Effect of Exercise Training on Physical, Cognitive, and Behavioral Function in People With TBI

Objective

The broad objective of this study is to examine the effects of moderate and more intense
aerobic exercise as an intervention on cognitive performance, physical functioning and
health-related quality of life in patients with chronic (more than 12 months post-injury)
traumatic brain injury (TBI). Importantly, structural and biological brain changes will be
measured to examine whether functional outcomes are related to exercise-induced adaptations.
It is hypothesized that in the chronic phase of persons with TBI, there will be improved: 1)
cognitive function, 2) physical fitness and fatigue severity, 3) motor performance and
balance, and 4) mood and depressive symptoms, in those that performed the exercise
intervention compared to a control group. It is also hypothesized that these functional
improvements will be related to exercise intensity, improved cortical connectivity, dopamine
transmission gene scores, and blood biomarkers related to neuroand angio-genesis.

Study Population

80 ambulatory adults with non-penetrating TBI will be enrolled. Subjects will be recruited
from NIH, affiliated hospitals/clinics and the community.

Design

All subjects will perform baseline assessments including cognitive and behavioral
performance, brain imaging, fitness, motor and balance testing, and selected blood and
genetic testing. Thereafter, subjects will be randomized to either a waitlist control, or one
of two exercise conditions: 1) 30 minutes at a fast pace, moderate-intensity (rapidresistive
exercise; RET); 2) 30 minutes at higher-intensity (aerobic exercise; AET). Both exercise
groups will perform the exercise on an elliptical trainer 3 times a week, for a session
duration of 45 minutes including warm-up and cool-down. The RET group will focus on rapid
reciprocal motion with minimal resistance, while the AET group will exercise at an elevated
intensity known to produce an aerobic effect. After 12 weeks, all groups will repeat the
baseline assessments (3 month follow-up). Following this assessment, the waitlist control
group will be randomized to either RET or AET and the exercise groups will cease formal
supervised exercise sessions. A third assessment visit will be performed after an additional
12 weeks (6 month follow-up).

Outcome Measures

Cognitive performance will be tested and interpreted compared to norms. Performance on motor
and balance tasks will be assessed with the Smart Balance Measurement System and the GAITRite
System. Physical fitness will be determined by peak oxygen consumption and aerobic threshold
as measured by pulmonary gas exchange during an exercise tolerance test on the treadmill.
Structural brain volumes will be determined by magnetic resonance imaging (MRI) and cortical
connectivity will be quantified using resting state functional MRI and Diffusion Tensor
Imaging (DTI) to evaluate integrity of and changes in white matter tracts in response to
exercise. Blood will be collected to quantify the presence of biomarkers (such as VEGF, BDNF
and IGF-1) and dopamine transmission. Other self-reported measures of quality of life,
fatigue severity, depression and sleep quality would also be collected.

- INCLUSION CRITERIA:

1. Ages 18 to 79 inclusive

2. Diagnosis of non-penetrating TBI

3. Injury occurred at least 12 months prior to enrollment

4. Physically inactive as identified by a physician

5. Able to stand and walk independently and safely without any assistance

6. Able to follow the study protocol

7. Fluent in English and able to provide informed consent

EXCLUSION CRITERIA:

1. History of exercise intolerance

2. History of heart disease

3. History of pulmonary disease, other than controlled, non-exercise-induced asthma

4. History of uncontrolled diabetes

5. Uncontrolled hypertension, defined as a resting blood pressure > 140/90 mmHg

6. On medications that would influence aerobic capacity or treadmill performance such as
beta blockers or antiretroviral therapy

7. Active substance abuse including ETOH

8. Presence of an injury to any extremity, or other medical condition that would affect
motor function or the ability to perform the assessment or the exercise program,
specifically balance problems due to vestibulopathy

9. Unable to refrain from smoking at least 4 hours prior to exercise testing sessions

10. Medical or psychological instability such that the subject could not reasonably be
expected to fulfill the study requirements

11. Pregnancy

12. BMI >40 kg/M(2) due to the limits of the treadmill, elliptical machine and MRI scanner

13. Planning to make a change in medication or therapy during the enrollment period with
the goal of improving mood, cognitive function or motor function

14. Have any of the following contraindications to having an MRI scan:

1. A ventriculo-peritoneal shunt

2. Have claustrophobia and not comfortable in small enclosed spaces

3. Have metal that would make an MRI scan unsafe such as: cardiac pacemaker, insulin
infusion pump, implanted drug infusion devise, cochlear or ear implant,
transdermal medication patch (nitroglycerine), any metallic implants or objects,
body piercing that cannot be removed, bone or joint pin, screw, nail, plate, wire
sutures or surgical staples, shunts, cerebral aneurysms clips, shrapnel or other
metal embedded (such as from war wounds or accidents or previous work in metal
fields or machines that may have left any metallic fragments in or near your
eyes).

4. Excessive startle reaction to or fear of loud noises