Effect of Exercise Training on Physical, Cognitive and Behavioral Function in Patients With Traumatic Brain Injury
Phase: NA
Conditions: Traumatic Brain Injury (TBI)
Sponsor: National Institutes of Health Clinical Center (CC)

Version 6/30/2020
Protocol Title: Effect of Exercise Training on Physical, Cognitive and Behavioral 
Function in Patients with Traumatic Brain Injury
Abbreviated Title: Exercise and cognition
Protocol Number: 15-CC-0164
Date of This Submission/Version: Version 15 (2/7/2023)
Principal Investigator
Diane Damiano, PhD
FAB/RMD/
CC
10 CRC/1-1469
301.451.7544
damianod@cc.nih.gov
Lead Associate Investigator
Lisa Chin, PhD
RMD/CC
10 CRC/1-2341
301.443.9072
lisa.chin@nih.gov
Human Research Protections Program Investigator and Staff Training:
For this protocol, the following “Just in time” human subjects protection training courses 
are required for investigators and staff: None
Total requested accrual: 100 subjects (80 TBI Patients and 20 healthy volunteers)
N = 26 Wait-list control
N = 27 Aerobic Exercise Intervention
N = 27 Rapid-Resistive Exercise Intervention
N = 20 Healthy Volunteer Controls      
Project Uses Ionizing Radiation:    No 
 Yes (attach RSC/RDRC documentation)
 Medically-indicated only
 Research-related only
 Both
IND/IDE
 No 
Yes (attach FDA documentation)
Drug/Device/#_____________________
Sponsor: __________________________
Durable Power of Attorney 
 No 
 Yes 
Multi-institutional Project
 No 
 Yes
Institution#1: Center for Neuroscience and Regenerative Medicine
              FWA #_ A00001628________ 
Date of IRB approval _September 15, 2016____(attach IRB documentation)
Institution#2: Department of Veterans Affairs Medical Center, Washington DC    
FWA # A00002475_ _______ 
Date of IRB approval _January 19, 2018________(attach IRB documentation)
Data and Safety Monitoring Board 
 No 
 Yes - Monitor

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John Leddy, MD
University Sports Medicine
State University of New York at Buffalo
160 Farber Hall, Buffalo, NY  14214
Office Phone: 716-829-5501
  e-mail: leddy@buffalo.edu
Technology Transfer Agreement 
 No 
 Yes – see Appendix 12
Agreement type and number 
Collaboration agreement with DCVAMC  Expiration Date__4/19/2022_
Samples are being stored 
 No  
 Yes 
Flesch-Kincaid reading level of consent form: _10.0___________ 

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Precis
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 neuro- 
and angio-genesis.
Study Population
80 ambulatory adults with non-penetrating TBI will be enrolled. We will also enroll up to 
20 healthy volunteers as a comparison group for some of the outcome measures.  
Subjects will be recruited from NIH, affiliated hospitals/clinics and the community.
Design
Healthy volunteers will have a limited assessment that includes brain imaging, blood 
draw for genetic testing, and a subset of the cognitive and behavioral testing at a single 
time-point. All subjects with TBI will perform baseline assessments including cognitive 
and behavioral performance, brain imaging, fitness, motor and balance testing, and 
selected blood and genetic testing. Thereafter, subjects with TBI will be randomized to 
either a waitlist control, or one of two exercise conditions: 1) 30 minutes at a fast pace, 
moderate-intensity (rapid-resistive 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 and compared to healthy 

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volunteers.  Blood will be collected to quantify the presence of biomarkers (such as 
VEGF, BDNF and IGF-1) and dopamine transmission, and compared to healthy 
volunteers.  Other self-reported measures of quality of life, fatigue severity, depression 
and sleep quality would also be collected, and compared to healthy volunteers.

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Table of Contents
1.   INTRODUCTION.................................................................................10
1.1 Statement of the Problem .....................................................................................10
1.2 Importance of the Problem...................................................................................10
1.2.1 Preliminary Results .....................................................................................12
2.   STUDY OBJECTIVES.........................................................................16
3.   SUBJECTS.............................................................................................17
3.1 Study populations.................................................................................................17
3.2 Inclusion criteria...................................................................................................18
3.3 Exclusion criteria..................................................................................................18
4.   STUDY DESIGN AND METHODS....................................................20
4.2 Recruitment ..........................................................................................................22
4.3 Screening..............................................................................................................23
4.3.1 Pre-Screening ..............................................................................................23
4.3.2 Screening.....................................................................................................24
4.4 Study procedures..................................................................................................24
4.4.1 Biospecimen Collection...............................................................................25
4.4.2 Questionnaires.............................................................................................25
4.4.3 Neuropsychological Assessments ...............................................................26
4.4.4 Motor Assessments......................................................................................27
4.4.5 Magnetic Resonance Imaging .....................................................................29
4.4.6 Physical Fitness Assessment .......................................................................31
4.4.7 Exercise Training Intervention....................................................................33
4.4.8 Randomization.............................................................................................34
4.5 Relationship to other protocols ............................................................................34
4.6 End of participation..............................................................................................35
5.   MANAGEMENT OF DATA AND SAMPLES ..................................35
5.1 Storage..................................................................................................................35
5.2 Data and Sample Sharing Plan.............................................................................36
6.   RISKS AND DISCOMFORTS ............................................................37
6.1 Risks of Exercise Training ...................................................................................37
6.2 Risk of Treadmill or Elliptical Use ......................................................................38
6.3 Risk of Motor and Balance Assessments .............................................................39
6.4 Risk of Neuropsychological Testing and Questionnaires ....................................39
6.5 Risk of MRI..........................................................................................................39
6.6 Risk of Blood Draw..............................................................................................40
6.7 Risk of EKG.........................................................................................................40
6.8 Risk Associated with Hypercapnic Challenge .....................................................40
6.9 Risks of Sharing Research Data...........................................................................40
7.   SUBJECT SAFETY MONITORING .................................................41

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7.1 Parameters to be Monitored .................................................................................41
7.2 Criteria for Stopping Procedures..........................................................................42
7.3 Criteria for Individual Subject Withdrawal..........................................................42
8.   OUTCOME MEASURES ....................................................................42
8.1 Primary Outcome .................................................................................................42
8.2  Secondary Outcomes...........................................................................................42
9.   STATISTICAL ANALYSIS.................................................................44
9.1 Analysis of data....................................................................................................44
9.2 Power analysis......................................................................................................45
10. HUMAN SUBJECTS PROTECTION ................................................45
10.1 Subject selection.................................................................................................45
10.2 Justification for exclusion of children................................................................45
10.3 Justification for exclusion of other vulnerable population.................................46
10.3.1 Justification for exclusion of older adults .................................................46
10.3.2 Justification for exclusion of pregnant women .........................................46
10.3.3 Justification for exclusion of mentally ill and those unable to consent 
themselves ............................................................................................................46
10.3.4 Justification for exclusion of non-English speaking subjects....................46
10.4 Safeguards for vulnerable populations...............................................................46
10.5 Qualifications of investigators ...........................................................................46
11. ANTICIPATED BENEFIT ..................................................................46
11.1 Direct benefits ....................................................................................................46
12. CLASSIFICATION OF RISK.............................................................47
13. CONSENT DOCUMENTS AND PROCESS .....................................47
13.1 Designation of those obtaining consent .............................................................47
13.2 Consent procedures ............................................................................................47
13.3 Consent documents ............................................................................................47
14. DATA AND SAFETY MONITORING ..............................................47
14.1 Data and safety monitor .....................................................................................47
14.2 Data and safety monitoring plan ........................................................................47
14.3 Criteria for stopping the study or suspending enrollment or procedures ...........48
15. QUALITY ASSURANCE.....................................................................48
15.1 Quality Assurance monitor.................................................................................48
15.2 Quality Assurance Plan ......................................................................................48
16. NIH REPORTING REQUIREMENTS ..............................................49
16.1 Adverse Event Definitions .................................................................................49
16.2 Expedited Reporting...........................................................................................49
16.3 IRB Requirements for PI Reporting at Continuing Review...............................49

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16.4 Clinical Director Reporting................................................................................49
17. ALTERNATIVES TO PARTICIPATION.........................................49
18. PRIVACY ..............................................................................................50
19. CONFIDENTIALITY...........................................................................50
20. CONFLICT OF INTEREST................................................................51
21. TECHNOLOGY TRANSFER .............................................................51
22. RESEARCH AND TRAVEL COMPENSATION .............................51
23. REFERENCES......................................................................................52
24. APPENDICES .......................................................................................55

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List of Abbreviations
ACSM
American College of Sports Medicine
ADT
Adaptation Test
AE
Adverse Event
AET
Aerobic Exercise Training
AI
Associate Investigator
ANOVA
Analysis of Variance
AT
Anaerobic Threshold
BDI
Beck Depression Inventory
BDNF
Brain-Derived Neurotrophic Growth Factors
BOLD
Blood Oxygen Level Dependent
Bpm
Beats per minute
BSI
Brief Symptom Inventory
BVMT
Brief Visual Memory Test
CC
Clinical Center
CDE
Common Data Element
CNRM
Center for Neuroscience and Regenerative 
Medicine
COG
Center of Gravity
COMT
Catecholomethyltransferase
CPET
Cardiopulmonary Exercise Test
CRADA
Cooperative Research and Development 
Agreement
CRIS
Clinical Research Information System
CVLT
California Verbal Learning Test
DAT
Dopamine Transporter Protein
DCVAMC
Washington DC Veterans Affairs Medical 
Center
D-KEFS
Delis-Kaplan Executive Function System
DoD
Department of Defense
DT
Dual Task
DTI
Diffusion Tensor Imaging
EKG
Electrocardiogram
ETOH
Ethyl Alcohol
FSS
Fatigue Severity Scale
FTT
Finger Tapping Test
GCS
Glasgow Coma Scale
GMU
George Mason University
GUID
Global Unique Identifier
HR
Heart Rate
HRR
Heart Rate Reserve
HRQOL
Health-Related Quality of Life
HSPU
Human Subjects Protection Unit
IGF-1
Insulin-like Growth Factor-1
LOC
Loss of Consciousness

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LOS
Limits of Stability
MCT
Motor Control Tests
MET
Metabolic Equivalent
MRI
Magnetic Resonance Imaging
MSVT
Medical Symptom Validity Scale
NBSI
Neurobehavioral Symptom Inventory
NIH
National Institutes of Health
NIMH
National Institute of Mental Health
PASAT
Paced Auditory Serial Addition Test
PI
Principal Investigator
PSQI
Pittsburgh Sleep Quality Index
PTA
Post-Traumatic Amnesia
QOLIBRI
Quality of Life after Brain Injury
RET
Rapid-Resistive Exercise Training
RMD
Rehabilitation Medicine Department
RPM
Revolutions per Minute
SAE
Serious Adverse Event
SOT
Sensory Organization Test
SSRT
Seashore Rhythm Test
SWLS
Satisfaction with Life Scale
TBI
Traumatic Brain Injury
TBI-QOL
TBI Quality of Life
THR
Target Heart Rate
TMT
Trail Making Test
ToPF
Test of Premorbid Functioning
USU
Uniformed Services University
USUHS
Uniformed Services University of Health 
Sciences
VEGF
Vascular Endothelial Growth Factors
VO2
Oxygen Consumption
WR
Work Rate
WRIISC
War Related Illness and Injury Study Center
ZCG
Impedance Cardiogram

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1.   Introduction 
Over 1.7 million people sustain a traumatic brain injury (TBI) each year, with more than 
50,000 resulting in deaths [1]. Almost 80% are treated and released from emergency 
departments [1], however over 100,000 will further experience long-term disability [2]. 
TBI costs the United States approximately $76.5 billion in direct and indirect costs [3], 
which includes medical costs from acute care and rehabilitation, and loss of productivity 
due to an inability to work. 
TBI may result in physical impairments, however neuropsychological problems affecting 
cognition, emotional functioning and behavior are often more problematic.  Particularly 
in those with mild TBI, subtle functional and cognitive deficits may be present that often 
go undetected in the acute setting or by routine clinical examination.  These patients can 
experience drastic changes in their quality of life [4], and have difficulties returning to 
daily activities and work [5].
This study was initially sponsored by the Center for Neuroscience and Regenerative 
Medicine (CNRM) and received CNRM funds directly for the conduct of the study.  
CNRM sponsorship for this study has ended. The study will continue in collaboration 
with CNRM. Under this collaboration, the study will continue to use CNRM Core 
resources including the CNRM Biospecimen Repository and CNRM Informatics Data 
Repository.
1.1 Statement of the Problem
The aim of rehabilitation of individuals with chronic TBI is to restore functioning, 
promote neurobehavioural and psychosocial skills for re-integration into the community 
[6] and to return to work [2].  However, the heterogeneous mechanism of injury that 
occurs with TBI presents a major challenge to researchers and clinicians for optimal 
rehabilitative strategies and management of those with TBI.  Another problem is the 
difficulty in comparing post-acute interventional studies because of differences in the 
method of data collection, outcome measures and intervention period [6]. While progress 
has been made in this area in recent years, research studies are needed to further develop 
rehabilitation strategies and our understanding of the clinical management of TBI. 
Considering the large proportion of patients that would benefit from rehabilitation, the 
need for specific interventions that would improve their quality of life is imperative.
1.2 Importance of the Problem
It is well recognized that physical exercise offers many benefits in both general and 
clinical populations. Besides the obvious cardiovascular and metabolic adaptations that 
occur with exercise training, physical activity has also been related to diminished cerebral 
inflammation and enhanced brain plasticity [7]. Exercise increases the release and 
synthesis of neurotrophic factors related to cognitive functioning, neurogenesis, 
angiogenesis and plasticity.  Among these include the brain-derived neurotrophic factor 
(BDNF), insulin-like growth factor (IGF-1) and vascular endothelial growth factor 
(VEGF).  

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In the animal model, deficits associated with TBI such as neuronal loss in the 
hippocampus [8, 9], have been found to be attenuated by exercise.  A well studied and 
reproducible finding in the animal model is exercise-related hippocampal neurogenesis 
[10], which is believed to be linked to the commonly observed improvements in learning 
and memory following a brain injury [11, 12]. BDNF is involved in hippocampal 
neuronal plasticity, thus plays a major role in exercise-induced cognitive improvements 
[11].  Exercise stimulates BDNF gene expression in the hippocampus of the rat [13-15] 
and is volume-dependent, such that greater BDNF is expressed with more exercise [13]. 
The presence of BDNF is of primary importance, as inactivation or even the absence of 
an increase in BDNF is related to attenuation of the exercise induced improvements in 
cognitive performance in TBI rats [11, 16]. 
Despite encouraging findings in the animal model with exercise interventions, there are 
very few studies that extend this research to the TBI population. Hippocampal volume 
has been observed to be reduced following TBI [17-20] with greater hippocampal atrophy 
related to reduced memory performance [18, 20, 21].  However, there are currently no 
studies in the literature that have examined the effect of exercise on hippocampal volume 
and BDNF levels in patients with TBI. Studies in other populations such as normal aging 
and schizophrenia have demonstrated exercise-induced increases in hippocampal volume 
[22, 23], while exercise training has been associated with increased resting BDNF levels 
in young adults [24, 25]. The combined body of evidence from TBI animal studies and 
those of other disease states in humans suggest that this line of research needs to be 
extended to the TBI population.
Review of the current literature on exercise interventions is also conflicting, with results 
being equivocal or the lack of studies on specific interventions making it unreasonable to 
draw conclusions.  For instance, cognitive function in TBI patients was found to be either 
improved [26] or unchanged [27] following 4 weeks of exercise training, while fewer 
cognitive symptoms were reported by TBI patients that were considered to be exercisers 
based on self-reported physical activity [28]. A major problem in these studies is that the 
exercise was mostly unsupervised [27], or based on the subject’s reported perceived 
exertion [26] or exercise habits [28].
The intensity of exercise that produces the greatest benefit in patients with TBI is also 
currently unknown.  While aerobic exercise training is generally viewed as having the 
greatest effect from a cardiovascular and metabolic perspective, this level of intensity 
may not be appropriate for all individuals with TBI. Exercising at a higher level of 
intensity is related to greater cardiorespiratory fitness, however the effect of exercise on 
cognitive performance is not strictly dose-dependent. Improved cardiorespiratory fitness 
is not always associated with greater cognitive improvements [29].  Indeed, exercise in 
the light to moderate intensity domain has been suggested as being ideal for stimulating 
hippocampal neurogenesis [30]. Considering that individuals with TBI experience wide 
variability at the cellular, macro and outcome-level, the exercise prescription should take 
into account these concerns [7]. Currently, there is not enough research in this area to 
warrant recommendations for intensities of physical exercise for optimal rehabilitative 
outcomes for patients with TBI.

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The existing data from the literature with regards to exercise training in chronic TBI 
patients are sparse.  There is a need for clinical research with an integrative approach that 
examines neuroplastic changes that occur concurrently with objective behavioural 
measures across multiple functional domains.
1.2.1 Preliminary Results
Two recent pilot studies were performed in the Rehabilitation Medicine Department in 
patients with chronic TBI. The findings are discussed below:
11-CC-0088: Effect of aerobic exercise training on cardiorespiratory function in 
patients with TBI
In this study, results from 10 subjects (age, 33 ± 7 years; mean ± SD) suggest that 
patients with TBI are able to demonstrate improvements in cardiorespiratory function 
with a training regimen that is generally prescribed to the general population. 
Specifically, patients increased their time to volitional fatigue, attained higher peak O2 
consumption and demonstrated improved aerobic capacity (Table 1).  Patients exercised 
on a treadmill for 30 minutes at an intensity considered to be “vigorous” (i.e., heart rate 
range of 70 - 80 % heart rate reserve), 3 times a week for 12 weeks.  Despite the 
challenging training regimen, patients were able to adhere and maintain their target 
intensity throughout the session duration (Table 2). These findings have been published 
and are available ahead of print [31].
Table 1. Results of the Cardiopulmonary Exercise Test
CPET Variables
Pre
Post
∆
P-Value
Time to peak VO2 (s) 
982 (113)
1066 
(142)
+84 (45)
< 0.001
Peak VO2 (ml/kg/min)
37.1 (8.2)
40.2 (8.1)
+3.1 (2.4)
0.003
Peak WR (W) 
324 (90)
383 (104)
+59 (48)
0.005
Time at AT (s) 
556 (92)
662 (92)
+106 (63)
< 0.001
VO2 at AT (ml/kg/min) 
18.9 (4.1)
22.5 (3.5)
+3.6 (2.1)
< 0.001
Abbreviations: VO2, oxygen consumption; WR, work rate; AT, anaerobic threshold
Table 2. Summary of Aerobic Exercise Training
Group Mean
Adherence, % 
93 (4)

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Average training heart rate, bpm 
155 (7)
% HRR 
78 (2)
Total AET time, min 
1005 (38)
Abbreviations: HRR, heart rate reserve; AET, aerobic exercise training
Neuropsychological testing was also performed on 7 consecutive subjects and these 
results are available ahead of print [32].  Significant improvements (p < 0.05) were 
observed for processing speed and executive functioning following AET, as measured 
with the Trail Making Test A and B (Figure 1). Overall cognitive function, including 
those specific to delayed memory and visuospatial/constructional was also improved after 
the exercise intervention (Figure 2).
Figure 1. Time taken to complete the Trail Making Test (TMT) A and B (left), with 
standardized t-scores (right) shown before and after AET.
 
*
*
*
*
A
B
*
*
*
*
*
*
*
*
A
B

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Figure 2. Averaged index scores for the Repeatable Battery for Assessment of 
Neuropsychological Status (R-BANS) at pre- and post-AET. Symbol with lines indicate 
the mean for a standardized sample based on age (20 – 49 years) and education level (> 
High school).
Results suggest that patients with TBI are able to safely perform intense aerobic exercise 
and gain not only physical benefits but likely mental improvements as well.
10-CC-0150: Effects of rapid-resistive exercise on ambulatory adults with traumatic 
brain injury
In this study, 10 patients (age, 32 ± 9 years) exercised on an elliptical trainer that focused 
on fast reciprocal motion of the arms and legs.  Patients were instructed to perform the 
exercise 5 days per week for 30 minutes, over the course of 8 weeks. This was a non-
aerobic exercise training program, where speed was gradually increased with slight 
resistance added as patients progressed.
Table 3. Compliance with exercise by patient-report and monitoring device on the pedal
# Training Sessions
% Completed
Subject
Patient Report
Monitor
Patient Report
Monitor
1
37
35
92.5%
87.5%
2
37
31
92.5%
77.5%
3
40
42
100.0%
105.0%
4
40
 
100.0%
- 
5
40
22
100.0%
55.0%
6
40
40
100.0%
100.0%
7
40
40
100.0%
100.0%
8
no sheet
36
 -
90.0%
9
37
37
92.5%
92.5%
10
40
26
100.0%
65.0%
11
39
32
97.5%
80.0%
12
40
7
100.0%
17.5%
AVERAGE
39
31.2
97.5%
78.0%
Preliminary results from this study showed significant improvement in the automatic and 
voluntary control of balance in TBI patients. The voluntary control of balance assessed 
with the Limits of Stability test measures the reaction time (Fig. 3A) and center of gravity 
(COG) displacement (Fig. 3B) of patients to respond to a command to lean as far and as 

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quickly as possible towards a target while standing without moving their feet. Reaction 
time was faster following rapid-resistive exercise training (RET) (Fig. 3A) and COG 
displacement was larger (Fig. 3B). The automatic control of balance assessed with the 
Motor Control Test measures the automatic reaction time (latency of response) between a 
translation movement in the forceplate and the torque at the ankle to regain balance 
during standing on a forceplate (Fig. 3C). Note that the reaction was faster following 
RET (Fig. 3C).
A.
B. 
C.
Figure 3. Balance measures performed prior to (Pre) and following (Post) RET. 
Measures of Limits of Stability test reaction time in seconds (A) and the Motor Control 
Test latency in milliseconds (B) improved at posttest. Measures of displacement of the 
COG expressed as a percentage of the patients theoretical limits of stability (C) also 
improved at post-test.
Furthermore, a significant correlation was found between a dual task word generation test 
and automatic balance changes, suggesting that patients with improved reaction time 
were able to walk faster while talking (generating words).
-8.0
-6.0
-4.0
-2.0
0.0
2.0
-20
-15
-10
-5
0
Dual Task (Words) Change 
Scores (sec)
MCT Latency Change Scores (msec)
r = 0.78
p = 0.02
(p = 0.037)
*
(p = 0.059)
(p = 0.001)
*

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Figure 4. Changes in dual task word generation and mean latency of the Motor Control 
Task between pre and post RET.
While no significant changes in cognition were observed, 7 of the 10 patients scored 
within the normal range at baseline which demonstrates an absence of cognitive 
impairment in the majority of patients enrolled in this study.  Therefore, little 
improvement would be expected from this subset of patients.
Both these pilot studies revealed improvements in different aspects of functioning in a 
TBI population using different exercise intensities.  Cardiorespiratory fitness and 
cognitive function was improved with vigorous intensity exercise training, while balance 
and motor control was improved with moderate levels of exercise intensity. Likely 
activation of different mechanisms/pathways occurred to result in the observed 
improvements in the respective studies. However, specific outcomes were selected for 
each study and there was limited overlap in the measured outcomes.  Whether similar 
improvements would be observed regardless of exercise intensity is therefore unknown.  
Considering the wide range of symptoms and deficits a patient with TBI may experience, 
the optimal type and intensity of exercise may also differ depending on the patient’s level 
of impairment.
2.   Study objectives 
The broad objective of this study is to determine the effectiveness of two types of 
exercise training in patients with non-penetrating TBI for improving cognitive 
performance, balance, physical fitness, fatigue severity and other behavioral or quality of 
life outcomes. This study will also measure structural and functional changes in the brain 
and specific biomarkers known to be involved in brain plasticity as well as to examine 
genetic factors that may affect responsiveness to the training.  This study may also 
identify the intensity of exercise training that is more highly associated with specific 
cognitive, functional and structural improvements.
The 2 exercise regimens to be used are as follows:
Aerobic Exercise Training (AET)
Aerobic exercise will be performed using an elliptical trainer. Exercise intensity would be 
vigorous (~70 – 80% of maximal VO2) and similar to a previous pilot study (11-CC-
0088). A target heart rate range will be used to ensure vigorous intensity is maintained 
throughout the training session. While treadmill walking was used previously (in 11-CC-
0088), adjustment of the resistance on the elliptical trainer will allow for aerobic exercise 
to be safely achieved with this mode.
Rapid-Resistive Exercise Training (RET)

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Rapid, reciprocal exercise will be performed using an elliptical trainer, which allows for 
safe fast speed training. Similar to the previous study (10-CC-0150), this type of training 
will involve rapid movement and coordination of all four extremities.  Emphasis will be 
placed on increasing speed, however resistance can be increased to keep the level of 
exercise at a light to moderate intensity. Exercise intensity would not exceed ~ 50% of 
maximal VO2 (moderate intensity).
The objectives of this study are:
o
Primary - To evaluate the effects of exercise training intensity on cognitive 
function in patients with TBI 
o
Secondary - To evaluate the effects of exercise training intensity on balance, 
physical fitness and quality of life in patients with TBI
o
Secondary - To evaluate the effects of exercise training intensity on structural 
and functional changes in the brain of patients with TBI
o
Secondary - To examine the relationship between cognitive, behavioral, and 
motor outcomes and brain imaging, biomarker and genetic outcomes or 
variables
o
Secondary – To examine structural/functional brain differences, blood 
biomarkers and a subset of cognitive and self-reported outcomes between 
patients with TBI and healthy volunteers within the same age range
Since the direct effects of physical exercise are well known, the primary focus here is on 
the effects of exercise on cognitive function and on brain connectivity. While we 
anticipate that exercise regardless of intensity will improve cognitive and behavioral 
outcomes, we anticipate that the effects will be greater for the aerobic training group such 
that when the results are analyzed separately for each exercise condition, only the aerobic 
group will demonstrate a significant change in the primary outcome measure. Study 
outcomes such as brain imaging, blood biomarkers, cognitive performance and self-
reported questionnaires in patients with TBI will also be compared to a healthy volunteer 
sample matched to the TBI cohort for sex and age within 5 years.
3.   Subjects
 3.1 Study populations
This study will recruit a maximum of 80 adults (aged between 18 and 79 years old) with 
non-penetrating TBI and a comparison group of up to 20 healthy volunteers matched to 
the TBI cohort for sex and age within 5 years.  The healthy volunteers will only undergo 
brain imaging assessments, blood collection and a subset of questionnaires and 
neuropsychological testing. The healthy volunteers will not participate in the intervention 
phase. Withdrawals or dropouts will be replaced to have at least 20 subjects with TBI in 
each group to complete the second assessment visit.  An eligibility checklist is included 
in Appendix 3A and B.
3.2 Inclusion criteria

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Inclusion criteria for those with TBI:
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
Inclusion criteria for healthy volunteers:
1. Ages 18 to 79 inclusive
2. Physically inactive as identified by a physician
3. Fluent in English
3.3 Exclusion criteria
Exclusion criteria for those with TBI:
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/m2 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:
a.
A ventriculo-peritoneal shunt
b. Have claustrophobia and not comfortable in small enclosed spaces
c.
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), 

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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).
d. Excessive startle reaction to or fear of loud noises
Exclusion criteria for healthy volunteers:
1. History or presence of cardiopulmonary or respiratory disease
2. History or presence of other disease of the neurologic, metabolic, or renal systems
3. Active substance abuse including ETOH
4. Pregnancy
5. BMI >40 kg/m2
6. Medical or psychological instability such that the subject could not reasonably be 
expected to fulfill the study requirements
7. Have any contraindications to having an MRI scan
4.   Study Design and Methods
4.1 Study Overview

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Figure 5. Overview and time point of assessment visits during the study for subjects with 
TBI.All subjects will be officially enrolled after informed consent, and physician 
assurance of meeting the inclusion criteria and absence of exclusion criteria.  Once 
enrolled, subjects with TBI will perform the baseline assessment visit consisting of 
neuropsychological testing, brain imaging scans, physical performance test, motor testing 
and questionnaires (Figure 5). Subjects with TBI who have completed the same 
neuropsychological assessments or motor assessments within 3 months under another 
CNRM study will not be required to repeat those assessments.  Instead, we will use the 
previously obtained assessments as the baseline measures. Healthy volunteers will 
complete only a single assessment visit consisting of blood collection, brain imaging 
scans and a subset of questionnaires and neuropsychological testing, which can be done 
over more than one day at the participants’ convenience. Healthy volunteers who have 
completed the same neuropsychological assessments or within 3 months under another 
CNRM study may not have to repeat those assessments and we may use the previously 
obtained assessments instead. The estimated time to complete testing is approximately 6 
hours for the healthy volunteers. Following completion of these assessments, study 
participation ends for the healthy volunteer. 

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Figure 6. Outline of assessment visit performed within a day for subjects with TBI. 
Various assessments to be performed are shown with estimated session duration. Order of 
assessments may vary depending on availability of subject and equipment, however, the 
physical assessment will never precede another assessment.  All assessments will be 
repeated at the post-intervention visit (3 and 6 months follow-up visits) unless noted 
otherwise. Assessments are described in detail in section 4.4 below. § indicates this test 
will be performed at the baseline visit only.
This assessment visit will last approximately 8 hours, including time for rest and meals, 
and may be performed within one day or over the course of several days within a 4 week 
period. Upon completion of all baseline assessments, patients will be block randomized 
to one of three groups: 1) a waitlist control, 2) an exercise intervention consisting of 
exercise at vigorous intensity (Aerobic exercise training group, AET), or 3) an exercise 
intervention consisting of exercise at moderate intensity (Rapid resistive exercise training 
group, RET). Both training interventions will be performed 3 times a week for 12 weeks, 
with a session duration of approximately 1 hour.  After 12 weeks, all patients will repeat 
the same assessments performed at baseline (3 month follow-up).  Patients in the control 
group will then be randomized to either AET or RET, while patients in the exercise 
training groups will cease their formal supervised exercise training regimen.  All patients 
will return after 12 weeks to perform their final assessment visit (6 month follow-up).
All assessments and training interventions are outpatient visits and will occur at the NIH 
Clinical Center in the Rehabilitation Medicine Department.
§

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4.2 Recruitment
Individuals with TBI and healthy volunteers may be recruited from participants that have 
previously participated in research protocols in the RMD that are led by other NIH 
investigators, including 10-CC-0188 “Long-term clinical correlates of TBI: Imaging, 
biomarkers and clinical phenotyping parameters”. Recruitment will be limited to 
participants that had indicated a willingness to be contacted regarding other on-going 
clinical studies. These participants will be contacted by phone. 
The recruitment strategy offered by the NIH/CC Office of Patient Recruitment, including 
sample recruitment messages and advertisements are attached as Appendix 1A and B.  
We will also utilize NIH Clinical Center-sponsored digital media resources such as 
Twitter, Facebook, CC Radio, CC TV, Photo Gallery; databases such as NIH Search the 
Studies Clinical Trials.gov and Research Match. Other recruitment methods will involve 
advertisements in the form of flyers to be posted in healthcare facilities or in the local 
community with approval of the venue or in accord with their policy. Flyers may be sent 
using commercially-available mailing lists via direct mail. If used for direct mail, the 
flyer will identify the source of the mailing list. Flyers for patients with TBI may be 
posted electronically on websites for brain injury and Veteran support groups (such as 
Brain Injury Association of Maryland, National Military Family Association, TerpVets, 
etc), neighborhood blogs (FitnessNow) and publications’ websites including the 
Washington Post, Washington Post Express, Montgomery County Sentinel and 
Montgomery Magazine. IRB-approved flyers for patients with TBI may also be placed in 
e-newsletters and community online boards of support or health care organizations for 
TBI and Veterans. Flyers may be sent electronically to those requesting study 
information. IRB-approved flyers for patients with TBI will also be shared with 
moderators of Facebook pages (related to brain injury and Veteran support groups) for 
posting (Appendix 1). These materials may also be shared with users that are authorized 
to post messages to the group. Permission for posting of these recruitment material will 
be made by the moderator, according to the groups’ rules and regulations. Direct 
communication with the administrators or moderators of Facebook pages will not occur 
through Facebook, rather will be achieved through other approved means (e.g. contact 
made through recruitment events, interested queries, etc.). These postings are not paid 
sponsored ads and Facebook will not be paid for “pushing” recruitment material for this 
study. IRB-approved recruitment message for patients with TBI can also be posted on 
listservs with the permission of the moderator and IRB-required statement on how the 
receiver was identified (Appendix 1). Listservs may include schools such as University of 
Maryland and George Mason University and advocacy or profession groups, such as 
TerpVets. IRB-approved advertisements in the form of flyers may be placed in local print 
publications of newspapers, newsletters, magazines and support or health care 
organizations for TBI, including Washington Post, Express, Gazette, Washingtonian, 
Bethesda Magazine, Washington Examiner, Military papers, the NIH Record/CC News.  
The flyers for the advertisements will be used in color as submitted, or may be printed in 
black and white. The color of the ads may vary. Color changes will not be used to change 
the emphasis of an ad. The size of the ads may vary, but all parts of the ads, including 

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fonts and pictures, will be changed proportionately to the rest of that ad. Disproportionate 
changes in size will not be used to change the emphasis of an ad. 
Approved recruitment materials for patients with TBI such as flyers may be left with 
clinics for interested treating physicians to refer subjects to this study with approval of 
the venue or in accord with their policy; self-referral is also permitted. Flyers may be 
given directly to those requesting study information. Recruitment efforts will also include 
an increased presence at local Brain Injury support groups, meetings, conferences and 
awareness events to broaden awareness of the research being performed on TBI at the 
NIH, and among the local community. Flyers may be made available at outreach exhibits, 
speaking engagements, support group meetings, parent groups, professional meetings or 
association/trade meetings with approval of the venue or in accord with their policy.
We will also work with the Washington DC Department of Veterans Affairs Medical 
Center (DCVAMC), specifically the War Related Illness and Injury Study Center 
(WRIISC) and Polytrauma Unit, to specifically target recruitment of Veterans that may 
be interested in participating in this study. Dr. Reinhard will lead the DCVAMC site 
specific recruitment protocol, and approved DCVAMC personnel will use the 
inclusion/exclusion criteria to identify Veterans who appear to qualify for participation 
through the Computerized Patient Record System and Clinician Referrals. Identified 
potential Veterans will be mailed an introductory recruitment letter (see Appendix 13 – 
DCVAMC Recruitment Letter) and followed up approximately 2 weeks later with a 
phone call inviting them to participate. As soon as a Veteran indicates that they are 
interested in participation, DCVAMC study staff will provide the patient with the contact 
information of the NIH study team for further pre-screening. If the Veteran does not 
answer the phone call, study staff will leave a message, and then call back a maximum 2 
more times—no more than once per day—before ceasing outreach with the veteran. The 
DCVAMC staff will not provide the consent and HIPAA authorization since Veterans 
will be acting on their own agency and reaching out to the NIH staff directly for study 
participation.
 
4.3 Screening
4.3.1 Pre-Screening
All interested participants will be pre-screened by protocol assistants and other members 
of the research team for general inclusion/exclusion criteria, by telephone or in person 
before consent is obtained (Prescreen Questionnaire (inclusion/exclusion criteria and 
interest); Appendix 2A and B). If the participant meets the inclusion criteria based on the 
Prescreen Questionnaire, an appointment will be scheduled for the participant to come to 
NIH CC RMD for a study eligibility evaluation. To prepare for this visit we will ask them 
for their full legal name, contact information (address, phone number, e-mail address), 
and date of birth to be entered into the NIH Admissions, Travel and Vouchers program. 
The medical records of those who appear to meet the study criteria may be requested 
(such as copies of recent medical evaluations, TBI-related medical history, diagnostic 
testing/imaging, rehabilitation evaluation and treatment) to further evaluate their 
inclusion into the study. Should the participant not qualify for the study, copies of these 
records will be destroyed (i.e., shredded) or returned to the participant. 

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4.3.2 Screening
Consent form will be obtained before any study procedures, including screening 
procedures, are done. Screening of healthy volunteers will include a brief history and 
physical by a credentialed RMD medical staff member to determine study eligibility. The 
standard MRI screening questionnaire (Appendix 4) will also be used to check for MRI 
exclusions. For women of child-bearing potential, a urine pregnancy test will be done 
within 24 hours before the MRI scan with the results available prior to the start of the 
scan. Formal screening for those with TBI includes a history and physical examination, 
resting electrocardiogram (EKG), blood sample collection and urine pregnancy testing (in 
women of childbearing potential). The history and physical examination will be 
performed by a credentialed RMD medical staff member. All participants with TBI will 
have a baseline resting EKG performed. Study eligibility will be documented using the 
subject enrollment checklist (Appendix 3). A MRI screen will be done for all participants 
using the standard MRI screening questionnaire to check for MRI exclusions (Appendix 
4). Should the participant choose not to participate in the study and had not completed the 
consent process, copies of their medical records will be returned to the participant or 
destroyed (i.e., shredded). Additional clinical consults and procedures (e.g. repeat EKG, 
echocardiogram, lab work, etc) may be performed as deemed necessary by medical staff 
to establish risk for exercise participation, inclusion and safe participation in the study by 
the subject. An in-person cardiology consult may also be performed for subjects with a 
family history of coronary artery disease and/or presence of other risk factors for 
cardiovascular disease. Subjects with TBI will also be screened for vestibular-related 
balance problems. If the medical staff member suspects vestibulopathy, the subject will 
be referred for a clinical evaluation, specifically the Sensory Organization Test (SOT) 
which is performed using the Neurocom Balance Master Equitest System, prior to 
enrollment. The test involves standing quietly under different conditions that challenge 
the 3 sensory systems involved in the control of balance: somatosensory, visual and 
vestibular systems. This test identifies how patients integrate normal and altered inputs 
from each system for the control of balance. There is a slight risk of falls especially in 
those with TBI since we are challenging their motor capabilities, but this risk should be 
no greater than those encountered in everyday life. A harness can be used during balance 
testing and the examiner will closely guard the patient. If the SOT confirms a deficit in 
the use of the vestibular system to control balance the subject will not be participating in 
the exercise program, and we will recommend that they discuss further follow-up for this 
with their own personal physician. If the test is normal, the subject will be allowed to do 
the rest of the study and will not need to repeat this test during the balance assessment of 
the baseline visit. This test will be performed by one of the trained physical therapists in 
RMD.
4.4 Study procedures
All healthy volunteers will perform biospecimen collection (section 4.4.1), brain imaging 
assessments (section 4.4.6) and a subset of questionnaires and neuropsychological testing 
as indicated in section 4.4.2 and 4.4.3 below. All subjects with TBI will perform the 
following assessments for research purposes at three time points (at baseline, 3 month 

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and 6 month follow-up; Participant’s flowchart, Appendix 5). The general order and 
duration of the assessments to be performed during the testing visit is as shown and 
described below. Assessments that are considered part of the TBI common data elements 
(CDE) are noted with an asterisk (*), while assessments that are similar to the CDE are 
hash-marked (#):
4.4.1 Biospecimen Collection
Urine sample:  Prior to each MRI, urine specimens will be collected from women of child 
bearing potential for pregnancy tests. A urine pregnancy test must be done within 24 hours 
prior to each MRI.  Subjects who have a positive pregnancy test will not undergo MRI and 
will be excluded from the study. Monthly pregnancy testing will also be performed in 
subjects undergoing exercise. Urine will not be stored.
Blood samples: Venous blood samples will be collected from study participants by a 
trained phlebotomist or nurse at the Clinical Center. During this study, up to 40 ml of 
blood may be collected from participants at each study visit. Part of the blood sample 
collected for participants with TBI may be used to examine their safety risk for exercise 
participation. Specimens will be used to study DNA and multiple biological markers* 
(e.g. BDNF, VEGF, IGF-1, tau proteins, dopamine transmission genes, epigenetic 
mechanisms through DNA methylation) that may be related to brain injury and plasticity, 
or in response to motor training and exercise. Some of the samples will be immediately 
analyzed. For samples not immediately analyzed, they will be saved in a secured freezer 
for batch analysis or transferred to a biorepository as outlined in section 5. Results of 
genetic tests obtained at NIH are often preliminary and difficult to interpret because the 
testing is being done for research purposes only and the laboratories are not clinically 
certified.  Results will not be shared with participants, their families, or insurance 
companies.
4.4.2 Questionnaires
Participants will complete self-reported questionnaires on quality of life, depression, 
symptoms, sleep quality and fatigue (Appendix 8). Total time for completion is 
approximately 1 hour. The questionnaires to be completed by the healthy volunteers are 
indicated by a symbol (‡).
A. Fatigue Severity Scale (FSS)*‡
An assessment used to monitor change in fatigue in response to therapeutic 
interventions. This scale is composed of nine items with a seven-point response 
format. A response of one indicates strong disagreement and a response of seven 
indicate strong agreement with statements regarding how fatigue affects physical and 
social functioning. Clinical improvement in fatigue is associated with reductions in 
scores on the FSS. The FSS is also a practical measure due to its brevity and ease of 
administration and scoring. The FSS takes less than 5 minutes to complete.
B. Pittsburgh Sleep Quality Index (PSQI)* ‡

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Assesses the duration, depth, number of arousals, latency, and restfulness of sleep. The 
PSQI has been used to assess sleep quality in apparently healthy individuals and those 
with a number of disorders including TBI. It takes 5 to 10 minutes to complete.
C. Beck’s Depression Inventory-II (BDI-II)* ‡
Measures the severity of depression and its interaction with other mood states. The 
BDI is a frequently used tool in clinical studies of depression and mood and in clinical 
evaluation. This assessment takes less than 5 minutes to complete.
D. Brief Symptom Inventory 18 (BSI-18)* ‡
Used to identify self-reported clinically relevant psychological symptoms in 
adolescents and adults.  The shortened form of the BSI instrument provides a highly 
sensitive assessment of psychological factors.  The BSI-18 takes approximately 10 
minutes to administer.
E. Neurobehavioral Symptom Inventory (NBSI)* ‡
A questionnaire that can be administered to someone who sustains a concussion or 
other form of traumatic brain injury to measure the presence and severity of 
symptoms.  The NBSI takes approximately 10 minutes.
F. Satisfaction With Life Scale (SWLS)* ‡
A short 5-item instrument designed to measure global cognitive judgments of 
satisfaction with ones’ life. The scale usually requires only about 1 minute of a 
respondent’s time.
G. Quality of Life after Brain Injury (QOLIBRI)*
This questionnaire was developed to assess health-related quality of life in individuals 
after traumatic brain injury. There are 37 items that cover 6 dimensions related to 
quality of life: cognition, self, daily life & autonomy, social relationships, emotions 
and physical problems. The QOLIBRI takes approximately 10 minutes to complete.
H. TBI Quality of Life (TBI-QOL) 
A comprehensive set of items (i.e. physical, emotional, cognitive and social) that 
specifically affect quality of life in person with TBI [33] will be administered using 
the computer adapted versions.  Total time for completion will be less than 20 
minutes.
4.4.3 Neuropsychological Assessments
The following battery of neuropsychological assessments would be administered to 
assess executive functioning, list learning, attention, motor speed and visual memory 
(Appendix 7). Total time is approximately 1.5 hours. The assessments to be completed by 
the healthy volunteers are indicated by a symbol (‡).
A. Delis-Kaplan Executive Function System (D-KEFS) Sorting Test (Free Sort 
Condition Only)*‡

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An executive functioning test of concept-formation, reasoning skills and problem-
solving abilities. The examinee is asked to sort six mixed-up cards into two groups, 
three cards per group, according to as many different categorization rules or concepts 
as possible, and to describe the concepts used to generate each sort. The Free Sort 
Condition of the D-KEFS Sorting Test takes approximately 10-15 minutes to 
administer.
B. Medical Symptom Validity Scale (MSVT)* ‡
A brief computerized verbal memory-screening test to help distinguish malingering 
from genuine impairments in memory. The MSVT takes approximately 5-10 minutes 
to complete.
C. Brief Visual Memory Test-Revised (BVMT)*
A test of visual memory with recall and recognition trials. Administration time is 10 -
15 minutes.
D. Trail Making Test A & B (TMT)#‡
An assessment of visual conceptual and visual motor tracking (involves motor speed 
and attention functions). The test requires visual scanning, numeric sequencing and 
visual motor speed.  The TMT takes approximately 5 minutes to administer. This test 
is similar to the D-KEFS Trail Making Test included as a CDE, however is not 
dependent on other baseline assessments.
E. Seashore Rhythm Test (SSRT)‡
An assessment of auditory attention and concentration. This test evaluates an 
individuals ability to discriminate between non-verbal sounds. Administration time is 
10 minutes. This assessment is not part of the TBI CDE, however it is a sensitive 
measure of attention in patients with TBI.
F. Test of Premorbid Functioning (ToPF)#‡
An assessment that estimates an individual’s pre-injury IQ and memory abilities and 
takes less than 10 minutes to complete. This is an update to the Wechsler Test of 
Adult Reading that is part of the TBI CDE. This test is only performed once at the 
baseline visit.  
G. California Verbal Learning Test (CVLT-II)*
A list-learning task to evaluate verbal learning/encoding, effects of interference, 
immediate and delayed recall, cued recall and delayed recognition. The CVLT-II 
takes approximately 20 minutes to administer.
H. Finger Tapping Test (FTT)‡
This is an assessment of motor speed to assist in motor lateralization. This task will 
take about 10 minutes to complete and is not part of the TBI CDE.
4.4.4 Motor Assessments

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These motor assessments# use specialized equipment that produces more detailed and 
likely more sensitive outcome measures than the recommended CDE for mobility and 
balance. Healthy volunteers will not perform this assessment.
 
A. Mobility assessment
Mobility will be assessed with the GAITRite System (CIR Systems Inc., Clifton, NJ, 
USA) to evaluate gait speed, stability and variability during various walking tasks as 
follows:
     
1. Free and fast walking: Walking will be evaluated along a hallway. Participants 
will be asked to walk across a 4.6 meter long electronic walkway (GAITRite) at 
their freely chosen speed and as fast as possible without running. This will be 
repeated each 2 times.  
2. Performance during a dual task (DT) paradigm: This assessment will use a 
“walking while talking” paradigm. Subjects will be tested under 3 conditions:
i. Single task cognitive: e.g. generating words that start with the letter “s” and 
counting backwards by 3s starting at number 150 for 30 sec, while seated
ii. Single task gait: walking quietly across the electronic walkway at a 
comfortable speed. This is performed as described above.
iii. Dual tasking: walking at their comfortable speed and talking at the same time. 
Subjects will perform 2 trials: 1) e.g. walking across the walkway while 
generating words that start with the letter “f”; 2) e.g. walking across the 
walkway while counting backwards by 3 starting at number 148.
3. Reciprocal Coordination Test: this test will be done in the motion analysis lab. 
Reflective markers will be placed on the subjects’ feet to record elliptical stepping 
performance during the freely chosen speed and a speed as fast as possible. The 
subject will grip the handrails and move the arms and legs smoothly in a forward 
elliptical motion. The subject will move at free and fast speeds for 20-30 seconds 
at each speed after an accommodation/warm up period of 1-2 minutes.
B. Balance assessment 
Participants will perform the balance assessment using the Balance Master and 
SMART Balance Master System® (NeuroCom International, Inc; Clakamas, OR). 
Tests are performed on a long force plate and inside a booth, as described in Appendix 
6. Center of gravity is measured during different tasks that are described below.
1. The Limits of Stability (LOS) Test: This test is performed on the long force plate. 
Participants are required to actively shift their center of balance while standing 
(lean without taking a step) towards 8 targets that are presented individually. 
Targets are arranged in a circular pattern, and light up one by one.  The system 
then computes changes in the person’s center of gravity (COG) and outputs 
postural reaction time, movement velocity, excursion and directional control. 
During this test, subjects are in a comfortable standing position at the start and 
initiate all movements by themselves. One trial is collected for each target. They 
are encouraged to keep good posture and stay within their own postural limits but 
will have both standby assistance on the left side and a wall on their right for 

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safety should they lose their balance. Outcome variables include reaction time, 
maximum and endpoint excursion and directionality.  
2. Sensory Organization Test (SOT): This test is performed inside the booth. The task 
is to stand quietly under different conditions that challenge the 3 sensory systems 
involved in the control of balance: somatosensory, visual and vestibular systems. 
There are 6 conditions: 1) normal vision + fixed support surface, 2) no vision + 
fixed support surface, 3) vision sway (the booth moves with the movement of the 
subject’s COG), 4) normal vision + surface sway (the surface moves with the 
movement of the subject’s COG, 5)  no vision + surface sway, 6) vision sway + 
surface sway. Three trials are collected for each condition. This test identifies how 
patients integrate normal and altered inputs from each system for the control of 
balance. The outcome variable measured in this test is called the equilibrium score. 
This score tells how well the patient’s sway remains within the expected angular 
limits of stability (12.5 degrees) during each condition. Scores close to 100 
indicate the patient was stable, there is very little sway. Scores that reach “0” 
indicate there was a fall.
3. Motor Control Tests (MCT): This test is performed inside the booth. The subject is 
instructed to maintain balance after sudden translations of the support surface. This 
test measures the latency of automatic postural response mediated by long loop 
pathways connecting the peripheral sensory and motor nerves to the brain. There 
are six conditions (translations):
i.
Small forward
ii.
Medium forward
iii.
Large forward
iv.
Small backward
v.
Medium backward
vi.
Large backward
Three trials are collected for each condition.
4. Adaptation Test (ADT):  This test is performed inside the booth. The subject is 
instructed to maintain balance after repeated rotations of the support surface. This 
test measures the participant's ability to minimize sway over time when exposed to 
repeated perturbations in support surface. There are 2 conditions (rotations): toes 
up and toes down. Each condition is repeated 5 times in a row. This test reflects 
the patients’ automatic ability to adapt to the perturbations by swaying less each 
time.
4.4.5 Magnetic Resonance Imaging
Brain imaging* is considered a TBI CDE and subjects must meet the criteria for MRI 
(repeated at each assessment time point). The MRI scans will be performed in the 
Department of Radiology in the NIH Clinical Center. Scanning will be performed on a 3 
Tesla scanner. There will be no radiation exposure and no gadolinium will be 
administered. MRI scans may use research sequences that adhere to Specific Absorption 
Rate (SAR) safety guidelines and/or use research coils approved by the NMR Center 
Safety Committee. During the MRI, participants will be asked to lie on a table that can 
slide in and out of the cylinder. The MRI scan session will typically last 90 minutes and 
is unlikely to be more than 2 hours.

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1. All women of childbearing potential will provide a urine sample for a pregnancy 
test performed no more than 24 hours before each MRI scan. Women who are 
discovered to be pregnant on their follow-up visit will no longer be eligible to 
participate in this study and will not perform any further imaging or study procedures.
2.  A physician’s order for a research brain MRI will be written in the subject’s 
medical chart or entered into the electronic medical record by a member of the 
research team with clinical privileges as per study site policy. The research coordinator 
or assistant will escort the participant to the MR scanner in the CNRM Neuroimaging 
Core, housed at the NIH Clinical Center and will be in attendance with the participant 
throughout the procedure.  
3.  Subjects will be screened for MRI safety using the Screening Questionnaire used 
by the Radiology and Imaging Sciences Program of the Clinical Center (Appendix 4). 
 4. Subjects may be asked to lie still for up to 12 minutes at a time.  While in the 
scanner they will hear loud knocking noises, and they will be fitted with earplugs or 
headphones to muffle the sound. They will be able to communicate with the MRI staff 
at all times during their scan, and they may ask to be moved out of the machine at any 
time. 
5.  Participants will first have a structural MRI scan.  The structural MRI sequences we 
will use do not require contrast. They are not required to do any tasks during the 
structural MRI.  Sequences used for the structural MRI may include T1 Magnetization 
Prepared Rapid Gradient Echo (MPRAGE), Fluid Attenuated Inversion Recovery 
(FLAIR), Diffusion Tensor Imaging (DTI), resting state functional connectivity 
(rfMRI), diffusion weighted imaging (DWI), Arterial Spin Labeling (ASL) to assess 
resting CBF, gradient echo (GRE) and/or T2* susceptibility weighted imaging (SWI).  
If image quality of a given sequence is inadequate due to patient motion for example, 
these may be repeated at the discretion of the MRI technologist or radiologist. The 
structural scan takes approximately 45 minutes.
6.  For the fMRI, the following cognitive test will be administered: 
Paced Auditory Serial Addition Test (PASAT): a measure of cognitive function 
that specifically assesses auditory information processing speed and flexibility, 
calculation ability, and working memory. Single digits are presented every 3 
seconds and the patient must add each new digit to the one immediately prior to it. 
The PASAT takes approximately 10-15 minutes to complete.
7.  The BOLD sequence with hypercapnia challenge will have a BOLD MRI scan with 
cerebral vascular reactivity (CVR) hypercapnia measurements. Region-specific CVR 
will be assessed using hypercapnia induced by breathing 5% carbon dioxide (CO2) 
mixed with 21% O2 and 74% N2. Study participants will be taken out of the scanner 
and fitted with a breathing mask that covers the mouth or a mouthpiece and nose clip 
to keep the patient from breathing through his/her nose.  After the mask or mouthpiece 

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and nose clip is in place, the patient is placed back into the magnet.  Hypercapnia will 
be induced via a Douglas bag fitted with a valve to switch between room air and 5% 
CO2
All or parts of the planned MRI procedures may be omitted for participants with non-
ferromagnetic metal or other substances in the head that do not constitute a safety 
hazard but may create an artifact that will interfere with analysis. We may evaluate the 
quality of previous MRIs on the participant if available or consult a radiologist to help 
in making this determination.
All MRI scans will be performed with dedicated radiofrequency coils that have 
received approval from the FDA or the NIH NMR Center Safety Committee. Research 
MRI coils that are not approved by the FDA may be used in this study. The NMR 
Center Safety Committee will approve all research coils for human use. A list of 
research MRI coils used will be submitted to the IRB at the time of continuing review. 
The CNS IRB has previously determined that research coils approved by the NMR 
Center Safety Committee are non-significant-risk devices and that no Investigational 
Device Exemption is needed. 
The IRB has determined that the 32-channel head coil that may be used in this study 
does not meet the definition of significant risk (SR) device in accordance with FDA 
regulations (21 CFR 812), and therefore is considered an NSR device.
A SR device means an investigational device that:
•
Is intended as an implant and presents a potential for serious risk to the health, 
safety, or welfare of a subject;
•
Is purported or represented to be for a use in supporting or sustaining human life 
and presents a potential for serious risk to the health, safety, or welfare of a subject;
•
Is for a use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and presents a 
potential for serious risk to the health, safety, or welfare of a subject; or
•
Otherwise presents a potential for serious risk to the health, safety, or welfare of a 
subject. (21 CFR 812.3(m))
4.4.6 Physical Fitness Assessment
These physical fitness assessments use specialized equipment that produces more detailed 
and likely more sensitive outcome measures than the recommended CDE for physical 
function. Patients will perform a cardiopulmonary exercise tolerance test on the treadmill 
with measures of pulmonary gas exchange to determine their maximal exercise tolerance. 
Healthy volunteers will not perform this assessment.
A. Cardiopulmonary exercise test (CPET) and EKG#   
A computerized treadmill with motor-driven speed and grade adjustments will be used 
for the graded exercise test.  The treadmill was chosen as the method of testing 
because it is well known to evoke higher values of O2 consumption (VO2) at 
maximum exercise, compared to other standard methods such as the leg cycle 
ergometer. Also, treadmill walking is a functional performance measure and the RMD 

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exercise laboratory personnel are well experienced in clinical treadmill exercise 
testing.
Subject preparation will consist of placing 10 electrodes on the chest at rest in the 
Mason-Likar 12-lead EKG modification for treadmill testing. The purpose of the EKG 
during the exercise test is to obtain digital HR information over the course of the 
CPET. After the electrodes have been placed, either a facemask placed over the lower 
portion of the subject’s face (mouth and nose) or a mouthpiece and nose-clip will 
house the subject interface for pulmonary gas exchange. After collection of seated and 
standing resting data, the subject will begin the treadmill test. The test protocol begins 
with subjects walking at a slow speed on a flat treadmill. The speed and grade will 
then gradually increase at a rate that is supposed to bring the subject to exertional 
intolerance within 8 to 12 minutes. The target endpoint is exertional intolerance 
defined as the subjects expressed desire to stop walking despite strong verbal 
encouragement from the testing staff.  A standard approach will be used to gain 
feedback from the subject regarding their current state of exhaustion during the test by 
frequently asking how they feel during the test. When they indicate they are becoming 
fatigued, the testing staff asks if they can continue for another minute.  If the answer is 
“yes,” after 30-45 additional seconds the subject is again asked if they can continue for 
an additional minute. If the answer is “yes,” the process is repeated. When the 
subject’s answer is “no,” the subject is asked if they can continue for another 30 
seconds.  If the answer is “yes,” then after an additional 15 seconds the subject is 
again asked if they can continue for an additional 30 seconds.  If the answer is “yes,” 
the process continues. When the answer is “no” or when the answer is “I must stop 
now,” the test is stopped and the treadmill speed and grade are decreased to cool down 
levels. The test may also be stopped immediately at the subject’s request, therefore the 
subject determines the stopping point and is never pushed beyond their expressed 
ability to continue.  No expressed disappointment is ever mentioned to the subject in 
an attempt to force continuation.  It is recognized that this stopping point is subjective 
and may occur at a level that is potentially lower than their actual metabolic capacity. 
To determine if the metabolic capacity has been reached there are two physiologic 
indices used.  One is the attainment of 90% of the subjects maximum predicted heart 
rate (220 beats per minute minus one beat per minute per year of life).  The other is 
attainment of an expiratory exchange ratio (total body oxygen consumption / carbon 
dioxide expiration) of 1.10 or greater as measured by pulmonary gas exchange 
analysis. One of these criteria must be met to substantiate attainment of maximal 
cardiorespiratory capacity. 
B. Pulmonary gas exchange
Pulmonary gas analyses will be performed using a computerized metabolic cart 
including rapid response oxygen and carbon dioxide analyzers, and a 
pneumotachometer interfaced with a microprocessor. Subjects will interface the 
system using a fitted facemask or mouthpiece and nose-clip attached to a plastic air 
collection pneumotachometer. The pneumotachometer is in turn attached to a plastic 
tube connected to a flow pump, which regulates the volume of air passing into the 
oxygen and carbon dioxide analyzers. The total volume of air expired and inspired 

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(passing through the plastic tube) is measured by a digital, bidirectional 
pneumotachometer. Gas exchange variables measured during the tests will be 
measured continuously, breath-by-breath. The main variable of interest obtained from 
pulmonary gas analyses is VO2. VO2 will be determined electronically by the Haldane 
equation for every breath and the highest value recorded at volitional exhaustion will 
be recorded as the score for the measurement. Other pulmonary gas exchange 
variables (such as anaerobic threshold) may be analyzed to assist in explaining 
subjects’ exercise response. These supporting variables will not require further data 
collection.
4.4.7 Exercise Training Intervention
TBI participants will be block randomized to one of 3 exercise training regimen for 12 
weeks.  All exercise training interventions will be supervised and performed 3 times per 
week, for 45 minutes each session at the NIH Clinical Center. All women of childbearing 
potential randomized to either exercise group will perform monthly pregnancy testing.  
The specific exercise intervention is as described below:
A. Aerobic exercise training (AET)
Subjects will perform physical exercise on an elliptical trainer, with emphasis on aerobic 
exercise being performed at a target heart rate (HR) range for 30 minutes.  The target HR 
will be calculated as a range of between 70% and 80% of the heart rate reserve (HRR); 
where HRR = 0.70 to 0.80 * (peak HR – resting HR) + resting HR.  The session will also 
include 15 minutes of warm-up and cool-down at sub-training intensity. Aerobic exercise 
will be continuous over the 30 minutes unless the patient cannot tolerate the regimen 
continuously. If the training regimen cannot be tolerated, exercise bouts will be alternated 
with rest intervals until the total time of 30 minutes of exercise at the target HR is 
achieved. The primary goal of this type of exercise is to increase the intensity at which 
the target HR is achieved.  This would be achieved by preferentially increasing the 
resistance on the elliptical trainer, rather than speed.  Subjects in AET would be 
exercising at ~ 70 to 80% of maximal VO2.  A paper-based log sheet will be used to 
record the heart rate, resistance and speed used in each session (Appendix 9).
B.
Rapid-resistive exercise training (RET)
Subjects will perform physical exercise on an elliptical trainer, with emphasis on 
maintaining a near maximal speed of movement for 30 minutes.  The session will also 
include 15 minutes of warm-up and cool-down at a slower speed. Subjects will be 
encouraged to progressively increase their maximal speed over time, while maintaining a 
smooth rhythm throughout the session. Once the subject has reached a speed of 80 RPM, 
resistance will be added.  It will be increased incrementally as long as adding resistance 
does not decrease their speed below 80 RPM and does not increase their heart rate 
beyond the target set for moderate exercise as described below. Rapid-resistive exercise 
will be continuous over the 30 minutes unless the patient cannot tolerate the regimen 
continuously. If the training regimen cannot be tolerated, exercise bouts will be alternated 
with rest intervals until the total time of 30 minutes of exercise at near maximal speed of 
movement is achieved. The primary goal of this type of exercise is to increase movement 
speed and reciprocal coordination, while being within moderate intensity.  Subjects in 

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RET would be exercising below their anaerobic threshold (determined from the CPET), 
which is typically about 50% HRR and maximal VO2. Therefore, the heart rate associated 
with ~85% of each subjects’ anaerobic threshold would be determined and this target 
heart rate would not be exceeded during their exercise sessions to ensure exercise is of 
moderate intensity.  A paper-based log sheet will be used to record the heart rate, 
resistance and speed used in each session (Appendix 9).
 
Subjects in the exercise training group will complete at least 30 of the 36 training 
sessions in twelve weeks to remain eligible for the study.  Subjects will wear a heart rate 
monitor during the sessions such that beat by beat heart rate is displayed continuously. 
The frequency of the sessions will be three times per week, unless make up sessions are 
needed to adhere to the minimum sessions required. Sessions will be supervised by 
credentialed RMD personnel.
Subjects randomized to the wait-list control will be further randomized to either AET or 
RET after Assessment Visit 2. In the first 3 months, subjects in the wait-list control will 
receive no exercise training; however they will be contacted monthly to ensure 
compliance and to maintain contact (Appendix 10). For subjects initially randomized to 
either AET or RET, they will no longer follow a formal exercise intervention at NIH 
following Assessment Visit 2. However, they will be contacted monthly for the next 3 
months and asked about their weekly physical activities (Appendix 10).
4.4.8 Randomization
Randomization of subjects will be performed using randomized blocks to keep groups as 
equal in numbers as possible and to avoid early filling of one of the groups. An 
independent randomizer that is not affiliated to the protocol will perform the 
randomization of subjects.
4.5 Relationship to other protocols
Potential participants do not have to enroll or participate in any other protocol in order to 
participate in this study.
This study is related to a number of other protocols and projects. The Center for 
Neuroscience and Regenerative Medicine (CNRM) is a collaborative intramural federal 
program involving the United States Department of Defense (DoD) and the National 
Institutes of Health (NIH). It joins clinicians and scientists across disciplines to catalyze 
innovative approaches to traumatic brain injury (TBI) research. 
The Uniformed Services University of Health Sciences (USUHS) heads the operation of 
the CNRM (www.usuhs.mil/cnrm). 
CNRM initially provided Henry Jackson Foundation staff and equipment to NIH through 
a CRADA. These staff included several providers who perform the assessment instruments. 
All providers are credentialed at the Clinical Center for work at NIH.

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The CNRM Informatics Core was created to store all imaging and clinical data from 
CNRM-related protocols. All clinical data will be coded and have personally identifying 
material removed prior to transfer to CNRM.
Research data from neuropsychological assessments, balancing and imaging performed 
within the past 3 months under other CNRM studies may be included as baseline 
assessments in this study. This is to avoid patient burden and practice effects. Research 
data from the same subject may also be shared directly with CNRM investigators in 
protocol 10-CC-0118 (Long-term Clinical Correlates of TBI: Imaging, Biomarkers and 
Clinical Phenotyping Parameters) and 11-N-0084 (Evaluation and Diagnosis of Potential 
Research Subjects with Traumatic Brain Injury).
4.6 End of participation
Subjects will remain under the care of their own providers for the duration of the study.  
Any incidental findings on brain images, laboratory or other assessment that may require 
further evaluation or may impact the subjects medical care will be recorded in the medical 
record and shared with the subject and their health care providers at subjects’ request. 
However, this study does not provide treatment and does not replace any therapy that a 
subject may be receiving as part of standard medical care for TBI.
There is one questionnaire that indicates the presence of depression.  If any question 
about suicidal ideation is answered in the affirmative, the study physician will talk with 
the patient and call in the NIH staff psychiatrist if there is a concern about the patient’s 
stability and safety. NIH policy will be followed concerning a patient who may be a 
danger to him/her self.
5.   Management of Data and Samples
5.1 Storage
The CNRM GUID is a number assigned by the CNRM Informatics Core. The Informatics 
Core has established an encrypted system and will provide access to the site for 
generation of a GUID, developed locally at each site, from personal health identifiers 
(PHI) data. Only the local site will have access to PHI. Local sites will maintain Master 
Keys matching GUIDs to PHI. Electronic/computer Master Keys will be kept on 
password protected terminal(s) in locked rooms with access limited to designated study 
personnel.
Electronic Master Key records will be backed up electronically at each site at least monthly. 
Physical print outs/copies of Master Keys will be kept in a locked cabinet in the office of a 
designated study investigator, and will be updated monthly or at more frequent intervals. The 
mapping from PHI to GUID will not be stored by or known to the CNRM Informatics Core 
or NIH CIT personnel, but the central registration of issued GUIDs will help ensure 
uniformity of identifiers across sites and the ability to identify the enrolling site.
 
Subjects receiving follow up visits will retain initially-assigned GUIDs throughout their 
participation and all data will be stored linked to this GUID. Requirements or requests for 

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subject future contact (re-identification) must pass through the enrolling site for GUID-
PHI Master Key deciphering. CNRM Master Keys will contain the following 
information: GUID, last name, last 4 digits SSN, date of birth, and/or medical record 
number.
All subjects’ data will be coded and kept on password-protected computers or files in 
locked offices with access only by study personnel.  Clinical data collected while at NIH 
will be coded and kept in locked cabinets. Data will also be stored using an electronic 
data capture system such as the NICHD Clinical Trials Database (CTDB), which is 
backed-up and password protected for acccess by pertinent research members. The 
CNRM Informatics Data Repository will provide for the CTDB data to be periodically 
transferred to NIH CIT, where the data repository is to be housed. Only study 
investigators and those associated with this protocol will have access to the samples and 
data. Any loss or destruction of saved data or samples will be reported to the IRB. The 
CNRM Informatics Core was created to store all imaging and clinical data from CNRM-
related protocols. All clinical data will be coded and have personally identifying material 
removed prior to transfer to CNRM.
Blood samples will be transported and immediately analyzed or stored in NINR secure 
freezers at the NIH Clinical Center until they are ready for batch analysis. Participant 
names and identifying information will be removed and the samples will be assigned codes. 
The key to the code will be kept in a separate, secure area. NINR will be responsible for 
the samples at NIH.
Any samples not analyzed will be stored in the CNRM Biospecimen Repository which is 
operated under USUHS Protocol No. CNRM-004 “Biorepository and Informatics 
Warehousing”. The samples will be stored at the CNRM Biospecimen Repository and de-
identified and stored there for the future measurements. Blood samples will be stored in 
secured freezers at the CNRM Biospecimen Repository.  The subject’s name and 
identifying information will not be on the samples; they will be assigned a code. The 
samples will be stored for up to 20 years. The purpose of the repository is to store a large 
number of samples and related data so that we can learn more about traumatic brain injury 
and how to rehabilitate people who may have it. The CNRM is a federal medical research 
program of the U.S. Department of Defense (DOD), and DOD is the custodian of the 
samples. The Uniformed Services University operates the CNRM and the USUHS IRB 
reviews the repository for patient protection and receives reports from a Biorepository 
Steering Committee on the operations of the repository.
Before sending blood samples, we will remove the subject’s name and identifying 
information; we will assign them a code. The key to the code will be kept in a separate, 
secure area. Once the samples and the code arrive at the CNRM Biospecimen Repository, 
a repository manager will be responsible for maintaining the samples and sending them to 
others who may use the samples for research. Subject’s blood samples will only be 
accessible by current and future CNRM Investigators after approval by all relevant IRBs.
5.2 Data and Sample Sharing Plan

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Results of genetic tests obtained at NIH are often preliminary and difficult to interpret 
because the testing is being done for research purposes only and the laboratories are not 
clinically certified.  Results will not be shared with participants, their families, or 
insurance companies.
Blood samples that are not analyzed at the NIH Clinical Center will be transferred to the 
CNRM Biospecimen Repository (USUHS Protocol No. CNRM-004 “Biorepository and 
Informatics Warehousing”) for storage and materials will be shipped in accordance with 
NIH and federal regulations. Data will be transferred to CNRM Informatics Data 
Repository (CNRMIDR-001). No personally identifiable data will be transferred to 
CNRM. A global unique identifier (GUID) that is not linked to any personal identifiers 
will be generated for each participant and be used  to share samples with CNRM. A 
materials transfer agreement will be put in place before any transfers are made.
6.   Risks and discomforts
6.1 Risks of Exercise Training 
The risks of this study are those associated with participation in vigorous aerobic 
exercise. The general risks of exercise include myocardial infarction, angina, shortness of 
breath, dizziness, early onset of fatigue and exhaustion, joint or muscle pain and 
numbness. Many of these symptoms may occur during the immediate post-exercise 
recovery phase, which is generally thought to be the first six minutes following strenuous 
exercise. 
Many subjects will experience delayed onset muscle soreness after the exercise tolerance 
tests or after the exercise-training phase. This soreness will be mild to moderate in 
intensity and could begin immediately after exercise or up to 48 hours following the 
exercise session. It will typically subside within a seven-day period. Continued 
participation in exercise training does not appear to increase or prolong delayed muscle 
soreness. Many subjects will also experience increased levels of fatigue that are sustained 
for up to 24 hours following the exercise sessions.  This fatigue will typically subside 
after one to three weeks.
The most serious risks for those participating in exercise are cardiovascular 
abnormalities. These risks are slight even in individuals with known severe coronary 
atherosclerosis during exercise tolerance testing. In studies that include patients with 
known heart disease as well as patients in whom the presence of heart disease is 
unknown, morbidity and mortality during maximal exercise testing remains low at 0.0 to 
8.3 per 100,000 and 0.0 to 1.0 per 100,000 respectively [33-42]. Morbidity and mortality 
remain at similar lows for maximal exercise testing environments that are attended by a 
physician and those supervised by a physician but conducted by qualified physician 
extenders [34, 37, 40, 43, 44]. Exercising at submaximal intensities, such as during AET, 
carries with it even lower risk of adversity.   
To minimize risk and maximize safety, all exercise tests will be carried out in 
laboratories that are in the NIH Clinical Center with immediate response backup. All 
subjects will be screened by medical history and medical examination to exclude those 

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with contraindications to exercise in whom testing and training might be unsafe. Subjects 
will be monitored during the treadmill exercise tests by 12-lead EKG. Subjects will be 
informed of the signs and symptoms of heart disease and questioned frequently during 
the test regarding the presence of symptoms of heart, neurological, or musculoskeletal 
conditions. An infographic (Appendix 14) for the common warning signs of a heart attack 
will also be available for subjects. As recommended by the American Heart Association 
and the American College of Sports Medicine, exercise will be overseen by personnel 
appropriately trained to extend physician services in the form of exercise testing and 
training in the clinical setting [45]. People with TBI comorbid with severe systemic 
illnesses will not be participants. The investigators and clinical exercise training and 
testing staff in our laboratory are highly experienced in treadmill cardiorespiratory 
testing, even in high-risk patients such as those with congestive heart failure and 
pulmonary artery hypertension. 
TBI is not thought to increase cardiovascular risk or the risk of life-threatening adverse 
events during treadmill testing. According to the American College of Sports Medicine, 
subjects in this study will be classified as low or moderate risk for adverse events [45]. 
Recommendations for this classification are that physical examination is not necessary 
for low risk subjects prior to participation and physician supervision of a peak or 
submaximal exercise test is not necessary.  In contrast, for moderate risk participants, a 
pre-training physical examination and physician supervision of a maximum exercise test 
is recommended, although physician supervision of a submaximal test is not necessary in 
the moderate risk group according to ACSM recommendations. However, RMD 
operating procedures are that a physician is in close proximity (in the department) at all 
times during an exercise test. This policy meets the definition of physician supervision in 
the ACSM guidelines [45].  In addition, all subjects will receive a physical examination, 
including the pre-participation history and physical exam parameters recommended by 
the ACSM [45]. All of the investigators and laboratory personnel are clinical exercise 
professionals certified by the ACSM, physical therapists, laboratory personnel certified 
and credentialed in the RMD exercise laboratory, or rehabilitation medicine physicians.  
All are trained in basic life support.  Rapid code team response is readily available for the 
RMD Exercise Testing Laboratory and Fitness Center. All treadmill testing and elliptical 
training procedures will rigorously conform to ACSM guidelines and stopping points 
[45] (Appendix 11).
6.2 Risk of Treadmill or Elliptical Use
Risk of injury also includes those related to falling on a moving treadmill belt, such as 
abrasions, contusions, cuts, sprains, and fractures. The likelihood that any of these 
injuries would occur is small and preventive measures will be enforced to insure that the 
risks remain at a minimum. 
The treadmill is equipped with handrails for aiding balance and providing increased 
stability.  The treadmill also is equipped with a “hot” switch that is easily within the 
reach of the subject while walking on the treadmill. When the switch is activated, the 
treadmill stops and ends the test immediately. Under this circumstance the treadmill 
cannot be restarted unless both the treadmill itself and the computer control are reset. 
Subjects are instructed in treadmill safety and the use of the hot switch before beginning 

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the test protocol. Subject response to the test is monitored visually, electronically, and by 
verbal interaction between the subject and the testing staff.
Risk of injury with the use of an elliptical machine includes falling off or tripping caused 
by slippage off the pedals.  Moving parts also create potential pinch hazards. There may 
also be feet, ankle and back discomfort if subjects are unused to the motion.  The 
likelihood of these injuries occurring is minimal and proper form and familiarity with the 
device would reduce these risks further.  Also sessions will be closely monitored by 
credentialed personnel and subjects will be asked for feedback during the exercise 
session.
6.3 Risk of Motor and Balance Assessments
There is a slight risk of falls especially in those with TBI since we are challenging their 
motor capabilities, but should be no greater than those encountered in everyday life. A 
harness will be used during balance testing and the examiner will closely guard the 
patient. The adhesive tape that will be placed on the skin may cause mild skin irritation or 
discomfort upon removal.
Stand-by assistance by a physical therapist or a safety belt or overhead harness will be 
used whenever there is a potential for unsteadiness that could lead to a fall during the 
motor and balance tests, or if the patient is concerned about falling.
6.4 Risk of Neuropsychological Testing and Questionnaires
The neuropsychological tests are not harmful, but may be frustrating or stressful. Filling 
out the questionnaires may be perceived as boring.
If the participant experiences distress, anger or any other emotional or behavioral 
symptoms during the neuropsychological tests, Dr. Chan will assess the situation and 
make recommendations or referrals as needed. All subjects will be informed prior to 
consent that they will be asked multiple questions that relate to their emotional and 
psychological health, and they will be told that they can refuse to answer any or all 
questions that they are not comfortable with. They may also stop the testing at any time 
for any reason.
6.5 Risk of MRI
People are at risk for injury from the MRI magnet if they have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm 
clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins 
and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery 
pump, or shrapnel fragments. Welders and metal workers are also at risk for injury 
because of possible small metal fragments in the eye of which they may be unaware. It is 
not known if MRI is completely safe for a developing fetus and therefore will not be done 
if the subject is pregnant. People with fear of confined spaces may become anxious 
during an MRI. Those with back problems may have back pain or discomfort from lying 
in the scanner. The noise from the scanner is loud enough to damage hearing, especially 
in people who already have hearing loss. Another risk is boredom in the MRI since 

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subjects will be asked to lie quiet and still for several minutes at a time. There are no 
known long-term risks of MRI scans.
All subjects will be screened for MRI contraindications before each scan, and if any are 
present, will not receive an MRI scan.  In addition, all magnetic objects (for example, 
watches, coins, jewelry, and credit cards) must be removed before entering the MRI scan 
room. The scan will not be done on anyone who is pregnant.  A pregnancy test will be 
done on all female subjects who have the possibility of being pregnant within 24 hours of 
having each MRI.  Everyone having a research MRI scan will be fitted with hearing 
protection.
6.6 Risk of Blood Draw
Needle punctures for drawing blood usually do not cause any serious problems. However, 
drawing blood may cause pain and carries a small risk of bleeding, localized bruising, 
discomfort and/or infection at the injection site, or temporary dizziness.  If any of these 
occurs, they will be treated. The study will draw no more than 120 mL of blood for the 
entire study, which is below the maximum amount of blood that can be drawn as required 
by NIH guidelines which is no more than 450 mL in any 6 month period.
6.7 Risk of EKG
There is minimal medical risk or discomfort from the EKG.
6.8 Risk Associated with Hypercapnic Challenge
Some of the side effects of early hypercapnia include flushed skin, increased heart rate, 
muscle twitches, hand flaps, and possibly elevated blood pressure. Severe hypercapnia 
can also cause disorientation, headaches, panic, hyperventilation, and unconsciousness. 
Symptoms disappear with the resumption of breathing regular room air. The hypercapnic 
challenge used is of short duration and very mild, and the subject will be monitored 
closely during this challenge for discomfort and symptoms. The subject will be 
immediately switched back to room air at the subjects request or if staff detect excessive 
subject discomfort.
6.9 Risks of Sharing Research Data 
Samples and data provided to the CNRM Biospecimen Repository (CNRM-004) and 
CNRM Informatics Data Repository (CNRMIDR-001) will be coded using a Global 
Unique Identifier (GUID) derived from PII and generated locally. Re-identification of data 
and samples collected at the NIH would be possible if repository data and samples are 
released with the GUID to other CNRM investigators who have access to the same subjects 
PII through participation in other IRB approved studies as they will generate the same 
GUID at their site.  Re-identification is unlikely, however, as the CNRM Repository 
intends in most cases to release data and samples without the GUID.
The following measures will be made to minimize breach of confidentiality of records or 
data:

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• All research procedures will be conducted by staff qualified to perform the procedure and 
with monitoring as defined in sections 7 and 10.
• Confidentiality will be protected as described in Section 19.
• Use of subject data that is re-identified through PHI used to generate a GUID is 
permitted only under IRB approved protocols with pre-defined research questions. 
7.   Subject Safety Monitoring
7.1 Parameters to be Monitored
Motor Assessment: All motor and balance assessments will be performed in the 
Functional & Applied Biomechanics Section under closely monitored conditions. A 
clinically credentialed staff member will remain with the subject at all times to ensure 
their safety and to assist them as needed. Subjects will be instructed to tell us if any of the 
tests are uncomfortable or concern them in any way. The primary parameters we will be 
monitoring are dizziness, unsteadiness, fatigue, or any indication that they are becoming 
distressed during the testing.
MRI: The subject will be in voice contact with MRI staff at all times during the scans and 
we will respond to their questions or concerns as needed. On site medical personnel and 
emergency medical assistance will be available for all MRI studies.
Treadmill CPET: All of the CPET tests will be performed in the RMD exercise testing 
laboratory in the Hatfield Clinical Research Center under closely monitored conditions. 
Clinically credentialed staff members will perform and monitor the tests and recovery 
period to ensure safety and assist the subjects as needed. Accepted clinical credentials are 
ACSM certification as a Clinical Program Director, Registered Clinical Exercise 
Physiologist, or Clinical Exercise Specialist, Licensed Physical Therapist, Licensed 
Physician, or individuals declared competent for administering exercise training and 
testing by the RMD. As part of their credentialing, staff members are knowledgeable in 
exercise test EKG monitoring and endpoints and will monitor EKG and blood pressure 
responses during the tests. The treadmill is equipped with handrails for aiding balance 
and providing increased stability to avoid risk of falling.
Exercise Training:  Exercise training will be conducted on elliptical machines located in 
the RMD’s Fitness Center, Exercise Testing Lab or Functional & Applied Biomechanics 
Lab. A clinically credentialed individual will monitor and record adherence to the target 
heart rate and session duration guidelines, changes in medications should they occur, 
exertional symptoms should they occur, and attendance.  Supervision by the clinically 
credentialed individual will take place in the same room as the participant.
Severe Depressive Symptoms and/or Suicidal Ideation: Physicians and study staff in this 
study will monitor subjects throughout the protocol procedures. Physicians and study 
coordinator or other research staff member will be with the participant and will monitor 
for any anxiety and will assess any issues that arise such as suicide ideation.  Procedures 
are done at the NIH Clinical Center and medical emergency services are available to 
participants in this study, if needed.

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7.2 Criteria for Stopping Procedures
Treadmill CPET: Subjects will be reminded of test stopping points and exertional 
symptoms and will be queried by the staff frequently during the tests regarding their 
presence. While volitional exhaustion is the target test endpoint on the CPET, other 
stopping points are those recommended by the ACSM [45] (Appendix 11).
7.3 Criteria for Individual Subject Withdrawal
Federal regulations require that subjects may withdraw from participation in the study at 
any point without prior notice and without adversely affecting their medical management, 
educational or employment status. At the time of withdrawal, subjects will also be able to 
withdraw their data from the study. The study investigators may also withdraw subjects 
from the study for medical, administrative or issues of non-compliance. If the subject 
experiences a clinically significant worsening of mood or behavioral symptoms (not an 
emergency), she/he will be removed from the study and the physician and/or 
neuropsychologist will ask the subjects if they would like them to make a referral for 
further outside evaluation and treatment. Any psychiatric emergency would also be cause 
for withdrawal from the study and will prompt immediate psychiatric evaluation at NIH. 
During the course of the study, subjects will be instructed to continue with their current 
care. Alterations of care must not include changes in therapy, exercise regimen or 
medication that would potentially alter cardiorespiratory capacity, mood, or cognitive or 
motor abilities, or the ability to achieve a training adaptation measurable by the methods 
used in this study. If the subject does make these types of changes, they will be 
administratively withdrawn from the study.  If a subject misses an assessment and is 
unable to reschedule it within four weeks, they will be withdrawn from the study.  We 
will replace all who withdraw or were withdrawn from the study for the above reasons.
8.   Outcome measures
8.1 Primary Outcome
The primary outcome measure for this study is the change in cognitive function as 
measured by Trail Making Test Part B (TMT-B). This is measured as the difference in 
the time taken to complete the test between pre and post-exercise intervention and 
compared to the control group. Standardized t-scores will be used to interpret the results 
of this test.
8.2  Secondary Outcomes
Secondary outcome measures included here are those which have been shown previously 
or that we hypothesize to improve as results of exercise.  Analysis will include comparisons 
of both exercise groups both combined and separately to the control group, and pre- to 
post-intervention changes within and across exercise groups in the following:

Changes in other measures of cognitive function as measured by the 

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neuropsychological assessments 

Changes in motor assessments including balance and reaction time to 
perturbations

Changes in cardiorespiratory fitness as measured by peak VO2 achieved and time 
on the treadmill

Change in fatigue severity as measured in the FSS; other quality of life, physical 
activity, and sleep quality scales will be used to enhance interpretation of the FSS 
findings

Changes in MRI findings, both structural and functional measures; e.g., increases 
in hippocampal brain volume, or increases in the degree of functional connectivity 
or fractional anisotropy between brain regions that sub serve motor, cognitive and 
behavioral functioning.  

Changes in biomarkers
We are also interested in examining relationships among various outcomes (functional, 
behavioral, structural, mechanistic, etc.) in persons with TBI. Therefore, secondary 
analyses may include correlations or comparisons of baseline measures within and across 
the groups. Comparisons of outcome measures including blood biomarkers, brain imaging, 
neuropsychological and questionnaire data will also be made to a reference healthy 
volunteer sample that is matched for sex and age within 5 years. 
Table 4. Summary of the Relevant Outcome Variables for the Secondary Outcome 
Measures
Motor Assessment
Test/Construct Measured
Relevant outcome variable
Gait Speed
Free and fast walking velocity
Dual Task Performance
Cognitive and motor cost (difference 
between DT and ST performance)
LOS/Dynamic Balance
Reaction time, maximal excursion
Elliptical Speed (reciprocal 
coordination)
Free and fast cadence on the elliptical
SOT/3 sensory systems
Equilibrium score for each sensory system
MCT/involuntary reaction time
Mean latency of responses
Adaptation/stability when 
perturbed
Sway velocity in 2 conditions
Neuropsychological Assessment
Test scores (and standardized scores) as indicated by the instrument 

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Questionnaires
Composite and domain scores as indicated by the instrument. 
Physical Performance
Test/Construct Measured
Relevant outcome variable
CPET
Peak WR, peak HR, time to volitional 
exhaustion
Pulmonary gas exchange
VO2 at peak exercise and AT
Imaging
Test/Construct Measured
Relevant outcome variable
Diagnostic MRI Scan
Volume of brain structures 
DTI
Tracking of white matter tracts and brain 
connectivity
BOLD
Regional differences in cerebral blood flow at 
rest and during hypercapnic challenge 
indicating cerebral vascular reactivity 
fMRI with PASAT
Comparison of active brain regions during a 
cognitive task
9.   Statistical Analysis
9.1 Analysis of data
The primary analysis is a mixed model (with time as the within-subject factor and 
exercise group as the between subject factor) analysis of variance (ANOVA) which will 
be used to determine significant differences in the primary (ANOVA) and secondary 
outcome variables (MANOVA by outcome category – i.e. motor, cognitive, behavioral, 
etc – to help control for multiple comparisons) as a result of exercise. Therefore, the data 
will include the time points immediately pre and post exercise for all subjects. We are 
interested in both main effects for time and exercise as well as potential interaction 
effects between exercise group and time.
All subjects completing the protocol and not withdrawing or presenting off study criteria 
will be included in the analyses. Secondary analyses related to protocol adherence and 
other aspects of feasibility are anticipated. Estimation of the necessary and sufficient 
sample size was calculated for a large effect change in the main outcome variable, pre- to 
post-training change in executive functioning.  Significance will be set at p < 0.05.

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While we do not anticipate that subjects will improve over time in the absence of 
exercise, we have included a waitlist control to evaluate this, and we will compare the 
amount of change over time in the control group versus the exercise group that were not 
waitlisted using an independent t-test.  Also for the exercise group that was not waitlisted, 
there will be a three month follow up period evaluated to determine whether there is any 
change compared to the end of the exercise period using paired t-tests.  
The change in aerobic capacity and fast elliptical speed will be correlated with changes in 
the other outcomes measures. Baseline dopamine transmission scores will also be 
correlated with all motor outcomes using linear regression.
9.2 Power analysis
Based on findings in the pilot study (11-CC-0088) [32], calculations indicate that 20 
subjects would be needed to detect a significant difference in the main outcome variable 
of executive functioning with Trail Making Test B for an α = 0.05 and β=0.05.  
Therefore, 20 subjects in each of the conditions are expected (total 60 subjects).  Attrition 
is approximately one-third for an exercise training protocol, so we predict recruitment of 
80 subjects with non-penetrating TBI to have at least 20 subjects complete the protocol in 
each condition. Recruitment will remain open until at least 20 subjects in each condition 
have completed the second assessment visit.
10. Human Subjects Protection
10.1 Subject selection
Subject demographics will be dependent upon the clinical population affected with TBI. 
Since the majority of TBI occur in men, it is likely that there will be a higher percentage 
of males in our cohort. However, no preference or exclusion will be granted according to 
gender or ethnic/racial background, and efforts will be made to recruit under-represented 
minorities and women.
10.2 Justification for exclusion of children
Individuals younger than 18 years of age will not be included in the protocol because 
reference ranges for normative aerobic capacity and aerobic fitness have not been 
established for these age ranges. The objectives of this project do not include establishing 
these normative reference ranges. This lack of information could introduce critical levels 
of bias into the interpretation and cause the interpretation of our results to be misleading. 
Thus the exercise responses and adaptations in children and adolescents with TBI should 
be studied in separate and specific protocols.
10.3 Justification for exclusion of other vulnerable population
10.3.1 Justification for exclusion of older adults
Individuals 80 years and older will not be included in the protocol as reference ranges for 
exercise, motor and balance tests for these individuals are not available or well 
established.

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10.3.2 Justification for exclusion of pregnant women
While women will be included in this study, pregnant women will be excluded.  This is 
because of the unknown risk of MRI to an unborn fetus, and the effects of pregnancy on 
aerobic capacity and the risk that may be associated with beginning a new exercise 
program while pregnant. Subjects will not be able to participate if the pregnancy test is 
positive.  Subjects that become pregnant during study participation will be 
administratively withdrawn from the study.
10.3.3 Justification for exclusion of mentally ill and those unable to consent 
themselves
Mentally ill subjects and individuals who cannot give consent themselves will not be 
included in this study as the research procedures require subjects to follow specific 
instructions (e.g. hypercapnia challenge in the MRI, neurocognitive measures, exercise 
and balance testing) and in some cases, provide reliable feedback related to their safety 
(e.g., indicating when they have approached their limit of tolerance during an exercise 
test).
10.3.4 Justification for exclusion of non-English speaking subjects
Non-English speakers will be excluded because the neuropsychological assessment 
instruments we are using are not validated or normed in other languages.  Furthermore, 
many of the tests we are performing would require a native speaking psychometrist to 
administer theses test, who is not available.
10.4 Safeguards for vulnerable populations
Prior to any MRI scans, urine pregnancy tests will be performed on women of child 
bearing potential. Monthly pregnancy tests will also be performed in those undergoing 
the exercise intervention.
10.5 Qualifications of investigators
The Principal Investigator has verified that all individuals working on this protocol 
required to take HRPP training under OHSRP Policy 201 (Education Program) have 
completed all required training.
11. Anticipated Benefit
11.1 Direct benefits
TBI subjects in this protocol have the potential to receive direct benefit from participating 
in this research.  TBI subjects may directly benefit from aerobic exercise training, where 
improvements in cardiorespiratory fitness enables individuals to accomplish a given 
amount of activity or work at a lower percentage of maximum capacity and with less 
fatigue. TBI subjects may also directly benefit from rapid-resistive exercise, with 
increased strength, flexibility, movement speed and balance. Exercise participation has 
been shown to be beneficial in the reduction of all-cause mortality and morbidity in some 
subsets of the population and is recommended for all who are physically able to 

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participate. Healthy volunteers are not expected to receive any direct benefits from 
participation in this study.
12. Classification of risk
This protocol is classified as a greater than minimal risk study.  The risks are reasonable 
in relation to anticipated benefits.
13. Consent documents and process
13.1 Designation of those obtaining consent
Study investigators designated as able to obtain consent, will obtain informed consent. 
All study investigators obtaining informed consent have completed the NIMH HSPU 
“Elements of Successful Informed Consent” training.
13.2 Consent procedures
All participants will receive a verbal explanation in terms suited to their comprehension 
of the purposes, procedures and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to review the written consent form 
carefully and ask questions regarding this study prior to signing. 
13.3 Consent documents
There is one consent form for the individuals with TBI that contain all the required 
elements for participating in this study. There is a separate consent form for healthy 
individuals.
14. Data and Safety monitoring
14.1 Data and safety monitor
Data and safety will be monitored by the Principal Investigator, Dr. Damiano at least 
once a year. In addition, a data and safety monitor, Dr. Leddy, will review all adverse 
events at least every 6 months (see section on Data and Safety Monitoring Plan).
14.2 Data and safety monitoring plan
Data and safety monitoring for this protocol is an ongoing process. The PI will meet 
weekly with the study team to discuss the protocol progress and any relevant activities or 
occurrences. However, research staff have been instructed to report any issues related to 
protocol safety and data as soon as possible after occurrence or when they first became 
aware of it to the PI. The PI is then responsible for evaluating these, proposing and 
implementing corrective action as needed, and reporting these to the IRB in a timely 
manner.
As the principle investigator, Dr. Damiano will be contacted after every serious adverse 
event that is related to the protocol and notified of all deaths. These will also be reported 
to the NIH and USUHS IRB’s with the continuing review.

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Dr. John Leddy is a physician with cardiology experience and specific expertise in 
rehabilitation and management of persons with concussion/brain injury. He has been 
enlisted to conduct an independent data and safety monitoring review no less than every 6 
months for this study. Dr. Leddy is board certified in Internal Medicine with a 
subspecialty in Sports Medicine, and is a Professor of Clinical Orthopaedics and 
Rehabilitation Sciences at the State University of New York at Buffalo. He is also the 
Medical Director of the Concussion Management Clinic in the Jacobs School of 
Medicine and Biomedical Sciences, and Division I Team Physician at the University at 
Buffalo. He will be apprised of all adverse events and will have access to study related 
data to make his assessment and review as deemed necessary.
14.3 Criteria for stopping the study or suspending enrollment or 
procedures
The PI, data and safety monitor (Dr. Leddy), and IRBs will assess the measures taken by 
the study team in response to safety issues that caused the study to be stopped or suspended. 
Revised safety measures taken by the study team will be in a written report submitted to 
the IRBs of record. Only when these entities agree in writing that the problems have been 
satisfactorily addressed can the protocol may be re-activated. 
Annually there will be a continuing review of this study at the NIH and USUHS IRBs.
15. Quality Assurance
15.1 Quality Assurance monitor
This study will be monitored for quality assurance through the NIH Clinical Center’s 
Quality Assurance Program. 
15.2 Quality Assurance Plan
Accrual and safety data will be monitored by the principal investigator, who will provide 
oversight to the conduct of this study. The PI will continuously evaluate implementation 
of the protocol for any unusual or unpredicted complications that occur and will review the 
data for accuracy and completeness.
The NIH Clinical Center’s Quality Assurance Program will conduct study monitoring at 
least annually. Monitoring visits will include a review of patient consent documents, 
primary outcome and safety laboratory results and diagnostic test results will be monitored 
for accuracy, correct dating, and agreement between case report forms and source 
documents. All regulatory reports, reviews and amendments, adverse events and problem 
reports related to study, along with investigator credentials, training records, and the 
delegation of responsibility log will also be reviewed during monitoring visits. Any major 
findings will be summarized in writing and reported to the study PI who will be responsible 
for submitting the monitoring report to the IRB.
All study staff will maintain current training in good clinical practice and protection of 
human subjects, and will complete other protocol- and role-specific training, as needed.

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16. NIH Reporting Requirements
16.1 Adverse Event Definitions 
Please refer to definitions provided in Policy 801: Reporting Research Events.
16.2 Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events. 
The data and safety monitor (Dr. Leddy) will also be notified of all adverse events at least 
every 6 months.
It is anticipated that participants in this study may fail to complete the entire list of 
assessments or procedures, such as questionnaires or neuropsychological tests. Omissions 
such as these will be considered expected events and not protocol deviations provided 
they are infrequent, not the primary outcome, not related to determination of the exercise 
training range and do not include data needed to assess safety for a procedure.  
Cumulative proportions of these missed events in the study population will be presented 
to the IRB at the time of Continuing Review. In addition, the rate of omissions will be 
monitored by the Investigators. If an individual misses more than 15% of the required 
assessments/procedures or if more than 15% of the participants miss completion of the 
same assessment or procedure, it will be considered a deviation and reported according to 
Policy 801.
16.3 IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events.
16.4 Clinical Director Reporting
Problems expeditiously reported to the IRB in iRIS will also be reported to the Clinical 
Director. A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
17. Alternatives to participation
Subjects do not receive any treatment in this study or forego any treatment in order to 
participate in this study.  The alternative, therefore, is not to participate.
18. Privacy
All research activities will be conducted in as private a setting as possible.

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19. Confidentiality
Confidentiality of patient files will be maintained at all times.  Samples and data will be 
de-identified, using codes that we assign.  Data will be kept in password-protected 
computers.  Samples will be kept in locked freezers in locked rooms.  Paper records and 
case report forms will be maintained in locked rooms, or in computer files protected by 
computer passwords. Only study investigators will have access to the samples and data. 
In the presentation of research results, no information will be given that may reveal the 
identity of the research subjects.  The consent form will discuss patient confidentiality 
protection.
De-identified results from clinical trials will be posted on clinicaltrials.gov
Confidentiality of the patient records will be protected to the extent possible under existing 
regulations and laws but cannot be guaranteed.  Complete confidentiality cannot be 
promised, especially to military personnel, because information bearing on their health may 
be required to be reported to appropriate medical or command authorities. Members of 
CNRM, Uniformed Services University, Henry M Jackson Foundation, US Department of 
Defense (DoD), and NIH, may have access to the study data for auditing purposes.
Each study participant will be assigned a study number that will be used on study data 
collection forms and samples. The link between the study number and participants’ identity 
will be kept on a password-protected computer.  Only study researchers and members of 
the IRB will have access to identified information. Data transmitted to the Data 
Coordinating Center will be coded. Investigators at the clinical site where consent was 
obtained will have access to identifying information for the patients enrolled in the study 
at their site.  Only coded de-identified information will be shared with persons outside of 
the enrolling site, except for audits. 
NIH will assign a Global Unique Identifier (GUID) to all data submitted to the CNRM 
Repository. The purpose of the GUID is to allow data on the same subject, from multiple 
protocols and from different institutions, to be identified as coming from a single individual 
and to be combined in the repository. PII will be entered on a local server and a one-way 
encryption using a keyed-hash algorithm will be used to assign the GUID.  CNRM will not 
receive PII.  The one-way encryption assures that the GUID cannot be used to back-
generate PII. Data that were delinked may then be sent to other non-CNRM 
Biorepositories.
Blood will be processed and frozen according to CNRM Biospecimen Repository 
guidelines for confidentiality. Samples will be assigned a unique identifier at time of blood 
draw. The key for the re-identification of samples will be maintained on a master list in the 
PI’s office and accessible only to his designees. Some information will be on a password-
secured server in one of the Investigator’s offices on the NIH campus. 

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20. Conflict of Interest
NIH guidelines on conflict of interest have been distributed to all investigators.  There 
are no conflicts-of-interest to report for NIH investigators.  Non-NIH investigators will 
abide by the conflict-of-interest policies of their own institutions.
21. Technology Transfer
A materials transfer agreement will be in place before any samples leave the NIH and are 
placed in the CNRM Biospecimen Repository. A collaborative agreement for the transfer 
of human de-identified data between NIH and investigators at DCVAMC will be in place 
before any data are shared. Investigators at DCVAMC shall not make any effort to re-
identify individuals who are the source of the shared de-identified data. A spreadsheet 
containing details and status of the technology transfer agreements for this study is 
included as Appendix 12.
22. Research and Travel Compensation
Assessment Visits (1, 2 and 3)
Participants will be compensated for time and research-related inconveniences as follows:
$20 for first hour (or part)
$10 for each additional hour thereafter for assessments performed in RMD for up to 5 
hours
$20 for blood draws
In addition, compensation for the MRI:
$80 (includes $60 for the procedures and $10 for up to 2 hours of time)
Exercise Intervention
Participants will be compensated for completing the exercise training intervention (either 
AET or RET):
$150 for completion of the 12-week exercise training (assuming 80% attendance)
If participants are unable to finish the study, they will be paid for parts completed.  
Payment will be processed after completion of the assessment visits.  The maximum 
compensation for participants with TBI is $660.00 for all 3 assessment visits and training 
intervention. The maximum compensation for healthy volunteers is $170.
Travel will not be provided.

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24. Appendices

Appendix 1A – Recruitment Material and Flyer for TBI

Appendix 1B – Recruitment Material and Flyer for Healthy Volunteers

Appendix 2A – Pre-screen questionnaire for TBI

Appendix 2B – Pre-screen questionnaire for Healthy Volunteers

Appendix 3A – Eligibility Checklist for TBI

Appendix 3B – Eligibility Checklist for Healthy Volunteers

Appendix 4 – MRI Safety Questionnaire

Appendix 5 – Participant Flowchart

Appendix 6 – Balance Description

Appendix 7 – TBI Neuropsychological Assessment List

Appendix 8 – TBI Questionnaire

Appendix 9 – Exercise Data Collection Form

Appendix 10 – Monthly Phone Call Form

Appendix 11 – Exercise Safety Stopping Points 

Appendix 12 – Data Sharing spreadsheet

Appendix 13 - DCVAMC Recruitment Letter

Appendix 14 – Infographic of the Warning Signs of a Heart Attack