Combinatory Rehabilitation for Traumatic Brain Injury

(CRUSH-IT Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Nancy D Chiaravalloti, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Kessler Foundation

Must not be taking: Steroids, Benzodiazepines

Disqualifiers: Neurological disorders, Severe mental illness, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

New learning and memory impairment (NLMI) is a common and devastating manifestation of TBI associated with substantial life burdens. Persons with moderate to severe TBI have shown improvement in NLM for prose material (e.g. story) as well as beneficial changes in default-mode network (DMN) activation during list-learning19 following treatment with the Kessler Foundation modified Story Memory Technique® (KF-mSMT®). Benefits, however, were moderate and did not yield downstream improvements in daily life. It is thus critical to examine other approaches to complement the KF-mSMT® for robustly managing NLMI in TBI. The proposed RCT will be the first to include aerobic exercise training (AET) as a highly-promising complement to the KF-mSMT® for robustly managing NLMI, examining impact on NLM, its neural correlates, and daily life in NLM impaired persons with moderate-to-severe TBI. We thus propose a two-arm, parallel group, double-blind RCT comparing the effects of the KF-mSMT+AET with the KF-mSMT+S/T (active control condition) on NLM (Aim 1), hippocampal MRI (Aim 2), and daily life outcomes (Aim 3). 60 NLM impaired persons with moderate-to-severe TBI will be randomized to one of 2 conditions (30 per condition). Each condition will take place 3 days per week for 12 weeks and will be supervised by KF personnel. Participants will be blinded as to the intent of the conditions. We will further explore baseline predictors of clinically meaningful changes in NLM for those completing the KF-mSMT + AET condition (Exploratory Aim 4). If successful, this trial will position combinatory KF-mSMT and AET within the clinician's arsenal for robustly managing NLMI in persons with TBI. By augmenting the effects of KF-mSMT with AET, this treatment aims to exert a powerful countermeasure to TBI-related NLMI, and ultimately help those with TBI-related NLMI return to the workforce, independently manage their everyday lives, and maintain optimal quality of life. Additionally, while rigorously designed to answer the scientific question of the relative benefit of AET with the KF-mSMT, the proposed study is will likely provide some level of benefit to all study participants. If successful, this trial will provide Class I evidence of combined KF-mSMT and AET for rehabilitating NLMI in TBI, based on standards published for therapeutic trials by the American Academy of Neurology, thus positioning such an approach within the clinician's arsenal for robustly managing NLMI. By augmenting the effects of KF-mSMT with AET, we anticipate this treatment will ultimately help those with TBI-related NLMI return to the workforce, independently manage their everyday lives, and maintain optimal quality of life.

Will I have to stop taking my current medications?

The trial requires that participants do not regularly take steroids or benzodiazepines. If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the treatment KF-mSMT Plus Aerobic Exercise Training for traumatic brain injury?

Research shows that the Kessler Foundation modified Story Memory Technique (KF-mSMT) improves learning and memory in people with traumatic brain injury (TBI). Additionally, aerobic exercise training has been shown to improve cardiorespiratory fitness and mood symptoms in TBI patients, suggesting potential benefits when combined with KF-mSMT. ^{1 2 3 4 5}

Is the combination of aerobic exercise and cognitive training safe for humans?

The research suggests that combining aerobic exercise with other types of training, like cognitive or strength exercises, is generally safe and can improve physical and cognitive functions, especially in older adults. ^{6 7 8 9 10}

How does the treatment KF-mSMT Plus Aerobic Exercise Training differ from other treatments for traumatic brain injury?

This treatment is unique because it combines cognitive rehabilitation with aerobic exercise, aiming to improve learning and memory in individuals with traumatic brain injury. The combination of the Kessler Foundation modified Story Memory Technique with aerobic exercise is designed to enhance cognitive function and physical fitness, which is not a standard approach in existing treatments for this condition. ^{2 3 5 11 12}

Research Team

Nancy D Chiaravalloti, PhD

Principal Investigator

Kessler Foundation

Eligibility Criteria

This trial is for adults aged 18-65 with moderate-to-severe traumatic brain injury (TBI) diagnosed at least a year ago. Participants should be physically inactive, right-handed, have memory impairments, and able to follow directions. They must not have severe mental illness, regular steroid or benzodiazepine use, significant vision impairment, unsafe conditions for MRI scans or high exercise risks.

Inclusion Criteria

I can follow directions well, as shown by my TICS-M score.

I was diagnosed with a severe brain injury over a year ago.

Having chronic medical conditions (e.g. diabetes) in addition to TBI will require approval to participate from a physician, consistent with PAR-Q+

Exclusion Criteria

Having moderate or high risk for exercise training contraindications (e.g. diabetes), defined as ≥1 YES on pages 2-3 of the Physical Activity Readiness Questionnaire for Everyone (PAR-Q+)

I regularly take steroids and benzodiazepines for medication effects.

Having a history of severe mental illness (e.g., schizophrenia, bipolar, severe major depression)

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 12 weeks of supervised exercise training, with aerobic cycling or stretching and toning, combined with the Kessler Foundation modified Story Memory Technique for cognitive rehabilitation

12 weeks

3 visits per week (in-person)

Follow-up

Participants are monitored for changes in hippocampal volume, functional connectivity, and everyday memory performance

4 weeks

Treatment Details

Interventions

• KF-mSMT Plus Aerobic Exercise Training (Behavioural Intervention)
• KF-mSMT Plus Stretching Exercise Training (Behavioural Intervention)

Trial Overview The study tests the Kessler Foundation modified Story Memory Technique (KF-mSMT) combined with either aerobic exercise training (AET) or stretching exercises. It's a double-blind randomized controlled trial aiming to improve new learning and memory in TBI patients by comparing these two methods over a 12-week program.

Participant Groups

Group I: KF-mSMT Plus Aerobic Exercise Training Experimental Treatment 1 Intervention

Participants will undergo 12 weeks of supervised aerobic cycling exercise training. During the last 8 weeks of cycling exercise, participants will also undergo treatment with the Kessler Foundation modified Story Memory Technique as an approach for cognitive rehabilitation.

Group II: KF-mSMT Plus Stretching Exercise Training Active Control 1 Intervention

Participants will undergo 12 weeks of supervised stretching and toning exercise training. During the last 8 weeks of stretching exercise, participants will also undergo treatment with the Kessler Foundation modified Story Memory Technique as an approach for cognitive rehabilitation.

Who Is Running the Clinical Trial?

Kessler Foundation

Lead Sponsor

Trials

190

Recruited

11,300+

Findings from Research

The modified Story Memory Technique (mSMT) significantly improved memory and learning in individuals with traumatic brain injury (TBI), as shown by changes in cerebral activation in key brain networks after treatment.

In a randomized clinical trial with 18 participants, the treatment group exhibited notable differences in brain activation compared to the placebo group, indicating that behavioral interventions like mSMT can effectively enhance cognitive function in TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining the Efficacy of the Modified Story Memory Technique (mSMT) in Persons With TBI Using Functional Magnetic Resonance Imaging (fMRI): The TBI-MEM Trial. Chiaravalloti, ND., Dobryakova, E., Wylie, GR., et al.[2019]

A 3-month community-based aerobic exercise training program showed a trend toward improved cardiorespiratory fitness (CRF) in individuals with traumatic brain injury (TBI), with an 8% increase in VO2peak compared to a 4% decrease in a stretching and toning group, indicating potential efficacy of aerobic exercise for this population.

The study demonstrated that while it is feasible to conduct exercise training in community settings for TBI patients, only 50% of participants adhered to the program, highlighting the need for strategies to improve adherence in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A proof-of-concept trial of a community-based aerobic exercise program for individuals with traumatic brain injury. Ding, K., Tarumi, T., Tomoto, T., et al.[2021]

This Phase I/II trial will assess the effects of 12 weeks of combined learning and memory rehabilitation with either aerobic cycling or stretching on cognitive outcomes in 60 individuals with moderate-to-severe traumatic brain injury (TBI).

The primary outcome will focus on improvements in new learning and memory, measured by the California Verbal Learning Test (CVLT)-III, potentially providing the first Class I evidence for the effectiveness of aerobic exercise in enhancing memory rehabilitation for TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of cognitive rehabilitation combined with aerobic exercise or stretching-and-toning on new learning and memory in persons with moderate-to-severe TBI: Protocol for a randomized controlled trial. Sandroff, BM., Weber, E., Wylie, GR., et al.[2023]

Combined aerobic exercise with resistance/strength training and other activities significantly improves physical performance in the elderly, enhancing strength, balance, mobility, and reducing fall risk.

Compared to single aerobic exercise, combined exercise (CEX) showed superior benefits in various physical fitness measures, including gait speed and lower limb strength, highlighting the importance of multi-component training for older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic Exercise Combination Intervention to Improve Physical Performance Among the Elderly: A Systematic Review. Bai, X., Soh, KG., Omar Dev, RD., et al.[2022]

The neuromotor multicomponent training program (MCTP) significantly improved executive function and functional fitness in 56 older women over a 30-week period, showing better results than both control groups in tests like the Stroop test and Timed Up and Go test.

MCTP also positively impacted body composition and health-related quality of life (HRQOL), while both exercise groups (MCTP and CONTROL-EXE) experienced reductions in blood pressure, indicating its overall health benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

120 min/week of neuromotor multicomponent training are enough to improve executive function and functional fitness in older women. Martinez-Navarro, I., Cordellat, A., Roldán, A., et al.[2021]

High-Intensity Functional Training (HIFT) combines elements of high-intensity interval training and strength exercises, leading to improved cardiovascular fitness and strength due to greater muscle recruitment compared to traditional aerobic exercises.

HIFT is associated with enhanced health markers, including cardiovascular and metabolic health, as well as cognitive function, which may contribute to reduced all-cause mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Intensity Functional Training: Molecular Mechanisms and Benefits. Ben-Zeev, T., Okun, E.[2022]

In a study involving 34 geriatric patients aged 64 to 92, the addition of Intermittent Hypoxic-Hyperoxic Training (IHHT) to a multimodal training program significantly improved cognitive performance, as measured by the Dementia-Detection-Test, compared to a control group that received placebo breathing.

The experimental group also showed a greater improvement in functional exercise capacity, with a 24.1% increase in the 6-Minute-Walk-Test distance, compared to a 10.8% increase in the control group, indicating that IHHT enhances both cognitive and physical abilities in elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adaptation to intermittent hypoxia-hyperoxia improves cognitive performance and exercise tolerance in elderly]. Bayer, U., Glazachev, OS., Likar, R., et al.[2018]

High-intensity interval training (HIIT) significantly enhances memory performance in sedentary older adults compared to moderate continuous training (MCT) and stretching, based on a study involving 64 participants.

Improvements in memory were correlated with increases in fitness levels, suggesting that exercise intensity may play a crucial role in cognitive benefits, although the study found no significant differences in brain-derived neurotrophic factor (BDNF) levels among the groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of aerobic exercise intensity on memory in older adults. Kovacevic, A., Fenesi, B., Paolucci, E., et al.[2021]

A survey of 555 Canadian rehabilitation clinicians revealed that the most common concussion management practices included education, sleep recommendations, goal setting, and energy management, with manual therapy also frequently used.

Only about one-third of clinicians incorporated aerobic exercise into their concussion management strategies, and those with a higher caseload of concussion patients were more likely to prescribe it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concussion Management Practices for Youth Who Are Slow to Recover: A Survey of Canadian Rehabilitation Clinicians. Dobney, DM., Gagnon, I.[2022]

In a study involving 360 veterans with moderate to severe traumatic brain injury (TBI), both cognitive-didactic and functional-experiential rehabilitation approaches showed similar long-term outcomes in terms of overall functional independence and return to work or school after one year.

However, participants receiving cognitive-didactic treatment demonstrated significantly better short-term cognitive function immediately after treatment, particularly benefiting younger individuals in terms of returning to work or school, while older participants with more education fared better in independent living with the functional-experiential approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rehabilitation of traumatic brain injury in active duty military personnel and veterans: Defense and Veterans Brain Injury Center randomized controlled trial of two rehabilitation approaches. Vanderploeg, RD., Schwab, K., Walker, WC., et al.[2009]

References

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

Examining the Efficacy of the Modified Story Memory Technique (mSMT) in Persons With TBI Using Functional Magnetic Resonance Imaging (fMRI): The TBI-MEM Trial. [2019]

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

A proof-of-concept trial of a community-based aerobic exercise program for individuals with traumatic brain injury. [2021]

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

An RCT to Treat Learning Impairment in Traumatic Brain Injury: The TBI-MEM Trial. [2022]

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

The effects of cognitive rehabilitation combined with aerobic exercise or stretching-and-toning on new learning and memory in persons with moderate-to-severe TBI: Protocol for a randomized controlled trial. [2023]

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

Aerobic Exercise Combination Intervention to Improve Physical Performance Among the Elderly: A Systematic Review. [2022]

7. England pubmed.ncbi.nlm.nih.gov

120 min/week of neuromotor multicomponent training are enough to improve executive function and functional fitness in older women. [2021]

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

High-Intensity Functional Training: Molecular Mechanisms and Benefits. [2022]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Adaptation to intermittent hypoxia-hyperoxia improves cognitive performance and exercise tolerance in elderly]. [2018]

10. Canada pubmed.ncbi.nlm.nih.gov

The effects of aerobic exercise intensity on memory in older adults. [2021]

11. Canada pubmed.ncbi.nlm.nih.gov

Concussion Management Practices for Youth Who Are Slow to Recover: A Survey of Canadian Rehabilitation Clinicians. [2022]

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

Rehabilitation of traumatic brain injury in active duty military personnel and veterans: Defense and Veterans Brain Injury Center randomized controlled trial of two rehabilitation approaches. [2009]