Cognitive Rehabilitation and Exercise for Multiple Sclerosis

(COMBINE Trial)

Overseen By Carly Wender, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Kessler Foundation

Must not be taking: Steroids, Benzodiazepines

Disqualifiers: Neurological disorders, Uncontrolled psychiatric, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 7

Duration: 12 weeks

78 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently using medications that may affect thinking, like steroids or benzodiazepines, you will need to stop taking them to participate in this trial.

What data supports the effectiveness of the treatment Aerobic Exercise Training (AET) plus Virtual Reality (IDEAL) for Multiple Sclerosis?

Research shows that combining virtual reality with physical therapy can improve balance, gait, and motor function in patients with neurological conditions like multiple sclerosis and traumatic brain injury. Virtual reality enhances motivation and engagement, which can lead to better outcomes in rehabilitation. ^{1 2 3 4 5}

Is the combination of exercise and virtual reality generally safe for humans?

Research shows that using virtual reality with exercise is generally safe for humans, with no major adverse events reported in studies involving mild cognitive impairment and neck rehabilitation. ^{6 7 8 9 10}

How does the Cognitive Rehabilitation and Exercise treatment for Multiple Sclerosis differ from other treatments?

This treatment is unique because it combines cognitive rehabilitation with physical exercise, addressing both mental and physical impairments in MS. Unlike standard treatments that may focus solely on physical rehabilitation, this approach aims to improve cognitive function and overall quality of life through a holistic method. ^{2 5 11 12 13}

What is the purpose of this trial?

The goal of this novel study is to compare the effect of a combined cognitive rehabilitation and exercise approach on new learning and memory (NLM) in persons with multiple sclerosis (pwMS) and mobility disability.

Research Team

Carly Wender, PhD

Principal Investigator

Kessler Foundation

Eligibility Criteria

This trial is for adults aged 18-70 with Multiple Sclerosis, who primarily speak English and have moderate mobility issues but are currently inactive. They must not have had a relapse or taken steroids in the last month and should be right-handed. People with other neurological disorders, uncontrolled psychiatric conditions, contraindications to exercise, certain medications affecting cognition, pregnancy, or MRI contraindications cannot participate.

Inclusion Criteria

I have some difficulty walking or moving around.

I haven't had a relapse or taken steroids in the last 30 days.

Currently physically inactive, based on the Godin Leisure Time Exercise Questionnaire (GLTEQ)

Exclusion Criteria

Have contraindications to exercise, based on the Physical Activity Readiness Questionnaire (PAR-Q)

I have no neurological disorders other than MS and my mental health is stable.

Currently pregnant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-intervention

Baseline assessments including fMRI and memory tests conducted

2 weeks

2 visits (in-person)

Treatment

Participants undergo cognitive rehabilitation combined with either aerobic exercise with VR or stretching and toning for 12 weeks

12 weeks

3 visits per week (in-person)

Post-intervention

Post-treatment assessments including fMRI and memory tests conducted

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aerobic Exercise Training (AET) plus Virtual Reality (IDEAL)
• Stretching and Toning (S/T)
• The Kessler Foundation modified Story Memory Technique® (KF-mSMT®)

Trial Overview The study tests if combining cognitive rehabilitation (using Kessler Foundation's modified Story Memory Technique) with physical exercises (stretching/toning and aerobic training enhanced by virtual reality) can improve new learning and memory in people with Multiple Sclerosis who also have mobility disabilities.

Participant Groups

Group I: Cognitive Rehabilitation + Stretching and Toning Experimental Treatment 2 Interventions

In the cognitive rehabilitation and stretching and toning (S/T) exercise condition, participants will complete 12 weeks of supervised S/T activities 3 days per week over the 12 week period. For seven weeks, participants will only complete S/T. During weeks 8-12, participants will complete the Kessler Foundation modified story Memory Technique (KF-mSMT®), a memory retraining program on 2 of the 3 days per week.

Group II: Cognitive Rehabilitation + Aerobic Exercise with Virtual Reality (VR) Experimental Treatment 2 Interventions

In the cognitive rehabilitation and aerobic exercise with VR condition, participants will complete a supervised, aerobic exercise training program (AET) integrated with virtual reality (Ideally Designed Exercise to Accelerate Learning/memory; IDEAL) three days per week over a 12 week period. For seven weeks, participants will only complete IDEAL. For weeks 8-12, participants will complete the Kessler Foundation modified story Memory Technique (KF-mSMT®), a memory retraining program on 2 of the 3 days per week.

Who Is Running the Clinical Trial?

Kessler Foundation

Lead Sponsor

Trials

190

Recruited

11,300+

National Multiple Sclerosis Society

Collaborator

Trials

100

Recruited

10,600+

Findings from Research

Robot-assisted gait training (RAGT) combined with virtual reality (VR) significantly improves psychological outcomes, such as positive attitude and problem-solving skills, in patients with multiple sclerosis (MS) compared to RAGT alone, based on a study of 40 patients over eight weeks.

While the physical balance and mobility measures showed small and non-significant differences between the two groups, the combination of RAGT and VR suggests that VR may enhance the effectiveness of rehabilitation by engaging various brain areas related to motor planning and learning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Robotic gait training in multiple sclerosis rehabilitation: Can virtual reality make the difference? Findings from a randomized controlled trial. Calabrò, RS., Russo, M., Naro, A., et al.[2022]

A 6-week virtual reality balance training program using the CAREN system significantly improved balance measures in people with multiple sclerosis (PwMS) compared to conventional balance exercises, as shown by better results in the Functional Reach Test and reduced fear of falling.

The study involved 32 PwMS, with 30 completing the trial, and both groups showed improvements in balance, but the VR group had notably better outcomes, indicating that VR can be a beneficial tool for enhancing balance in PwMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial. Kalron, A., Fonkatz, I., Frid, L., et al.[2022]

A 58-year-old man with right hemiplegia showed significant improvements in gait and lower limb motor function after 8 weeks of VR-based physical therapy combined with traditional therapy, indicating the efficacy of this approach.

The use of VR technology provided real-time feedback that enhanced rehabilitation outcomes, as evidenced by increased step length, stride length, and a rise in the Fugl-Meyer assessment score from 18 to 23 points.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Balance, Gait, and Lower Limb Motor Function in a 58-Year-Old Man with Right Hemiplegic Traumatic Brain Injury Following Virtual Reality-Based Real-Time Feedback Physical Therapy. Kim, KH., Kim, DH.[2023]

In a study involving 62 participants with moderate-to-severe traumatic brain injury (TBI), the Kessler Foundation modified Story Memory Technique® (KF-mSMT®) did not show a significant treatment effect on learning slopes compared to a placebo, indicating that processing speed (PS) may not directly influence learning outcomes.

However, processing speed was found to be a significant predictor of post-treatment changes following KF-mSMT®, suggesting that cognitive dysfunctions beyond learning and memory can affect the overall benefits of cognitive rehabilitation for TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of information processing speed on benefit from learning and memory rehabilitation in TBI: a sub-analysis of the TBI-MEM trial. Chiaravalloti, ND., Costa, S., Armknecht, C., et al.[2023]

The study involving 24 older women (average age 70.5 years) demonstrated that a combined pelvic floor muscle exercises and virtual reality rehabilitation (PFM/VRR) program is feasible, with high participation and adherence rates (91% and 92% respectively).

Post-treatment results showed significant improvements in urinary incontinence symptoms and quality of life, with 91% of participants reporting high satisfaction with the program, indicating its potential as an effective treatment option for mixed urinary incontinence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virtual reality rehabilitation as a treatment approach for older women with mixed urinary incontinence: a feasibility study. Elliott, V., de Bruin, ED., Dumoulin, C.[2019]

The SPRINT protocol, which combines aerobic and resistive training using a flywheel device, was tested in a pilot study with five healthy male subjects over 2 weeks, showing that while physiological effects were similar, the addition of a VR simulation improved motivation, mood, and overall well-being during exercise.

The study suggests that incorporating a VR 'exergaming' simulation with real-time biometric feedback could enhance the psychological benefits of exercise, making it a valuable tool for astronauts facing isolation during long-duration space missions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virtual Reality "exergames": A promising countermeasure to improve motivation and restorative effects during long duration spaceflight missions. Keller, N., Whittle, RS., McHenry, N., et al.[2022]

A 31-year-old male service member with mild traumatic brain injury (mTBI) showed significant improvement in balance and resolution of postconcussion symptoms after a 6-session rehabilitation program in a virtual reality environment.

The intervention combined clinical techniques and simulated military tasks, allowing the patient to successfully return to full duty and training, highlighting the effectiveness of tailored rehabilitation for mTBI in both military and civilian populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of a mild traumatic brain injury rehabilitation program in a virtual realty environment: a case study. Rábago, CA., Wilken, JM.[2011]

A 4-week program of nonimmersive virtual reality (VR) exercise significantly improved cognitive functions, such as attention and memory, in 13 adults with traumatic brain injury (TBI) compared to control groups.

A single session of VR exercise also led to notable improvements in reaction and movement times, suggesting that even short bouts of exercise in a virtual environment can enhance cognitive performance in TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving cognitive function after brain injury: the use of exercise and virtual reality. Grealy, MA., Johnson, DA., Rushton, SK.[2022]

Home-based virtual reality (VR) exercise is safe and feasible for individuals with mild cognitive impairment, with participants completing 99% of the prescribed sessions over 6 weeks without major adverse events.

While most participants enjoyed the VR program and reported physical benefits, no significant changes were observed in physical or cognitive outcomes after the 6-week intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Home-Based Nonimmersive Virtual Reality to Encourage Physical and Cognitive Exercise in People With Mild Cognitive Impairment: A Feasibility Study. Sheehy, L., Sveistrup, H., Knoefel, F., et al.[2022]

In a study involving 20 healthy participants, a fully immersive virtual reality game (VRPhysio) successfully prompted neck movements that were identified by physiotherapists as appropriate rehabilitation exercises.

No adverse events were reported during the session, suggesting that VR gamification could be a safe and effective method for encouraging adherence to neck rehabilitation exercises, warranting further evaluation in randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamification of Cervical Spine Physiotherapy by Virtual Reality Software: Is This Real Rehabilitation? Gavish, L., Weissberger, O., Barzilay, Y.[2023]

Inpatient rehabilitation for multiple sclerosis (MS) can improve functional independence but has limited long-term success in reducing neurological impairment, with severely disabled individuals benefiting as much as or more than those with less disability.

Exercise, particularly aerobic activities that include balance training and social interaction, has been shown to enhance fitness and maintain function in individuals with mild to moderate MS, suggesting that rehabilitation should be an ongoing process tailored to individual needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise and rehabilitation for individuals with multiple sclerosis. Brown, TR., Kraft, GH.[2022]

A systematic review of nine randomized clinical trials involving 424 participants found that Virtual Reality (VR) significantly improves fatigue, quality of life, and balance in people with Multiple Sclerosis (MS) compared to conventional exercises.

However, VR did not show significant benefits for functional mobility, indicating that while it can enhance certain aspects of rehabilitation for MS patients, it may not be more effective than traditional methods for improving mobility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Virtual Reality Rehabilitation in Persons with Multiple Sclerosis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Nascimento, AS., Fagundes, CV., Mendes, FADS., et al.[2021]

A six-week resistance training program using bodyweight exercises significantly improved physical fitness in 36 patients with multiple sclerosis, suggesting that strength training can be beneficial for MS sufferers.

This study highlights the importance of incorporating muscular strength development into rehabilitation programs for MS, which have traditionally focused more on aerobic exercises.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a resistance training program in multiple sclerosis Spanish patients: a pilot study. Ayán Pérez, C., Martín Sánchez, V., De Souza Teixeira, F., et al.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Robotic gait training in multiple sclerosis rehabilitation: Can virtual reality make the difference? Findings from a randomized controlled trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Improved Balance, Gait, and Lower Limb Motor Function in a 58-Year-Old Man with Right Hemiplegic Traumatic Brain Injury Following Virtual Reality-Based Real-Time Feedback Physical Therapy. [2023]

4. England pubmed.ncbi.nlm.nih.gov

The influence of information processing speed on benefit from learning and memory rehabilitation in TBI: a sub-analysis of the TBI-MEM trial. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Virtual reality rehabilitation as a treatment approach for older women with mixed urinary incontinence: a feasibility study. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Virtual Reality "exergames": A promising countermeasure to improve motivation and restorative effects during long duration spaceflight missions. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Application of a mild traumatic brain injury rehabilitation program in a virtual realty environment: a case study. [2011]

8. United States pubmed.ncbi.nlm.nih.gov

Improving cognitive function after brain injury: the use of exercise and virtual reality. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

The Use of Home-Based Nonimmersive Virtual Reality to Encourage Physical and Cognitive Exercise in People With Mild Cognitive Impairment: A Feasibility Study. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Gamification of Cervical Spine Physiotherapy by Virtual Reality Software: Is This Real Rehabilitation? [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Exercise and rehabilitation for individuals with multiple sclerosis. [2022]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Effectiveness of Virtual Reality Rehabilitation in Persons with Multiple Sclerosis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Effects of a resistance training program in multiple sclerosis Spanish patients: a pilot study. [2019]