The Effect of Exercise on Neurorecovery Following Mild Traumatic Brain Injury

Study Overview
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Brief Summary
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The study is a proof-of-principle project to examine the safety and feasibility of implementing a 1-week aerobic exercise program in the post-acute phase after mild traumatic brain injury (mTBI). The study will define the extent to which the exercise program improves recovery from mTBI in terms of relevant functional outcomes (cognition, mood, and physical status) and biomarkers (peripheral brain-derived neurotrophic factor [BDNF] concentration).

Detailed Description
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This is a proof-of-principle project for human subjects to examine the safety and feasibility of implementing a 1-week aerobic exercise program in the post-acute phase after mild traumatic brain injury (mTBI). This study will define the extent to which the exercise program improves recovery from mTBI in terms of relevant functional outcomes (cognition, mood, and physical status) and biomarkers (peripheral brain-derived neurotrophic factor [BDNF] concentration). This project will also lay the foundation for understanding the relationship between exercise and BDNF in the area of mTBI neurorecovery, thereby allowing future studies to develop best-practice methods for implementing exercise interventions as a treatment option for brain injuries.

Official Title
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The Effect of Exercise on Neurorecovery Following Mild Traumatic Brain Injury

Conditions
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Brain Concussion

Intervention / Treatment
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* Behavioral: Aerobic Exercise
* Behavioral: Non-Aerobic Exercise


Participation Criteria
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Eligibility Criteria
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Mild traumatic brain injury (mTBI) group: Inclusion Criteria: Meet criteria for mTBI as set forth by the American Congress of Rehabilitation Medicine mTBI was sustained 14-25 days before beginning the exercise intervention Exclusion Criteria: comorbid orthopaedic injury that inhibits movement history of serious psychiatric disturbance with hospitalization, prior history of neurologic disease, current or past history of substance abuse disorder, diabetes previous history of moderate or severe head injury, neurological disorder unrelated to TBI (e.g., seizure disorder) physician recommendations against exercise non-English speakers Non-injured Group: Inclusion Criteria: - Gainesville, Florida community member Exclusion Criteria: History of mTBI or other brain injury in the past year comorbid orthopaedic injury that inhibits movement history of serious psychiatric disturbance with hospitalization, prior history of neurologic disease, current or past history of substance abuse disorder, diabetes previous history of moderate or severe head injury, neurological disorder unrelated to TBI (e.g., seizure disorder) physician recommendations against exercise non-English speakers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mTBI Aerobic Exercise Group<br>Participants are two-three weeks post-mild traumatic brain injury are randomized to receive a daily aerobic exercise intervention lasting 1-week. | Behavioral: Aerobic Exercise<br>* Aerobic exercise will consist of riding a stationary bicycle at moderate intensity for 2 consecutive, 20-minute periods with a 5-minute break in between. Moderate intensity is defined as maintaining 65-75% of estimated maximum heart rate based on the calculation (HRmax = 208 - 0.7 × age).<br>|
| Experimental: mTBI Non-Aerobic Exercise Group<br>Participants are two-three weeks post-mild traumatic brain injury are randomized to receive a daily non-aerobic exercise intervention lasting 1-week. | Behavioral: Non-Aerobic Exercise<br>* Non-Aerobic exercise will consist of very low-intensity movements including static stretching and toning exercises.Participants will complete 2 consecutive, 20-minute periods with a 5-minute break in between, mirroring the aerobic exercise condition. Heart rate will be monitored by research staff to ensure that it remains below 50% of estimated maximum heart rate.<br>|
| No Intervention: Non-injured Reference Group<br>Non-injured, healthy participants will serve as a reference group for functional outcome measures. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Symptom Score on the Sport Concussion Assessment Tool (SCAT3) | Obtained from the 22-item symptom evaluation included in the Sport Concussion Assessment Tool (SCAT3). The participant's present experience of each symptom is rated on a likert scale from 0 (none) to 6 (severe). The symptom score represents how many symptoms the participant endorses experiencing at a level greater than 0 (maximum 22 points). | Baseline and up to day 8 | 
| Change in Symptom Severity on the Sport Concussion Assessment Tool (SCAT3) | Symptom evaluation included in the Sport Concussion Assessment Tool (SCAT3). The participant's present experience of each symptom is rated on a likert scale from 0 (none) to 6 (severe). The symptom severity represents the total summed severity ratings for all symptoms (maximum 132 points). | Baseline and up to day 8 | 
| Change in sleep quality | Obtained from the Medical Outcomes Sleep Scale (MOS). This measure has 12 items and asks the participant to rate different aspects of their sleep experiences and sleep quality. The first two questions inquire about sleep times and the remaining questions utilize a likert scale ranging from 1 (all of the time) to 6 (none of the time). Some items are reverse scored and the scale yields several subscale measures, so scoring rules depend on the specific subscale. | Baseline and up to day 8 | 
| Change in postural stability | The Balance Error Scoring System (BESS) will be used to measure postural stability, which is sensitive to deficits in balance following mild head injury. A modified version of (SCAT3) will be used. It includes three different stances, double leg, single leg, and tandem stance. A point is added for committing an error during the test interval and if the participant is unable to maintain his or her balance for more than 5 seconds, the trial is discontinued and maximum points are awarded. The total score ranges from 0 (better postural stability) to 30 (worse postural stability). | Baseline and up to day 8 | 
| Change in verbal learning and memory | Measured by the California Verbal Learning Test, 2nd Edition (CVLT-II). This test measures word recall and assesses the following skills: immediate recall, short delay free recall, short delay cued recall, long delay free recall, long delay cued recall, and long delay recognition. | Baseline and up to day 8 | 
| Change in auditory-linguistic memory | Measured by the Wechsler Memory Scale, 3rd Edition (WMS-III), Logical Memory subtests. Two stories are read to participants and then they are asked to freely recall items after a short and a long delay. A recognition trial is administered following the long delay. | Baseline and up to day 8 | 
| Change in word-fluency | Measured by the Controlled Oral Word Association (COWA). Participants are asked to say as many words beginning with a specified letter as they can in a one minute time period. Three trials with different letters are administered. | Baseline and up to day 8 | 
| Change in semantic fluency | Measured by the Verbal Fluency Test - Categories. Participants are asked to say as many items belonging to a specified semantic category as they can in a one minute time period. | Baseline and up to day 8 | 
| Change in psychomotor/executive functioning | Measured by the Delis-Kaplan Executive Functioning System (D-KEFS), Trail Making Test. The test consists of five different conditions where participants are asked to draw trails according to specified rules. | Baseline and up to day 8 | 
| Change in problem solving and abstract reasoning | Measured by the Wisconsin Card Sorting Test (WCST). Initially, a number of stimulus cards are presented to the participant. The participant is told to match the cards, but not how to match; however, he or she is told whether a particular match is right or wrong. A total of 128 cards are played. | Baseline and up to day 8 | 
| Change in attention | Measured by the Wechsler Adult Intelligence Scale, 3rd Edition (WAIS-III), Digit Span subtest. Participants are asked to repeat digit strings that are verbally administered exactly as they hear them (digits forward) or to repeat them backwards (digits backward). | Baseline and up to day 8 | 
| Change in processing speed | Measured by the Wechsler Adult Intelligence Scale, 3rd Edition (WAIS-III), Digit Symbol-Coding subtest. Participants are given three minutes to draw symbols as quickly and as accurately as possible according to a key code. | Baseline and up to day 8 | 
| Change in visual memory | Measured by the Wechsler Memory Scale, 3rd Edition (WMS-III), Visual Reproduction subtest. Participants are asked to draw abstract figures from memory at different time intervals. The subtest assesses the following visual memory skills: immediate free recall, long delayed free recall and a long delayed recognition. | Baseline and up to day 8 | 
| Change in sustained and selective attention | Measured by the Ruff 2 & 7 Selective Attention Test. The test consists of a series of 20 trials of a visual search and cancellation task. The participant detects and marks through all occurrences of the two target digits: 2 and 7. In the 10 Automatic Detection trials, the target digits are embedded among alphabetical letters that serve as distractors. In the 10 Controlled Search trials, the target digits are embedded among other numbers that serve as distractors. Correct hits and errors are counted for each trial and serve as the basis for scoring the test. | Baseline and up to day 8 | 
| Change in working memory and attention | Measured by the Paced Auditory Serial Addition Test (PASAT). Participants are read a series of numbers at specified time intervals. The participants are instructed to add the number to the preceding number and continue adding them together until the end of the trial. Four trials with 50 items each are administered with a 30 second break in between. | Baseline and up to day 8 | 
| Change in depression symptoms | Measured by the Beck Depression Inventory, 2nd Edition (BDI-II), which is a self-report questionnaire with 21 multiple choice items. The total score ranges from 0 to 63 with higher numbers indicating greater severity of depression symptoms. | Baseline and up to day 8 | 
| Change in anxiety symptoms | Measured by the State Trait Anxiety Inventory (STAI), which is a self-report questionnaire with 40 questions on a 4-point likert scale. The STAI measures two types of anxiety - state and trait scores. Higher scores are positively correlated with higher levels of anxiety. | Baseline and up to day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in functional neuroimaging activation | Functional resting state sequences will be performed on the Phillips 3 tesla magnetic resonance (MR) research scanner. | Baseline and up to day 8 | 
| Change in Symptom Score on the Sport Concussion Assessment Tool (SCAT3) | Obtained from the 22-item symptom evaluation included in the Sport Concussion Assessment Tool (SCAT3). The participant's present experience of each symptom is rated on a likert scale from 0 (none) to 6 (severe). The symptom score represents how many symptoms the participant endorses experiencing at a level greater than 0 (maximum 22 points). | Baseline and up to day 70 | 
| Change in Symptom Severity on the Sport Concussion Assessment Tool (SCAT3) | Symptom evaluation included in the Sport Concussion Assessment Tool (SCAT3). The participant's present experience of each symptom is rated on a likert scale from 0 (none) to 6 (severe). The symptom severity represents the total summed severity ratings for all symptoms (maximum 132 points). | Baseline and up to day 70 | 
| Change in sleep quality | Obtained from the Medical Outcomes Sleep Scale (MOS). This measure has 12 items and asks the participant to rate different aspects of their sleep experiences and sleep quality. The first two questions inquire about sleep times and the remaining questions utilize a likert scale ranging from 1 (all of the time) to 6 (none of the time). | Baseline and up to day 70 | 
| Change in postural stability | The Balance Error Scoring System (BESS) will be used to measure postural stability, which is sensitive to deficits in balance following mild head injury. A modified version of (SCAT3) will be used. It includes three different stances, double leg, single leg, and tandem stance. A point is added for committing an error during the test interval and if the participant is unable to maintain his or her balance for more than 5 seconds, the trial is discontinued and maximum points are awarded. The total score ranges from 0 (better postural stability) to 30 (worse postural stability). | Baseline and up to day 70 | 
| Change in depression symptoms | Measured by the Beck Depression Inventory, 2nd Edition (BDI-II), which is a self-report questionnaire with 21 multiple choice items. The total score ranges from 0 to 63 with higher numbers indicating greater severity of depression symptoms. | Baseline and up to day 70 | 
| Change in anxiety symptoms | Measured by the State Trait Anxiety Inventory (STAI), which is a self-report questionnaire with 40 questions on a 4-point likert scale. The STAI measures two types of anxiety - state and trait scores. Higher scores are positively correlated with higher levels of anxiety. | Baseline and up to day 70 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mild Traumatic Brain Injury, Aerobic Exercise, Brain-Derived Neurotrophic Factor