 (day 28)
Population: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Split-belt Treadmill Training Without TENS | Change in Adaptation Savings | People with Multiple Sclerosis | 0.0032 Unitless Relative Step Length Asymmetry | Standard Error 0.0103 |
| Split-belt Treadmill Training Without TENS | Change in Adaptation Savings | Healthy Controls | 0.0221 Unitless Relative Step Length Asymmetry | Standard Error 0.0124 |
| Split-belt Treadmill Training With TENS | Change in Adaptation Savings | People with Multiple Sclerosis | 0.0451 Unitless Relative Step Length Asymmetry | Standard Error 0.0096 |
| Split-belt Treadmill Training With TENS | Change in Adaptation Savings | Healthy Controls | 0.0278 Unitless Relative Step Length Asymmetry | Standard Error 0.0112 |
Comparison: Statistical analysis comparing savings between TENS ON and TENS OFF conditions in people with multiple sclerosis.p-value: 0.014Mixed Models Analysis
Comparison: Statistical analysis comparing savings between TENS ON and TENS OFF conditions in healthy controls.p-value: 0.878Mixed Models Analysis
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).
Time frame: Training session 1 (day 1), training session 2 (day 28)
Population: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Split-belt Treadmill Training Without TENS | Change in Cortical Activation | People with Multiple Sclerosis | 0.054 Unitless GLM beta weight (HbO) | Standard Error 0.021 |
| Split-belt Treadmill Training Without TENS | Change in Cortical Activation | Healthy Controls | 0.074 Unitless GLM beta weight (HbO) | Standard Error 0.025 |
| Split-belt Treadmill Training With TENS | Change in Cortical Activation | People with Multiple Sclerosis | -0.024 Unitless GLM beta weight (HbO) | Standard Error 0.021 |
| Split-belt Treadmill Training With TENS | Change in Cortical Activation | Healthy Controls | -0.016 Unitless GLM beta weight (HbO) | Standard Error 0.025 |
Comparison: Statistical analysis comparing cortical activation between TENS ON and TENS OFF conditions in people with multiple sclerosis.p-value: 0.007Mixed Models Analysis
Comparison: Statistical analysis comparing cortical activation between TENS ON and TENS OFF conditions in healthy controls.p-value: 0.008Mixed Models Analysis
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.
Time frame: Training session 1 (day 1)
Population: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Split-belt Treadmill Training Without TENS | Rate of Step Length Asymmetry Adaptation | People with Multiple Sclerosis | -0.090 Unitless Relative Step Length Asymmetry | Standard Error 0.012 |
| Split-belt Treadmill Training Without TENS | Rate of Step Length Asymmetry Adaptation | Healthy Controls | -0.095 Unitless Relative Step Length Asymmetry | Standard Error 0.014 |
| Split-belt Treadmill Training With TENS | Rate of Step Length Asymmetry Adaptation | People with Multiple Sclerosis | -0.088 Unitless Relative Step Length Asymmetry | Standard Error 0.013 |
| Split-belt Treadmill Training With TENS | Rate of Step Length Asymmetry Adaptation | Healthy Controls | -0.103 Unitless Relative Step Length Asymmetry | Standard Error 0.016 |
Comparison: Statistical analysis comparing rate of adaptation between TENS ON and TENS OFF conditions in people with multiple sclerosis.p-value: 0.898Mixed Models Analysis
Comparison: Statistical analysis comparing rate of adaptation between TENS ON and TENS OFF conditions in healthy controls.p-value: 0.698Mixed Models Analysis