A Multi-modal Evaluation of a Physical Intervention Approach to Treating Post-Concussive Symptoms
Phase: NA
Conditions: Persistent Post-Concussive Syndrome
Sponsor: Lakehead University

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Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
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CLINICAL RESEARCH STUDY PROTOCOL 
 
Study Title: 
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent Post-
Concussive Symptoms 
TBRHSC Research Program Tracking Number: 
RP-506-07112017 
Version number: 
1.5 
 
Version date: 
November 30th, 2018 
 
Research Site(s):  
Lakehead University 
Funding Mechanism: 
Funding for this study was obtained from the Northern Ontario Academic Medical Association 
through their Clinical Innovation Opportunities Fund. Other sources of support include in-kind 
contributions of time as described in the study budget from the Principal and Co-Investigators 
(see Appendix 16.6) 
  
Principal Investigator:  
  
First and last name 
Contact information 
Affiliations 
Details 
Dr. Sheryl Wark 
swark@nosm.ca 
NOSM 
Assistant Professor 
 
 
 

 
2
Names, Affiliations, and Roles of Co-Investigators/Collaborators:  
First and last name 
Contact information 
Affiliations 
Details 
Dr. Simon Lees 
simon.lees@nosm.ca 
(807)-766-7435 
NOSM 
Associate Professor 
Dr. Paolo Sanzo 
psanzo@lakeheadu.ca 
(807)-343-8647 
Lakehead University 
Associate Professor 
NOSM 
Dr. Carlos Zerpa 
czerpa@lakeheadu.ca 
(807)-343-8940 
Lakehead University 
Assistant Professor 
Dr. Jane Lawrence-
Dewar 
dewarja@tbh.net 
 (807)-684-7289 
Lakehead University 
Adjunct Professor 
Dr. Michael Wesner 
mwesner@lakeheadu.ca 
(807)-343-8457 
Lakehead University 
Associate Professor  
 
CONFIDENTIALITY STATEMENT 
The information contained in this document has been provided to you in confidence, as an 
investigator, potential investigator, trainee, staff or consultant, for review by you, your staff or an 
applicable Research Ethics Board. It is understood that this information will not be disclosed to 
others without written authorization from the Principal Investigator, except to the extent 
necessary to obtain informed consent from those participants for whom the study may be 
implemented.   
 
 

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V 1.5: November 30th, 2018                                                                                                                      
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
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ABBREVIATIONS/DEFINITIONS  
  
Lakehead University – LU 
Northern Ontario School of Medicine – NOSM 
Persistent Post-Concussive Symptoms – PCS 
Healthy control – HC 
Standard of care – SC 
Aerobic and balance retraining program – AET 
International Physical Activity Questionnaire – IPAQ 
Balance Error Scoring System – BESS 
Heart rate variability – HRV 
 
 
 
 

 
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1. BACKGROUND / RATIONALE .............................................................................................. 7 
RATIONALE, SIGNIFICANCE, AND JUSTIFICATION ....................................................... 9 
ASSESSMENT OF OUTCOME/HYPOTHESIS....................................................................... 9 
3. EXPECTED RISKS/ BENEFITS ............................................................................................. 10 
3.1 Expected Risks .................................................................................................................... 10 
4. ELIGIBILITY ........................................................................................................................... 11 
4.1 Study Setting Description ................................................................................................... 11 
4.2 Study Sample Description................................................................................................... 11 
4.3 Justification when a sample includes vulnerable populations or excludes certain 
populations ................................................................................................................................ 11 
4.4 Participant Inclusion Criteria .............................................................................................. 11 
4.5 Participant Exclusion Criteria ............................................................................................. 12 
4.6 Participant Withdrawal Criteria .......................................................................................... 12 
5. STUDY DESIGN...................................................................................................................... 12 
5.1 Study Design ....................................................................................................................... 12 
5.2 Number of Participants/Assignment to Treatment Groups ................................................. 13 
5.3 Duration of Study and Study Timeline ............................................................................... 13 
5.4 
Length of Participation ................................................................................................... 13 
6.1 Participant Identification and Recruitment Procedures ...................................................... 13 
6.2 Procedures for Informed Consent ....................................................................................... 14 
6.3 Procedures for Participant Screening .................................................................................. 14 
6.4 Procedures for Participant Enrolment /Allocation /Randomization ................................... 14 
6.5 Procedures for Participant Retention .................................................................................. 15 
7. STUDY PROCEDURES .......................................................................................................... 15 
7.1 Time and Events Schedule .................................................................................................. 15 
7.2 Description of Study Procedures, Assessments and Participant Activities ........................ 15 
Physical and Cognitive Assessment: ........................................................................................ 15 
Biomarker Assessment: ............................................................................................................ 16 
Neuroimaging: .......................................................................................................................... 17 
ODDBALL paradigm: .......................................................................................................... 17 
FLANKER task:.................................................................................................................... 18 
Behaviour Measure (Driving Simulator): ................................................................................. 18 
Aerobic and Balance Retraining Program: ............................................................................... 19 

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8. DATA MANAGEMENT.......................................................................................................... 20 
8.1 Data Collection ................................................................................................................... 20 
8.2 Data Management ............................................................................................................... 21 
9. SPECIMEN MANAGEMENT ................................................................................................. 22 
10. DATA / SPECIMEN ANALYSIS .......................................................................................... 22 
11. STATISTICAL CONSIDERATIONS ................................................................................... 23 
11.1 Sample Size Calculation ................................................................................................... 23 
11.2 Statistical Analysis ............................................................................................................ 23 
12. OTHER STUDY ADMINISTRATION CONSIDERATIONS.............................................. 24 
12.1 Concomitant use of medications or interventions during the course of the study ............ 24 
12.2 Allocation sequence generation and concealment mechanism ......................................... 24 
12.3 Blinding Procedures .......................................................................................................... 24 
12.4 Premature discontinuation or termination of the study ..................................................... 24 
12.5 Ancillary and post-trial care.............................................................................................. 24 
13. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 24 
13.1 Data Integrity Measures .................................................................................................... 25 
13.2 Training Study Staff .......................................................................................................... 25 
13.3 Auditing and Monitoring .................................................................................................. 25 
14. REGULATORY CONSIDERATIONS .................................................................................. 25 
14.1 Participant privacy and confidentiality ............................................................................. 25 
14.2 Ethical Review .................................................................................................................. 26 
14.3 Scientific Review .............................................................................................................. 26 
14.4 Institutional Review .......................................................................................................... 26 
14.5 Clinical Trial Registration................................................................................................. 26 
14.6 Retention of Study Documents ......................................................................................... 26 
14.7 Data Monitoring Committee ............................................................................................. 26 
14.8 Unanticipated Problems .................................................................................................... 26 
14.9 Publication of Data and Protection of Trade Secrets ........................................................ 27 
14.10 Dissemination ................................................................................................................. 27 
14.11 Declaration of interests ................................................................................................... 27 
15. References ............................................................................................................................... 28 

 
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16. APPENDICES ........................................................................................................................ 31 
16.1 Recruitment materials ....................................................................................................... 31 
16.2 Informed consent materials ............................................................................................... 34 
16.3 Screening checklists .......................................................................................................... 48 
16.4 Data abstraction form ........................................................................................................ 50 
16.5 International Physical Activity Questionnaire .................................................................. 51 
16.6 Study budget ..................................................................................................................... 54 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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1. BACKGROUND / RATIONALE  
Each year, 120,000 people sustain a traumatic brain injury (TBI) in Canada1, with an 
estimate of 80-90% of TBIs being categorized as mild2,3. Mild TBIs, also known as concussions, 
have been referred to as the silent epidemic in North America, as the incidence is much higher 
and effects more persistent than once thought. Concussions can result in a variety of long-term 
cognitive, psychological, and physical symptoms. Self-reported memory and attention 
complaints are the most common cognitive effects and may persist for several years post-injury4–
6. It has also been reported that in 75% of all sports-related concussions, athletes experience 
reduced balance and symptoms of dizziness7. These residual symptoms may also negatively 
impact the ability to engage in regular activities of daily living such as work, sports, and driving. 
Driving safe is a complex task and requires perception of speed and distance, along with good 
coordination for steering and braking8. 
After concussion, participants are slower to respond to traffic hazards8 and this has been 
related to increased crash frequency9. The goal of the proposed study is to examine the effect of 
an aerobic and balance retraining program (AET) on common persistent symptoms of concussion 
using measures of cognition and brain function, mental and physical health, and driving 
performance.  
To date, the majority of randomized controlled trials (RCTs) have used rest and 
psychological approaches to alleviate persistent concussion symptoms and have focused on 
providing individuals with recovery-related information, reassurance, or education. Most of these 
studies have found no benefit or reported inconclusive findings10. Of the research that has 
focused on treatment, AET11 has shown to be promising for overall symptom reduction. The 
conclusions of these studies, however, are limited by the lack of control groups, biased samples, 
and the inclusion of TBIs of all severities. In addition, many of the interventions were delivered 
prior to the period when symptoms are typically considered persistent. Controlled studies are 
needed to test the specific effects of treatment on the persistent symptoms in a post-concussion 
syndrome sample lasting greater than one month post-concussion. The intervention we plan to 
test is AET in a controlled/stepwise exercise training program using RCT methodology. Recent 
evidence indicates that an active rehabilitation program may be useful for individuals with 
persistent concussion symptoms12 and that exercise can also be effective at improving mood13.  
Studies have also shown that levels of brain-derived neurotrophic factor (BDNF) are 
significantly increased as a result of aerobic exercise in healthy individuals. In particular, 
preliminary data from our group14 demonstrated an increase in salivary BDNF levels in a healthy 
control group following 4 weeks of AET (the same protocol we are proposing). BDNF is a 
secreted protein that has been shown to play a central role for neural health and brain 
plasticity15,16. BDNF has been demonstrated to be a useful biomarker of brain injury post-
concussion17 with animal research showing significantly reduced levels of BDNF several hours 
or days after a concussion18. Notably, aerobic fitness and BDNF share a relationship that is 
predictive of memory performance in healthy individuals19–21. Also, it is known that executive 
function and circulating BDNF both decline with age, however, changes in serum BDNF 

 
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predicts improvements in cognitive outcomes in response to aerobic exercise in older 
individuals22.  
This provides strong evidence to further examine this intervention in people who are 
experiencing residual cognitive and/or physical complaints after concussion, but are otherwise 
healthy. One of the reasons for the lack of response to treatment in previous studies may be, in 
part, due to the heavy reliance on subjective self-report measures. Therefore, in addition to 
obtaining self-report measures of persistent complaints, we plan to obtain objective measures of 
functioning using sophisticated technology, including event-related potentials (ERP) during 
computerized cognitive tasks, biomarkers (BDNF), force plate measures of balance, and driving 
simulation measures of participant reaction times under dual tasking situations.  
While self-reported cognitive complaints can persist after concussion, they are rarely 
detected using traditional neuropsychological tests23,24. Using more complex attention and 
memory tasks, however, slower and less accurate performance can be detected up to several 
years’ post-injury25–27. Non-invasive imaging techniques, such as event-related potentials (ERP) 
can also provide further insight into inefficient neural processing after concussion. ERP is a 
method of surface electroencephalography (EEG) that non-invasively detects the neural signaling 
in relation to an event (stimulus or task). In individuals with concussion, ERP studies have 
previously found deficits in stimulus discrimination28, and inhibitory control29 reflected by 
increased errors and variable response times in behavior as well as reductions in electrical 
potentials. Previous studies have found decreased amplitude and increased latency following 
concussion suggesting a decrease in speed and cognitive resources available for attentional 
processing29–33. 
One of the main goals of recovery from persistent concussive symptoms is the ability to 
return to daily living. While evaluating performance in daily living activities can be difficult 
(e.g., driving), we are able to evaluate performance using devices such as driving simulators. 
Measurements of performance in a simulator (e.g., response time) may become a useful tool as 
part of a comprehensive assessment for physicians as they recommend return to daily activities.  
 
2. OBJECTIVES / STUDY AIMS   
The primary objective of our proposed study is to implement AET to reduce persistent symptoms 
after concussion. Our secondary objective is to investigate the usefulness of BDNF as a 
biomarker of persistent concussive symptoms responsiveness to AET. 
Our 4 specific goals are to help people with persistent concussive symptoms by: 
1. Minimizing the occurrence of persistent cognitive and physical symptoms following 
concussion. 
2. Improving performance and efficiency of neural processing during cognitive tasks. 
3. Correlating BDNF levels with severity of symptoms and correlating change in BDNF levels to 
improvements in physical symptoms and balance.  

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4. Improving functioning in activities of daily living, such as driving  
RATIONALE, SIGNIFICANCE, AND JUSTIFICATION 
The clinical significance, rationale, and justification of this collaborative effort is 
demonstrated by both clinical and research initiatives at treating people with concussion directly 
in our community. With the recruitment assistance by medical professionals, this project has a 
strong foundation and the potential to make a direct impact here in Thunder Bay. The group 
format of the AET is a cost- and time-effective method by which to treat a subgroup of the 
concussion population who experience long-lasting symptoms. This subgroup is growing as 
diagnostic protocols are becoming more standardized and the potential persistent effects are 
becoming general knowledge, especially due to increased media coverage around sport or 
military related injuries related to concussion. If successful, the AET protocol and salivary 
BDNF biomarker test may help in the assessment and treatment of persistent concussion 
symptoms that currently are often treated with rest and education. The findings from the 
proposed study will help clinicians to also monitor progress to aid in return to play, school, or 
work decisions, resulting in significant savings to the healthcare system and employer as a result 
of lost work time. Also, by improving physical health, AET may improve the quality of life. 
  
ASSESSMENT OF OUTCOME/HYPOTHESIS   
1. It is anticipated that the concussed participants receiving the AET will exhibit less mental, 
cognitive, and physical symptoms related to post-concussion syndrome. These signs and 
symptoms will be measured via the SCAT-3 and the RPSQ scores. 
2. It is anticipated that AET will result in increased efficiency of neural processing during 
cognitive tasks in post measures compared to SC and with less difference than compared to HC 
compared to pre- intervention comparisons. Cognitive efficiency will be measured by the 
amplitude and latency of two event related electrical potentials associated with attention and 
conflict monitoring processing. 
3. It is anticipated that concussed participants receiving the AET will exhibit improved balance. 
This will be measured using the force platform centre of pressure area, displacement, and 
velocity measures while completing the various static stance positions using the BESS protocol. 
4. It is anticipated that concussed participants receiving the AET will exhibit increased 
improvements in salivary BDNF levels, indicative of an improvement in concussion symptoms. 
Salivary BDNF will be quantified using the BDNF ELISA assay and changes in pre- vs. post-
intervention concentrations will be assessed. Additionally, we hypothesize that lower levels of 
BDNF upon entry to the study will indicate more pronounced concussive symptoms. This 
relationship will be determined by correlating the pre-intervention BNDF concentration to 
measures of the post intervention assessments. 

 
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5. It is anticipated that concussed participants receiving the AET will exhibit improved reaction 
times compared to the SC group during dual tasking scenarios to avoid crashing in dangerous 
traffic situations. 
3. EXPECTED RISKS/ BENEFITS  
  
3.1 Expected Risks  
Low intensity aerobic and balance exercise poses minimal risk for healthy individuals. 
Like all types of exercise, there is a slight risk of sustaining a musculoskeletal injury such as a 
sprain or strain. There is a small risk, however, when performing aerobic and balance exercises 
while experiencing PCS; participants may see an increase or worsening of his/her symptoms. In 
order to minimize this risk, exercise will begin at a very low intensity and gradually increase. All 
exercise sessions will be monitored by a research team member to ensure that the session is 
being completed at the proper intensity. Should a participant report any PCS during a session, the 
session will be stopped immediately. Furthermore, to ensure that participants are healthy enough 
to participate in exercise, all participants will be medically cleared by Dr. Wark prior to 
participating in the study. 
There is a minor risk that, when using the driving simulator, participants may experience 
symptoms such as nausea or dizziness. Breaks will be allowed during the assessment in an effort 
to prevent this. Water will also be readily available during the assessment should the participant 
require it. If a participant experiences any of these symptoms and is unable to continue, the 
session will end. 
Physical and cognitive assessment, neuroimaging, and biomarker assessment should pose 
minimal risk to participants. 
There is a minor social risk with respect to confidentiality. This risk will be minimized by ‘de-
identifying’ the personal information with codes. All names will be removed from data/samples. 
All data will be stored in an encrypted file on the secure Sync.com account on a password-
protected computer in a locked office at LU. Any hard copies of data such as screening 
checklists or the IPAQ will be coded and stored in a locked filing cabinet in a secure office at LU 
(Dr. Zerpa’s current office, SB 1007). All saliva samples will be coded and stored in Dr. Lee’s 
secure lab. 
The results of this study will be published with aggregate data, that is, data which is combined 
and summarized so that no individual participant can be identified.  
 
3.2 Expected Benefits  
This study may directly benefit participants in the AET and SC group by potentially improving 
his/her PCS. This study also has benefits to the scientific community and society, in that there is 
scarcity of research on the effects of an AET program in individuals with PCS.  

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4. ELIGIBILITY  
 
4.1 Study Setting Description  
This study will be taking place at multiple sites at Lakehead University and around Thunder Bay. 
Participants will be recruited through the use of recruitment flyers (attached, Section 16.1) 
posted at various locations as well as on social media (Lakehead University School of 
Kinesiology Twitter and Facebook). Recruitment flyers will also be posted at Fairway 
Physiotherapy, as well as other local doctor’s offices.  
Participants will complete informed consent, screening checklist, questionnaires, ImPACT, and 
physical measures at the School of Kinesiology, Lakehead University.  
Saliva will be collected at the School of Kinesiology, Lakehead University 
Oddball and Flaker tasks will be completed at Dr. Michael Wesner’s Vision Laboratory, 
Lakehead University 
The driving simulation will be completed at the Centre for Research on Safe Driving, Lakehead 
University 
 
4.2 Study Sample Description  
For the experimental group, the population being evaluate is anyone age 18-50 years, at least two 
weeks post injury, experiencing at least one PCS symptom that is mild in severity, as well as the 
remaining inclusion criteria (see attached screening checklist, Section 16.3). For the heathy 
control group, the population being evaluated is anyone age 18-50 years, as well as the 
remaining inclusion criteria (see attached screening checklist, Section 16.3) 
  
4.3 Justification when a sample includes vulnerable populations or excludes certain 
populations  
Please refer to the exclusion criteria below. Persons who have been previously diagnosed with a 
psychological/neurological disorder, substance abuse disorder/impairment, or are currently 
seeking therapy/counselling will be excluded from the study. Participants will also be excluded if 
he/she verbally states that he/she does not have a valid driver’s license and 12 months of driving 
experience. 
4.4 Participant Inclusion Criteria  
A participant is eligible for inclusion in the study if the individual meets all of the following 
criteria:  
1. Man or woman aged 18-50 years.  

 
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2. Reports at least one PCS symptom that is mild in severity.  
3. It has been between two weeks and six months since date of injury. 
4. Is able to provide consent in English 
 
4.5 Participant Exclusion Criteria  
A participant is ineligible for the study if the individual meets any of the following criteria  
1. Has been previously diagnosed with a psychological/neurological disorder 
2. Has been previously diagnosed with a substance abuse disorder/impairment,  
3. Is currently seeking therapy/counselling for depression, 
4. Does not have valid driver’s license and 12 months of driving experience. 
  
4.6 Participant Withdrawal Criteria  
Withdrawal will occur upon participant request. A participant who wishes to withdraw consent 
from the study will be asked to specify if he/she wish for any data or samples collected to be 
withdrawn from the study. Samples and data will be withdrawn in accordance with the 
participant’s wishes.     
 
5. STUDY DESIGN  
 
5.1 Study Design  
This study is designed as a randomized controlled trial. Potential PCS participants will be 
referred to another member of the research team by Dr. Wark. Potential participants will then 
complete the informed consent process and pre screening checklist. Potential healthy participants 
will contact the research team directly and set up a time to complete the informed consent, pre 
screening process, and IPAQ. After being deemed eligible based on the screening criteria 
(screening checklist attached, section), PCS participants will be randomly assigned to either an 
AET or standard of care (SC) intervention (see section 7). Using minimization software, each 
intervention group will be balanced by age and sex. Healthy participants will serve as the control 
group (HC) and will receive no treatment. Once participants in the SC group have completed the 
study, the AET will be offered, although it will not be included in the data analysis. Following 
informed consent, PCS participants will be provided with Garmin VivoSmart HR unit to monitor 
aerobic activity outside of the study (accelerometer, heart rate monitor, and step counter 
capabilities). Participants will be required to wear the Garmin units as often as possible for the 
duration of the study. In place of the Garmin VivoSmart HR unit, participants in the HC group 
will complete the IPAQ to determine physical activity levels prior to participating in the study,. 
All participants will compete a series of pre and post intervention assessments (see section 7.2) 
over the course of one week at Lakehead University. Following the pre intervention assessments, 

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participants in the AET group will complete an eight week aerobic and balance retraining 
program at the School of Kinesiology, Lakehead University (see section 7.2). Participants in the 
SC group will continue with his/her standard of care for eight weeks. Healthy participants will be 
instructed not to significantly change his/her lifestyle (diet, physical activity) for the duration of 
the study weeks. After eight weeks, all participants will complete the assessments once again. 
 5.2 Number of Participants/Assignment to Treatment Groups   
It is anticipated that 60 participants will be recruited into this study. Participant enrollment will 
be split between the AET, SC, and HC group. There will be 20 participants in each group.   
5.3 Duration of Study and Study Timeline   
The study is expected to last one year in total following the coordination of the research team 
and ethics approvals. Note: These dates are subject to change based on the date we begin 
participant recruitment. The relative timeline will remain the same.  
  
Timeline 
Milestone Targets 
Sept 2017 - Dec 2017 
Obtain ethics approval 
Coordinate research team 
March- Dec 2019 
Project start date (March 2018) 
Recruitment, intervention, data collection 
Oct 2019- Dec 2019 
Data analysis 
Feb 2020 
Manuscript completion 
Conference presentations 
 
5.4 Length of Participation  
Participation in this study will last 10 weeks, depending on scheduling of the pre and post 
intervention assessments. Pre intervention assessments will be conducted at Lakehead University 
before beginning intervention. The AET intervention will occur three times per week for eight 
weeks. Each session will last approximately one hour. The SC intervention will be ongoing 
throughout the eight weeks. The HC group will not complete an intervention. Final assessments 
will be completed after any intervention has concluded. 
6. PARTICIPANT ENROLLMENT  
 6.1 Participant Identification and Recruitment Procedures  
The recruitment will include the use of flyers (attached, Section 16.1) and social media. 
Recruitment flyers directed at potential participants with PCS will be placed in Dr. Wark’s office 
at Fairway Physiotherapy, as well as other healthcare clinics around Thunder Bay. In order to 
recruit healthy participants, and to reach the general public, the research team will post the 
recruitment poster on the Lakehead University School of Kinesiology Facebook page and 
Twitter page. Posters will also be displayed around Lakehead University and various public 
spaces around Thunder Bay. If a potential PCS participant expressed interest in participating, 

 
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he/she will be referred by his/her healthcare provider, or referred by his/her self to Dr. Wark, 
who will forward his/her information to the research team if appropriate. If a potential healthy 
participant is interested in participating, he/she will contact the research team using the contact 
information on the recruitment posters. An appointment will be set up between he/she and a 
member of the research team at the Lakehead University School of Kinesiology.  
6.2 Procedures for Informed Consent  
If a potential participant contacts, or is referred to the research team, an appointment will be set 
up to complete the informed consent process and pre screening checklist. During this meeting, a 
research team member with TCPS-2 training, other than Dr. Wark, will go through the 
information letter and consent form (attached, Section 16.2) with the potential participant. The 
potential participant will be given at least 24 hours to consider volunteering for the study, as well 
as ask any questions they may have regarding the study. Potential participants are welcome to 
contact another member of the research team or any of the listed Research Ethics Boards to ask 
such questions prior to signing the consent form. If the potential participant wishes to consent to 
the study, they will indicate this by signing the consent form (attached, 16.3) and providing it to 
a research team member. The participant will be given a copy of the consent form to take home. 
The original will be retained by the research team as part of the study file.  
  
6.3 Procedures for Participant Screening  
Once informed consent is obtained, a trained member of the research team will determine the 
potential participant’s eligibility using the screening checklist (attached, Section 16.3). If the 
potential participant meets these criteria, they will be included in the study and given a 
participant code number. If the potential participant does not meet these criteria, their signed 
consent form as well as the screening checklist and will be marked as a screen-fail and kept in a 
“Screen-Fail” binder in a locked filing cabinet in a secure office to be kept for a minimum of five 
years.   
  
6.4 Procedures for Participant Enrolment /Allocation /Randomization  
To achieve adequate enrolment, recruitment flyers will be placed at several locations and clinics 
around Thunder Bay. Once informed consent has been obtained, and the potential participant has 
been deemed eligible through the screening process, age and sex of the participant will be used 
to randomly assign the participant to an intervention group through a process called 
minimization. This process ensures group sizes are equal and eliminates potential bias that may 
be introduced which is important for clinical research of small sizes. The NOSM research 
assistant would then communicate the enrolment and group assignment to Dr. Paolo Sanzo who 
will administer the AET intervention. The SC intervention will continue under the supervision of 
the participant’s healthcare provider. Participants will be assigned a code number by the research 
assistant to ensure confidentiality is maintained during the transfer of data or samples between 
locations.  
  

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6.5 Procedures for Participant Retention  
If potential PCS participants complete the intervention, they will be allowed to keep the Garmin 
VivoSmart HR unit. Participants in the HC group will be eligible for a $15 gift card after 
completion of pre, and post assessments  
 
7. STUDY PROCEDURES  
  
7.1 Time and Events Schedule  
Event/Activity/Pro
cedure 
Medical 
appoint
ment 
Inform
ed 
Conse
nt 
Visit 
Pre-
intervent
ion 
assessm
ent A 
(LU) 
Pre-
intervent
ion 
assessm
ent B 
(LU) 
Pre-
intervent
ion 
assessm
ent C 
(LU) 
Pre-
intervent
ion 
assessm
ent D 
(LU) 
AET (3x 
week)/SC
/HC 
Post-
intervent
ion 
assessm
ent (A, 
B, C, D) 
Referral 
X 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Screening 
 
X 
 
 
 
 
 
 
ImPACT 
 
 
X 
 
 
 
 
X 
BESS 
 
 
X 
 
 
 
 
X 
Saliva 
 
 
 
X 
 
 
 
X 
Oddball and 
Flanker task 
 
 
 
 
X 
 
 
X 
Driving Simulation 
 
 
 
 
 
X 
 
X 
Intervention 
 
 
 
 
 
 
X 
 
 
 
7.2 Description of Study Procedures, Assessments and Participant Activities  
Once participants have been randomized into groups, participants will be scheduled to complete 
the pre intervention assessments at Lakehead University over a period of one week. These 
assessments will include a physical, cognitive, neuroimaging, biomarker, and driving behaviour 
assessmentt. These assessments will also be completed after the intervention in PCS participants, 
and after eight weeks in HC. 
Physical and Cognitive Assessment:  
Participants will complete the Immediate Post-Concussion Assessment and Cognitive 
Testing (ImPACT) at the School of Kinesiology, Sanders building, Lakehead University. The 
ImPACT will be used as a standard measure of cognitive abilities including: attention, working 
memory, processing speed, and reaction time. At a mutually agreed upon date and time, 
participants will meet a member of the research team at the Lakehead University Sanders 
Fieldhouse. Before beginning the assessments, a member of the research team will verbally 
restate the participant’s rights and confirm that he/she is still willing to participate in the study. 

 
16
Participants will then be set up at a computer station, where they will follow the on screen 
instructions for completing the ImPACT battery. Following completion of the ImPACT battery, 
participants will be asked to stand in a variety of static positions including: narrow based double 
leg stance, single leg stance, and tandem stance with one foot behind the other. Participants will 
perform each stance position with his/her eyes open and closed and on a firm and soft surface 
using the Balance Error Scoring System (BESS) protocol. Each stance will be performed over an 
AMTI force platform. This approach will be used to measure participant sway, centre of pressure 
displacement, and to count for the number of perturbation errors induced during the balance 
test34. The session should last approximately one hour. 
Biomarker Assessment:  
Brain-derived neurotropic factor (BDNF) will be assessed using a morning saliva sample. 
Participants will be asked to refrain from brushing his/her teeth, smoking, and consuming food or 
drink within two hours of the sample collection. Participants will also be asked to avoid alcohol 
consumption 12 hours prior to sampling. At a mutually agreed upon date and time, the 
participant will meet a member of the research team at the Sanders building, Lakehead 
University. Before beginning saliva collection, the member of the research team will verbally 
restate the participant’s rights and confirm that he/she is still willing to participate in the study. 
Saliva will then be collected from participants in room SB-1025 (biohazard containment level 1) 
via the passive drool method into a tube, which will then be put on ice and transported to Dr. 
Lees’ lab for processing. Processed saliva samples will be stored until samples have been 
collected from all participants. If the sample is collected immediately prior to the physical and 
cognitive assessments, participants will be provided with light refreshments after saliva has been 
collected. 
To analyze salivary samples for BDNF, a sandwich ELISA technique will be used 
(Mandel, Ozdener, & Utermohlen, 2011). A 96-well microtiter plate (Nunc Maxisorp; VWR, 
West Chester, PA) will be incubated overnight at four degrees Celsius. In the 96-well plate, a 
total of 100 µl of monoclonal mouse anti-human BDNF (clone 35928.11; Millipore, Etobicoke, 
ON) will be diluted to 1 µg/ml in a filter-sterilized phosphate buffered saline (PBS) at a pH of 
7.4. The plate will be washed three times, soaking for one minute between washed. It will be 
washed with tris-buffered saline (TBS) plus 5% tween (TBST), and blocked with 300 µl of 3% 
bovine serum albumin (BSA) in 0.05% PBST for two and a half hours at room temperature. 
Samples will then be acidified for 20 minutes to a pH of 3.0 using 1M of HCl. Samples will be 
neutralized after 20 minutes using 1M NaOH diluted in a 1% BSA buffer in PBST to a ratio of 
1:4. Comparison will be made between samples and standards diluted in the same buffer as the 
samples. These will range from 15.63 to 500 pg/ml using a full-length, homodimeric 
recombinant BDNF (Peprotech, Rocky Hill, NJ). The plate will then be washed five times, 
before adding in duplicate 100 µl of sample/standard. At room temperature, the plate will then be 
incubated at room for two hours with agitation, before being washed five more times. After 
being washed again, a total of 100 µl of polyclonal chicken anti-human BDNF (2.5 µg/ml; 

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Promega, Madison, WI) will be added to the plate. After two and a half hours, the plate will be 
washed five times again. Following this incubation, 100 µl of anti-chicken IgY-HRP (1 µg/ml; 
Promega) will be added to each well, before being incubated for one hours. The pate will be 
washed five times after this incubation. A total of 100 µl of room temperature Pierce 1-Step 
Ultra TMB solution (Pierce Biotechnology, Rockford, IL) will then be added to each well for 
fifteen minutes. To stop the reaction at fifteen minutes, 100 µl 1M HCl will be added to each 
well to stop the reaction. The assay will be read at 450 nanometres (nm). Total BDNF (pg/ml) 
will be calculated by using the standard regression equation provided with the standards. To the 
research team’s knowledge, BDNF is not used as a diagnostic tool, thus no incidental findings 
are expected. 
Neuroimaging:  
Neural processing will be assessed by using continuously recorded EEG during the 
performance of computer based tasks commonly used in experimental psychology for assessing 
divided attention and inhibitory control. At a mutually agreed upon date and time, participants 
will meet a member of the research team at the Sander building, Lakehead University. A member 
of the research team will then escort he/she to Dr. Michael Wesner’s Vision Laboratory at 
Lakehead University. Before beginning the procedures, the member of the research team will 
verbally restate the participant’s rights and confirm that he/she is still willing to participate in the 
study. Participants will be seated at a desk and fitted with an EEG cap and 32 channels will be 
prepared with gel. Once all recording sites are ready for recording the participant will be 
familiarized with the task procedures and equipment. At the desk he/she is seated at, he/she will 
view a monitor and be provided with a response pad.  The order of the tasks presented will be 
counter-balanced in order to reduce the chance of order effects. Participants will be offered 
opportunities for breaks in between blocks of each task as well as in between the start of tasks. 
Event related potential (ER) will be measured for the duration of the tasks. Completion of the 
session should require two hours.  
ODDBALL paradigm: 
The Oddball paradigm is a commonly used task to test attention by requiring participants 
to make a specific response to rare target stimuli amongst more repetitive, distractor stimuli35. In 
this visual version, participants will be provided an instruction at the outset of a block that 
indicates what the target stimulus for that block will be. During each trial, a stimulus 
(shape/letter) will be displayed for 200 milliseconds (ms). Participants will be instructed to 
respond to each stimulus as quickly and accurately as possible with a button press of one of two 
buttons; a button to denote distractor stimuli, and a button to indicate target stimuli. The 
interstimulus interval will be variable (1400-1600 ms) to reduce anticipation. Participants will 
complete 400 trials separated into 5 blocks with an option for rests between each block. 

 
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FLANKER task: 
The Flanker task is commonly used to test the ability to attend to central relevant 
information (the direction of an arrow) while disregarding irrelevant distracting stimuli (pairs of 
flanking arrows presented on either side of the central arrow). To identify the direction of the 
central arrow, participants will press a left or right button to indicate the direction of the central 
arrow. Data will be separated into time frames containing the components of interest (the N200 
and P300). The session is concluded after completion of the oddball and flanker tests twice.  
Behaviour Measure (Driving Simulator):   
The performance of participants in a driving simulator will be assessed by measuring 
his/her reaction time and counting the number of passes and failures when anticipating 
potentially dangerous traffic situations. Reaction time will also be measured during dual-tasking 
activities. At a mutually agreed upon date and time, the participant will meet a member of the 
research team at the Sanders building, Lakehead University. A member of the research team will 
then escort he/she to the Centre for Research on Safe Driving (Braun Building, room 1024). 
Before beginning the assessment, the member of the research team will verbally restate the 
participant’s rights and confirm that he/she is still willing to participate in the study. Participants 
will then be fitted with a POLAR SP0810 heart rate monitor before being introduced to the 
STISIM Drive® Model 400 driving simulator. Participants will be seated approximately 70% of 
his/her arm’s length from the steering wheel with a backrest inclination of 10° (Majid et al., 
2013; Yoo, An, Lee, & Choi, 2013)36,37. The simulator will be connected to a PowerLab (16/30) 
data acquisition unit which will be interfaced with LabChart 7 software. Heart rate (HR), heart 
rate variability (HRV), and reaction time (RT) will be measured using LabChart 7. 
 
Participants will perform a 10 minute orientation drive to familiarized his/herself with the 
control and feel of the driving simulator. During the orientation drive, he/she will be exposed to 
examples of the dual tasking activities so that he/she will know how to successfully respond to 
the prompts. Once a participant feels comfortable with the simulator, the 20 minute simulation 
and data collection will begin. The simulation will be based on the Thunder Bay road system 
with traffic and pedestrians present. Weather will be clear and visibility will not be reduced. 
Reaction times will be measured during predetermined scenarios and will be recorded from the 
moment stimulus occurs to the moment the brake is depressed or evasive maneuver performed. 
Heart rate and HRV will be recorded throughout the duration of the simulation and will be 
marked at the beginning and end of each dual task scenario and reaction time activity. 
Participants will be exposed to several scenarios. These scenarios include: Vehicle incursion at 
intersection, pedestrian incursion from side of the road, sudden braking by a vehicle in front of 
participant, pedestrian incursion in school zone, braking by a vehicle in front of participant, and 
animal incursion (attached) 
During dual task events, red triangles will be displayed over either of the side mirrors. 
These triangles will be deactivated by the press of a button on either side of the steering column, 
accounting for the dual tasking component of the reaction time scenarios. These scenarios will 

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have a three second threshold for time to react before the scenario will be considered a fail 
(National Safety Council, 2012; Triggs & Harris, 1982)38,39. 
In the event a participant is unsuccessful during a dual tasking scenario and collides with 
on screen stimuli, he/she will continue with the simulation with no second chance at completing 
that specific activity. If a participant begins to experience symptoms of simulator sickness, the 
scenario will be paused to allow him or her to take a break from the screen and/or have 
something to drink or eat. The research team member will have water on hand, if required by the 
participant. When he/she feels ready to proceed, the simulation will be resumed from the point of 
the original pause. If a participant feels that he/she is unable to continue, the simulation will be 
stopped and data collection terminated. 
Aerobic and Balance Retraining Program:  
After completing baseline assessments, PCS participants assigned to the AET 
intervention will complete an eight week supervised AET program. The program will consist of 
three sessions per week, approximately 40-60 minutes each. Each session will be completed 
under the supervision of a trainer with the Canadian Society for Exercise Physiology (CSEP-
CPT) certification. At mutually agreed upon dates and times, participants will meet a member of 
the research team at the Sanders building, room SB-1025. Before beginning the intervention, the 
member of the research team will verbally restate the participant’s rights and confirm that he/she 
is still willing to participate in the study. Participants will then be outfitted with a Polar F2 heart 
rate monitor, in order monitor exercise intensity during the session. Exercise intensity for each 
session will be based on the participant’s heart rate reserve (HRR). At the first session, the 
participants HRR will be calculated using the Karvonen formula; Target Exercise Heart Rate = 
((220-Age-Resting Heart Rate) × % Intensity) + Resting Heart Rate. Once the participant’s HRR 
has been calculated, the participant will begin the aerobic component of the session. 
 
The aerobic component of the session will be performed on a cycle ergometer. 
Participants will begin with a five minute warmup at a self selected speed, which will be used to 
bring the participant’s heart rate to the desired intensity. Intensity for each session will start at 
20% of HRR, and increase linearly by 10% for the first four weeks; at week four, participants 
will be cycling at an intensity of 50%. Weeks five and six will be performed at 55% of HRR, 
week seven will be performed at 60% of HRR, and week eight will be performed at 65% of 
HRR. Duration will follow a similar pattern for weeks one to four, beginning at 20 minutes and 
increasing in five minutes/week increments. At week five, duration will be reduced to 25 
minutes, and then increase to 30 minutes for weeks six to eight. 
 
Following completion of the aerobic portion of the session, participants will rest for five 
minutes before beginning the balance component of the session. Participants will perform three 
balance exercises (in order) each session: narrow based double leg stance, single leg stance, and 
tandem stance. Difficulty of these exercises will be progressively increased by modifying the 

 
20
duration, surface, and whether the participant’s eyes are open or closed. For weeks one and two 
participants will perform the exercises with his/her eyes open; participants will perform each 
exercise for 15 seconds on a firm service in week one, and on a low density foam block in week 
two. In weeks three and four, participants will perform the exercises with his/her eyes closed; 
exercises in week three will be performed on a firm surface, while week four will be performed 
on a low density foam block. Duration will be increased to twenty seconds per exercise for 
weeks three and four. Weeks four to eight will follow the same eyes open/closed and surface 
progression as weeks one to four; eyes open for weeks five and six, eyes closed for weeks seven 
and eight. Exercises will be performed on a firm surface in weeks five and seven, and on a low 
density foam block in weeks six and eight. Participants will perform each exercise for 35 seconds 
in weeks five and six, and 40 seconds in weeks seven and eight. Following the completion of the 
aerobic and balance components of the session, participants will complete a cool down 
consisting of a series of static stretches. Each session will conclude after the completion of the 
cooldown. 
After completion of 24 sessions (eight weeks x three-one hour sessions per week), 
participants will repeat the procedures for the previously described baseline assessments. 
Similarly, HC and SC participants will complete the baseline assessments again after eight 
weeks.  
8. DATA MANAGEMENT   
 
8.1 Data Collection  
A trained member of the research team will obtain age (years), sex, height (cm), and weight (kg), 
as well as the pre screening form (see attached screening checklist, 16.3). This data will then be 
uploaded to the sync.com account and completed, if necessary, by Dr. Wark. 
Dr. Sanzo will administer the ImPACT and BESS. ImPACT results will be recorded and stored 
on the secured, password protected, ImPACT Applications, Inc. server. Data will be immediately 
coded by the researcher. BESS computer data will stored on a secure, password protected 
computer in Dr. Sanzo’s secure office (currently SB-1009).  
Dr. Lees will oversee the collection of the saliva sample at the School of Kinesiology, Lakehead 
University. The research assistant will label the tube with the participant code and will transport 
it back to NOSM (unless already at NOSM), where it will be immediately processed. 
Oddball and Flanker tasks will be overseen by Dr. Lawrence-Dewar and Dr. Wesner. All data 
will be collected and analyzed in Dr. Wesner’s Vision Laboratory at Lakehead University. 
The driving simulation will be overseen by Dr. Zerpa at the Centre for Research on Safe Driving 
and recorded by the STISIM Drive® Model 400 driving simulator. 
  

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8.2 Data Management  
The research team (Principal Investigator, Co-Investigators and research assistant) has access to 
all data if necessary. The research assistant will create a code key that will be kept on a secure 
Sync.com account (see below for further information, access provided through NOSM) in an 
encrypted file, along with the electronic coded data abstraction files. These files will be kept 
separate from the code key in order to prevent participant identification.   
The hard copy screening checklists will be coded and stored in Dr. Zerpa’s current office in a 
locked filing cabinet at School of Kinesiology, Lakehead University (SB-1007). Electronic 
copies will be uploaded to the secure Sync.com account.  
Saliva samples will be immediately coded and processed/stored in the NOSM laboratory. Results 
of the saliva analysis will be stored in an encrypted file on a password protected computer in a 
secure office.  
Dr. Sanzo will extract ImPACT data from the ImPACT Applications, Inc. server to a password 
protected computer in a secure office. Electronic data collected from the BESS will be 
transferred to a secure USB (for data transfer) and then to a password protected computer in a 
secure office. All paper and electronic data will be coded and uploaded to the secure Sync.com 
account. 
Electronic data collected from the Oddball and Flanker tasks will be coded to a secure USB (for 
data transfer) and transferred to a password protected computer in a secure office. Data will then 
be uploaded to the secure Sync.com account. 
Electronic Data collected from the driving simulation will be coded and transferred to a secure 
USB (for data transfer) and then to a password protected computer in a secure office. Data will 
then be uploaded to the secure Sync.com account. 
Sync.com account details:  
The website states the following:  
Sync's unique, zero-knowledge storage platform guarantees your privacy by providing end-to-
end encryption, and most importantly - only you have access to the encryption keys. We can’t 
read your files. Neither can the NSA.  
 -Zero-knowledge, end-to-end encryption  
 -Privacy guarantee (we can’t access your files or file metadata)  
 -2048 bit RSA, 256 bit AES, SSL and TLS encryption   
-Files encrypted in transit and at rest   
-Share controls, permissions and user administration  
-Remote logout   

 
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-Remote wipe   
-File audit logs   
-Account notifications   
-Two-factor authentication  
9. SPECIMEN MANAGEMENT  
A research assistant, will facilitate the collection of the saliva following an establish passive 
drool protocol.  Participants will be instructed to drool though a straw into a collection tube.  The 
samples will be transported Lakehead University School of Kinesiology to NOSM for processing 
and analysis. Salivary BDNF will be quantified using an established protocol in Dr. Lees' lab, 
which utilizes an enzyme-linked immunosorbent assay.  All samples will be labeled with the 
participant code number as well as a letter for each time point. For example, A for pre-treatment, 
B for post-treatment. Samples will be kept until all analysis is completed, after which all labels 
will be removed and samples will be disposed of as biohazardous waste.   
10. DATA / SPECIMEN ANALYSIS  
Dr. Lees and the NOSM research assistant will be performing data analysis on the saliva samples 
at NOSM. Dr. Sanzo, Dr. Lawrence-Deware, Dr. Wesner, and Dr. Zerpa will be performing 
analysis on the physical and cognitive measures at Lakehead University. The main analysis will 
be a comparison of the pre- and post-outcomes.  
Dr. Paolo Sanzo will perform the analysis of the data collected related to balance from the AMTI 
force platform and ImPACT neurocognitive assessment. The AMTI force platform measures the 
ground reaction forces that are generated by a body standing or moving across the plate.  The 
AMTI force plate is also capable of measuring torques about each axis and has six degrees of 
freedom, which includes three forces (fz, fx, and fy) and three moments (Mz, Mx, and My). All of 
these measures are fed into an AMTI amplifier and converted to digital signals via an analog to 
digital converter. The information collected by the force platform is then uploaded into 
BIOSOFT computer software which allows the researcher to view and analyze data following 
collection. The BIOSOFT computer software calculates the x and y moments of postural sway 
which are used to compute the variables of interest and produces graphical representations of this 
data. Descriptive statistics will be calculated to provide the mean and standard deviations for the 
variables of interest including the area of the centre of pressure, velocity of centre of pressure, 
length of centre of pressure, and displacement of centre of pressure.  The main objective of the 
analysis is to compare pre- and post-treatment changes in balance.  The ImPACT 
measures components of cognitive functioning including: attention, concentration, reaction time, 
memory, processing speed, decision making, problem solving, and response variability. The 
main objective of this component of the analysis will be to compare pre- and post-treatment 
changes in composite scores for the variables described. 
 
Dr. Carlos Zerpa will perform the analysis on the data collected from the driving simulator. This 
analysis will include the comparison of people with concussion who will undergo AET to those 

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going through regular standard of care and healthy control on measures of reaction time for dual 
and non dual tasking driving events. The analysis will be performed pre and post intervention to 
examine the interaction effect between group and time on measures of reaction time. The 
statistical analysis will include descriptive statistics to calculate means and standard deviation for 
each group for the pre and post test data. A mixed factorial analysis of variance will also be 
performed with group as the independent factor, time (pre and post intervention) as the repeated 
measure and reaction times as the dependent variable to examine the effect of the AET. 
Preprocessing and analysis may either occur on Dr. Wesner’s recording computer using asa-lab 
software or a separate analysis computer (also password protected) using EEGlab software. Prior 
to analysis data will be segmented into epochs around each event (trial) presentation.  Data will 
be temporally filtered. Baseline line correction using the 200 ms before the stimulus presentation 
will be applied. Artifact detection and removal will be applied to remove trials that have been 
affected by excessive head motion (for example blinking, general body movement). Once 
preprocess, all the trials from the same condition type will be averaged to create an event-related 
potential for each condition type. This data, for each participant will be exported for statistical 
analysis (performed in JASP). Repeated measures ANOVA will be used to determine if there are 
significant between group and between condition differences. 
Missing data will be handled according to the type of data that is missing.  For analyses that 
depend on change (pre- vs post-), if a participant misses an assessment (i.e saliva) we will have 
to exclude the participant’s results for that assessment. If the rest of the assessments were 
completed pre and post intervention, then they will be included in the data analysis. 
There will be no interim analysis.  
 11. STATISTICAL CONSIDERATIONS 
 
11.1 Sample Size Calculation  
 A priori power analysis was conducted to determine that we would have 80% power at alpha = 
.05 (two tailed) to detect a medium to large effect size with 12 participants in each group, leaving 
room for a 13% dropout rate. We therefore propose 20 participants per group. 
11.2 Statistical Analysis  
The main analysis will be a mixed factorial ANOVA to examine interaction effects between 
group (AET, SC, and HC) and time (pre- and post-) on measures of ERP, balance, BDNF and 
reaction time. If an interaction is found between group and time on any of the dependent 
variables (ERP, balance, BDNF and reaction time), the interaction will be explained using simple 
main effects. If no interaction is found for any of the dependent variable measures, the main 
effects for time and groups will examined by a post hoc analysis to determine differences 
between groups. We anticipate greater change in the AET group compared to SC and HC group. 

 
24
 
12. OTHER STUDY ADMINISTRATION CONSIDERATIONS  
 
 12.1 Concomitant use of medications or interventions during the course of the study  
All relevant concomitant care and interventions are permitted throughout the study.  
12.2 Allocation sequence generation and concealment mechanism  
To randomize participant group assignment, an online program called QMinim 
(http://rct.mui.ac.ir/qminim/) will be utilized. This program uses a process called minimization 
which ensures group sizes are equal and eliminates potential bias that may be introduced which 
is important for clinical research of small sizes (BMJ 2005;330:843).  
12.3 Blinding Procedures  
Participants will no be blinded to his/her group assignment. Participants placed into the SC group 
will be given the option of receiving the AET after completion of the study, although this will 
not be included in data analysis. 
Dr. Lees, Dr. Zerpa, Dr. Lawrence-Dewar, and Dr. Wesner will be blinded from group 
assignment for data analysis purposes.   
12.4 Premature discontinuation or termination of the study  
The study sponsor/investigator and the Research Ethics Board reserve the right to terminate this 
research study at any time. Reasons for termination include but are not limited to:  
The occurrence of adverse events poses a potential health risk for participants;  
Unsatisfactory participant enrollment;  
Investigator request to withdraw from study;  
Noncompliance with the protocol or regulatory guidelines are not being followed; 
REB decision to terminate or suspend approval for the investigation or Investigator.  
 
12.5 Ancillary and post-trial care  
Participation in this study is not expected to cause any harm, and the participant can withdraw at 
any time. There is no compensation as the participant agrees to the risks outlined in the 
information letter.  
13. QUALITY CONTROL AND QUALITY ASSURANCE  
We are able to track adherence to the protocol because the intervention requires a visit which is 
documented in the data abstraction form. All data will be translated into the data abstraction 
forms. To promote data quality, all team members will be trained in their duties. All 
questionnaires to be used are valid (see Section 7.2).  

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13.1 Data Integrity Measures  
See above. All members of the research team are responsible for adhering to the protocol and 
ensuring data quality.  
13.2 Training Study Staff  
All members of the research team will be protocol trained. All duties to be performed by 
members of the research team will be delegated by the Principal Investigator. Appropriate task 
training will be completed by the PI/research team prior to the study start. All supervisors for the 
AET program will be certified by the Canadian Society for Exercise Physiology. The NOSM 
research assistant is TCPS 2 CORE trained in order to administer informed consent. Dr. Lees 
will supervise the NOSM research assistant who is already trained in all protocols covering the 
roles of saliva analysis and group assignment.   
13.3 Auditing and Monitoring   
  
There is no auditing conduct.  
 14. REGULATORY CONSIDERATIONS  
 14.1 Participant privacy and confidentiality  
Data will be kept confidential throughout the study through the following measures:  
-a key will be created with a list of participant names and their respective codes, in a password 
protected encrypted document on a secure computer at Lakehead University. This computer will 
remain in a locked cabinet in a locked office except when in use at one of the research sites, as 
well as when in transport between sites. Only the research team will have access to the key.  
-The key will be kept in a separate file (using a different password) from all original raw data,  
- To ensure participant data can be immediately coded following collection, the key will be 
placed in an encrypted folder in a secure Sync account, (see below for more details) to which 
only research team members will have access.  
- Saliva samples will be coded immediately following the draw 
 - All data abstraction forms and screening tools will be coded and abstraction forms will only be 
electronic (saved into password protected folders on secure Sync account),  
- No data will leave the collection site uncoded, -Only members of the research team will have 
access to the data, 
 - Data will be stored in secure offices on password protected computers at the location they were 
collected,  
- All data published will use aggregate data so no individual person can be identified.  
  

 
26
The data will not be disclosed to third parties, and original signed consent forms/coded screening 
tools will stay in secure filing cabinets in Dr. Zerpa’s secure office at the Lakehead University 
School of Kinesiology (currently number SB 1007). All data will be kept for a minimum of five 
years, after which it will be destroyed. Any data collected during the screening process (signed 
consent forms, screening checklists) for a potential participant who does not meet the criteria, 
and who will therefore not be included in the study, will be securely destroyed in a locked 
Enviroshred box for confidential shredding.  
14.2 Ethical Review  
It is the understanding of the sponsor that this protocol as well as appropriate consent procedures 
will be reviewed and approved by the Thunder Bay Regional Health Science Centre. This board 
operate in accordance with the current Canadian Regulations. Approval from the board will be 
obtained before starting the study, and will be documented in a letter to the investigator 
specifying the date on which the board met and granted the approval. All protocol modifications 
will be reviewed and approved by the appropriate Research Ethics Boards in accordance with 
local requirements, before the changes can be implemented. Modifications which eliminate an 
apparent immediate hazard to participants do not require pre-approval by the Research Ethics 
Board. Such deviations will be recorded and explained in the annual REB report.  
14.3 Scientific Review   
The Northern Ontario Academic Medical Association has reviewed this study.  
14.4 Institutional Review  
This protocol as well as required resources will be reviewed and approved by the Thunder Bay 
Regional Health Sciences Centre Research Program. Approval must be obtained prior to 
initiating the study.  
14.5 Clinical Trial Registration  
This study will be registered as a clinical trial at ClinicalTrials.gov 
14.6 Retention of Study Documents  
All original signed consent forms and screening checklists will be maintained confidentially at 
Lakehead University School of Kinesiology in a locked filing cabinet in Dr. Zerpa’s secure 
office (currently SB-1007). To protect participant data, each participant will be given a code. A 
code key will be created in a password-protected and encrypted file away from raw data. This 
key will also be placed on the secure Sync.com account. All data abstraction forms will be 
electronic and coded. They will be stored in an encrypted file on the Sync.com account.. All data 
will be kept for a minimum of 5 years after which it will be destroyed securely.   
14.7 Data Monitoring Committee  
There will be no data monitoring committee.  
14.8 Unanticipated Problems  
All adverse events will be recorded and will be reported appropriately as outlined in the REB 
guidelines. 

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14.9 Publication of Data and Protection of Trade Secrets  
The results from this study will be published in a peer-reviewed scientific journal as aggregate 
data. The research team will have access to all coded data until the storage period is complete.  
14.10 Dissemination  
Participants can inquire about his/her own as well as aggregate study results. Aggregate data will 
be communicated to healthcare professionals and the public via presentations at local scientific 
conferences (such as the Northern Heath Research Conference, Northern Constellations, or the 
Showcase of Healthcare Research) and a publication in a peer-reviewed scientific journal.  
All research team members who have contributed intellectual input into the study design and/or 
interpretation of results, or contributed to data collection and/or analysis will be included as 
authors. Members of the research team will write any manuscripts resulting from the study.  
14.11 Declaration of interests  
There are no financial or other competing interests for any member of the research team. 
 
 

 
28
15. References 
1. Iverson, G. & Lange, R. in The black book of neuropsychology [...] 663–696 (Springer, 
2011). 
2. Sosin, D. M., Sniezek, J. E. & Thurman, D. J. Incidence of mild and moderate brain 
injury [...]. Brain Inj. 10, 47–54 (1996). 
3. Kraus, J. & Chu, L. in Textbook of traumatic brain injury 3–26 (American Psychiatric 
Publishing, Inc., 2005). 
4. Alves, W. Postconcussive symptoms [...]. J. Head Trauma Rehabil. 8, 48–59 (1993). 
5. Meares, S. et al. The prospective course of postconcussion syndrome [...]. 
Neuropsychology 25, 454–465 (2011). 
6. Villemure, R., Nolin, P. & Le Sage, N. Self-reported symptoms during post-mild 
traumatic brain injury [...]. Brain Inj. 25, 53–64 (2011). 
7. Murray, N., Salvatore, A., Powell, D. & Reed-Jones, R. Reliability and validity evidence 
of multiple balance assessments in athletes with a concussion. J. Athl. Train. 49, 540–549 
(2014). 
8. Preece, M. H. W., Horswill, M. S. & Geffen, G. M. Driving after concussion [...]. 
Neuropsychology 24, 493–503 (2010). 
9. Darby, P., Murray, W. & Raeside, R. Applying online fleet driver assessment to help 
identify, target and reduce occupational road safety risks. Saf. Sci. 47, 436–442 (2009). 
10. Al Sayegh, A., Sandford, D. & Carson, A. J. Psychological approaches to treatment of 
postconcussion syndrome [...]. J. Neurol. Neurosurg. Psychiatry 81, 1128–1134 (2010). 
11. Leddy, J. J., Sandhu, H., Sodhi, V., Baker, J. G. & Willer, B. Rehabilitation of 
Concussion and Post-concussion Syndrome. Sports Health Multidiscip. Approach 4, 147–
154 (2012). 
12. Makdissi, M. et al. Revisiting the modifiers: how should the evaluation and management 
of acute concussions differ in specific groups? Br. J. Sports Med. 47, 314–320 (2013). 
13. Zoladz, J. A. & Pilc, A. The effect of physical activity on the brain derived neurotrophic 
factor [...]. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 61, 533–541 (2010). 
14. McGeown, J., Sanzo, P., Zerpa, C., Lees, S. & Niccoli, S. The Effects of Exercise on 
Cognitive Function, Balance, and Salivary Brain Derived Neurotrophic Factor [...]. Res. 
Neurosci. 5, 15–23 
15. Alsalaheen, B. A. et al. Vestibular rehabilitation for dizziness and balance disorders after 
concussion. J. Neurol. Phys. Ther. JNPT 34, 87–93 (2010). 
16. Ratey, J. & Hagerman, E. in Spark - The revolutionary new science of exercise and the 
brain 9–35 (Little, Brown and Company, 2008). 
17. Papa, L., Ramia, M. M., Edwards, D., Johnson, B. D. & Slobounov, S. M. Systematic 
Review of Clinical Studies Examining Biomarkers of Brain Injury [...]. J. Neurotrauma 
(2014). doi:10.1089/neu.2014.3655 
18. Kozlovsky, N. et al. Long-term down-regulation of BDNF [...]. Int. J. 
Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP 10, 741–
758 (2007). 
19. Griesbach, G. S., Hovda, D. A. & Gomez-Pinilla, F. Exercise-induced improvement in 
cognitive performance after traumatic brain injury […] Brain Res. 1288, 105-115 (2009) 

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20. Whiteman, A. S. et al. Interaction between serum BDNF and aerobic fitness predicts 
recognition memory [...]. Behav. Brain Res. 259, 302–312 (2014). 
21. Zoladz, J. A. et al. Endurance training increases plasma brain-derived neurotrophic factor 
[...]. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 59 Suppl 7, 119–132 (2008). 
22. Leckie, R. L. et al. BDNF mediates improvements in executive function [...]. Front. Hum. 
Neurosci. 8, 985 (2014). 
23. Belanger, H. G., Curtiss, G., Demery, J. A., Lebowitz, B. K. & Vanderploeg, R. D. 
Factors moderating neuropsychological outcomes following mild traumatic brain 
injury[...]. J. Int. Neuropsychol. Soc. JINS 11, 215–227 (2005). 
24. Rohling, M. L. et al. A meta-analysis of neuropsychological outcome after mild traumatic 
brain injury[...]. Clin. Neuropsychol. 25, 608–623 (2011). 
25. Cicerone, K. D. Attention deficits and dual task demands after mild traumatic brain 
injury. Brain Inj. 10, 79–89 (1996). 
26. Bernstein, D. M. Information processing difficulty long after self-reported concussion. J. 
Int. Neuropsychol. Soc. JINS 8, 673–682 (2002). 
27. Ozen, L. J. & Fernandes, M. A. Slowing down after a mild traumatic brain injury[...]. 
Arch. Clin. Neuropsychol. Off. J. Natl. Acad. Neuropsychol. 27, 85–100 (2012). 
28. Kontos, A. P. et al. Preliminary evidence of reduced brain network activation in patients 
with post-traumatic migraine following concussion. Brain Imaging Behav. 10, 594–603 
(2016). 
29. Parks, A. C. et al. The association between a history of concussion and variability in 
behavioral and neuroelectric indices of cognition. Int. J. Psychophysiol. Off. J. Int. 
Organ. Psychophysiol. 98, 426–434 (2015). 
30. Broglio, S. P., Pontifex, M. B., O’Connor, P. & Hillman, C. H. The persistent effects of 
concussion on neuroelectic indices of attention. J. Neurotrauma 110306202455053 
(2009). doi:10.1089/neu.2008-0766 
31. De Beaumont, L. et al. Brain function decline in healthy retired athletes [...]. Brain 132, 
695–708 (2009). 
32. Gaetz, M. & Weinberg, H. Electrophysiological indices of persistent post-concussion 
[...]. Brain Inj. 14, 815–832 (2000). 
33. Moore, R. D., Hillman, C. H. & Broglio, S. P. The Persistent Influence of Concussive 
Injuries on Cognitive Control and Neuroelectric Function. J. Athl. Train. 49, 24–35 
(2014). 
34. Golriz, S., Hebert, J. J., Foreman, K. & Walker, B. F. The reliability of a portable clinical 
force plate used for the assessment of static postural control [...]. Chiropr. Man. Ther. 20, 
14 (2012) 
35. Squires, N. K, Squires,  K. C, & Hillyard,  S. A. Two varieties of long-latency positive 
waves evoked by unpredictable auditory stimuli in man. Electroencephalogr Clin 
Neurophysiol. 38(4):387-401. (1975) 
36. Majid, N., Edzuan Abdullah, M., Jamaludin, M., Notomi, M., & Rasmussen, J.  
Musculoskeletal analysis of driving fatigue: The influence of seat adjustments. AEF, 10, 
373-378. (2013). 

 
30
37. Yoo, K., An, H., Lee, S., & Choi, J. Maximal torque and muscle strength is affected by 
seat distance from the steering wheel when driving. Journal of Physical Therapy Science, 
25(9), 1163-1167. (2013). 
38. National Safety Council. Understanding the distracted brain: Why driving while using 
hands-free cell phones is risky behaviour. National Safety Council. (2012) Retrieved 
from http://www.nsc.org/DistractedDrivingDocuments/Cognitive-Distraction-White-
Paper.pdf 
39. Triggs, T., & Harris, W. Reaction time of drivers to road stimuli. Clayton, Vic.: Human 
Factors Group, Dept. of Psychology, Monash University. (1982). 
 
 
 
 

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16. APPENDICES 
16.1 Recruitment materials 

 
32
 

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34
16.2 Informed consent materials 
 

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** On Lakehead University, Northern Ontario School of Medicine, and Thunder Bay Regional 
Health Sciences Centre letterhead** 
Healthy control information letter 
Principal Investigator:  
Dr. Sheryl Wark,  
Family & Sport Medicine Physician,  
Fairway Physiotherapy   
Assistant Professor, Northern Ontario  
School of Medicine (NOSM)  
(807-344-5242)  
Co-Investigators  
Dr. Simon Lees,  
Associate Professor, NOSM  
  
Dr. Paolo Sanzo, Associate Professor, 
NOSM and Lakehead University, School 
of Kinesiology  
  
Dr. Jane Lawrence-Dewar  
  
Dr. Carlos Zerpa, Assistant Professor,  
Lakehead University, School of  
Kinesiology  
  
Dr. Michael Wesner, Associate  
Professor, Lakehead University,  
Psychology Department  
  
Funding provided by:  
Northern Ontario Academic Medical 
Association (NOAMA)  
  
  
Dear Potential Participant,  
We are inviting you to participate in a research study. The name of this study is “A Multi-modal 
Evaluation of a Physical Intervention Approach to Treating Persistent Post-Concussive 
Symptoms”. Please keep in mind that this is an invitation, and by no means are you required to 
participate. This study has been funded through the Northern Ontario Academic Medical 
Association (NOAMA) through their Clinical Innovation Opportunities Fund. We have asked 
you to participate because you are a healthy individual, 18-50 years of age, free of any 
psychological/neurological disorder, no history of substance abuse, are not currently undergoing 
therapy or counselling for depression, and have a valid drivers license  

 
36
  
We are a group of researchers and doctors from the Northern Ontario School of Medicine 
(NOSM) and Lakehead University. The research team includes Dr.  
Sheryl Wark, Dr. Simon Lees, Dr. Paolo Sanzo, Dr. Jane Lawrence-Dewar, and Dr. Carlos 
Zerpa, and Dr. Michael Wesner.  
  
What is the usual treatment?  
Treatment of concussions usually involves complete physical and mental rest until symptoms are 
no longer present. In many people, symptoms of a concussion can resolve in 7-10 days. In a 
minority of people, these symptoms can last longer than 710 days and may last months or years. 
In persons who experience long term symptoms, some studies have shown that mental and 
physical rest may not be beneficial.  
  
Why is this study being done?  
Persons with PCS may experience difficulties completing day to day tasks, such as driving, 
concentrating, or exercising. This reduces a person quality of life and puts a strain on the 
healthcare system. The goal of the research study is to determine the effectiveness of an aerobic 
exercise therapy (AET) on PCS, which will include mild aerobic and balance training. An AET 
program has previously been studied for the treatment of PCS, and results have been promising. 
As a participant who does not have PCS, if you are participating, you will complete a few initial 
assessments. These assessments include a computerized concussion test, balance test, reaction 
test, driving test, and a saliva test over a one week period. After eight weeks, you will complete 
the same assessments again.  
  
If you would like to participate in this study, an appointment will be set up between you and a 
member of the research team at Lakehead University. The purpose of this appointment will be to 
inform you of your rights as a participant and fill out an informed consent form. Over the course 
of the whole study, you will be asked to participate in up to eight assessment visits, four at the 
beginning, four at the end (described below), including a computerized concussion test, simple 
balance test, reaction tests, and driving simulation. Your saliva will also be collected at some 
point during this week as well.  
  
The ImPACT computerized concussion test and balance test will be conducted at the Sanders 
building, Lakehead University. For the ImPACT test, you will be seated at a computer station, 
where you will follow on screen instructions designed to evaluate mental functioning. The 
ImPACT test should last 30-45 minutes. The balance test will involve single and double leg 
stances, with and without your eyes closed. The balance test will be performed on a force 

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37
platform, which will measure how much your center of mass and center of pressure moves, as 
well as the speed at which they move. The entire session should last approximately one hour  
  
For the computerized reaction test, you will meet a member of the research team at the Sanders 
building, Lakehead University, where you will be escorted to Dr. Dr. Michael Wesner’s Vision 
Laboratory at Lakehead University. Here, you will complete two computerized reaction tests 
while wearing a specialized head cap. This cap will allow us to measure brain activity non-
invasively during these tests. The tests will involve a series of visual stimuli on a computer 
screen, which will require you to press a corresponding button to the stimuli shown. The reaction 
tests should last approximately two hours.  
For the driving simulation, you will meet a member of the research team at the Sanders building, 
Lakehead University, where you will be escorted to the Centre for Research on Safe Driving in 
the Braun building, Lakehead University. The simulation will replicate driving conditions of 
Thunder Bay, and ask you to respond to a series of scenarios including: vehicle entering an 
intersection, pedestrian running on to the road, sudden braking by a vehicle in front of you, 
pedestrian running on to the road in a school zone, braking by a vehicle in front of you, and an 
animal running onto the road. These assessments will also be completed while you are required 
to perform a second task during the scenario, such as pressing a button when your side mirror is 
covered. This visit should take less than an hour.  
  
The saliva draw will be completed in the Sanders building, room SB-1025, Lakehead University. 
For the saliva draw, you will be asked not to brush your teeth, smoke, eat, or drink for 2 hours 
before saliva collection. You will also be asked not to consume alcohol for 12 hours before saliva 
collection. You will passively drool into a tube, which will be collected and analysed in a lab for 
brain-derived neurotrophic factor (BDNF). Higher levels of BDNF have been associated with 
improvements in mental functioning.  
  
Following the baseline assessments, you will be asked to return after eight weeks to take the tests 
once again. During this time, you will be instructed not to significantly change your physical 
activity level. Upon completion of the study, you will be eligible for a $25 gift card.  
  
What will happen during this study?  
  
You will be asked to complete the baseline assessments. After eight weeks, you will be 
asked to return and complete the assessments again. Below you will find an overview of the 
study.  
  

 
38
Study Overview:  
  
Week  
1 & 10  
   
   
   
2-9  
Event  
ImPACT & 
balance  
Reaction 
test  
Driving 
simulation  
Saliva  
None  
Time  
Required   
1 hour  
2 hours  
1 hour  
15 
minutes  
No required 
appointments  
  
  
How many people will take part in this study?  
It is anticipated that 60 participants will be recruited into this study.  
Recruitment, data collection and analysis will continue over the span of 6 months. Your direct 
participation, however, will only last 9-10 weeks depending on scheduling of the preliminary and 
final assessments.  
 
What are the risks or harms of participating in this study?  
No serious side effects or risks such as stroke, heart attack or death are anticipated due to 
participation in this study. During the driving simulation, there is a small chance that you will 
experience dizziness or nausea. If this happens, the simulation will be paused to allow you to 
rest, or stopped completely.  
  
What are the benefits of participating in this study?  
The purpose of this study is to gather this information and our research may impact how people 
suffering from PCS are treated. Research investigating PCS and AET is important work and this 
study will serve to expand the knowledge in this field.   
  
Can participation in this study end early?  
Your participation in this study may end early if you choose to withdraw for any reason. If you 
wish to withdraw consent from the study, you will be asked to specify if you wish for any data or 
samples collected to be withdrawn as well. Samples and data will be withdrawn in accordance 
with your wishes. You are under no obligation to participate in this study, and you may choose to 
withdraw from it at any point by contacting Dr. Carlos Zerpa (807-343-8940), the primary 
contact for this study. During the course of the research project, you will be given all information 

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39
that is relevant to your decision to continue or withdraw from the study, as well as information 
on your right to request the withdrawal of collected data.   
  
What are the costs of participating in this study?   
There are no fees associated with participation in the research. If you choose to park at the 
assessment locations, there are fees associated with these parking lots. Parking fees at Lakehead 
University for study visits will be reimbursed.   
  
What happens if I have a research related injury?   
There is no compensation or insurance coverage for research-related injuries, however, we do not 
anticipate any to occur during your participation in this study. Please note that by consenting to 
participate in this study, you have not waived any rights to legal recourse in the event of 
research-related harm.  
  
Are study participants paid to participate in this study?   
There will be no prorated payments. Parking costs for study visits at Lakehead University will be 
reimbursed. Upon completion of the study, you will be able to keep the activity monitors.  
  
How will my information be kept confidential?  
As described above, all personal data (test scores and saliva samples) that are collected will be 
de-identified through a coding process, and only the research team will have access to this data 
and the samples. Collected hard copies of the data will be stored in a secure file cabinet in a 
locked office. Computer data will be kept on a secure server on a password protected computer. 
Saliva samples will be stored in a secure laboratory at NOSM until analysis, after which they will 
be securely disposed of. All data/samples will be stored for a minimum of five years. When the 
study is finished, we will write up our aggregate results, that is, data which is combined and 
summarized so that no individual participant can be identified in manuscripts. These manuscripts 
may then be published in academic journals. We will also present our results at academic 
conferences. If you are interested in the results of the study, we can arrange to have those results 
sent to you. Please ask a member of our team; we would be happy to provide them to you. Dr. 
Carlos Zerpa will be the sponsor for this study, and the research team as a whole will act as study 
monitors and auditors. These people, as well as the research ethics boards at TBRHSC will be 
granted access to the information you provide and data collected as a result of your participation 
in this study for verification of clinical trial procedures/data without violating your 
confidentiality to the extent permitted by the applicable laws and regulations. A description of 

 
40
this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.   
  
Do the investigators have any conflicts of interest?  
There will be no commercialization of the study findings by the researchers. There are no real, 
potential, or perceived conflicts of interest on the part of the researchers, their institutions, or the 
research sponsors. None of the research team members will receive a fee for your enrollment.   
  
What are the rights of participants in a research study?   
If you have any questions regarding this study, please feel free to contact the research team. The 
primary contact for this study is Dr. Carlos Zerpa and he can be reached at 807- 343-8940; 
czerpa@lakeheadu.ca. This project has been approved by the ethics board at TBRHSC. If you 
have any concerns regarding your rights as a research participant, or wish to speak to someone 
other than a research team member about this research project, you are welcome to contact the:  
  
Chair, Research Ethics Board   
Thunder Bay Regional Health Sciences Centre  
 Phone: 807-684-6422   
Fax: 807-684-5904   
Email contact for REB: TBR_REO@tbh.net   
  
  
  
  
  
  
  
We understand that you may need some time to consider your participation, so you may take at 
least 24 hours to assimilate the information provided, pose any questions you may have, and 
discuss and consider whether you will participate.   
  

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41
  
We thank you for your time,  
  
Dr. Sheryl Wark,  
          Dr. Simon Lees,  
Dr. Paolo Sanzo,  
Dr. Jane Lawrence-Dewar  
Dr. Carlos Zerpa  
          Dr. Jane Lawrence-Dewar  
Dr. Michael Wesner            Sarah Niccoli   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
42
PCS information letter 
Principal Investigator: 
Dr. Sheryl Wark, 
Family & Sport Medicine Physician, Fairway 
Physiotherapy  
Assistant Professor, Northern Ontario School 
of Medicine (NOSM) 
(807-344-5242) 
Co-Investigators 
Dr. Simon Lees, 
Associate Professor, NOSM 
 
Dr. Paolo Sanzo, Associate Professor, NOSM 
and Lakehead University, School of 
Kinesiology 
 
Dr. Jane Lawrence-Dewar, Assistant Professor 
NOSM, Adjunct Professor Lakehead 
University, School of Kinesiology 
 
Dr. Carlos Zerpa, Assistant Professor, 
Lakehead University, School of Kinesiology 
 
Dr. Michael Wesner, Associate Professor, 
Lakehead University, Psychology Department 
 
Funding provided by: 
Northern Ontario Academic Medical 
Association (NOAMA) 
 
 
Dear Potential Participant, 
We are inviting you to participate in a research study. The name of this study is “A Multi-
modal Evaluation of a Physical Intervention Approach to Treating Persistent Post-Concussive 
Symptoms”. Please keep in mind that this is an invitation, and by no means are you required to 
participate. This study has been funded through the Northern Ontario Academic Medical 
Association (NOAMA) through their Clinical Innovation Opportunities Fund. We have asked 
you to participate because you have been referred by Dr. Wark, are currently experiencing 
persistent post-concussive symptoms (PCS) and it has been two weeks to six months since the 
date of injury, are 18-50 years of age, free of any psychological/neurological disorder, no history 
of substance abuse, are not currently undergoing therapy or counselling for depression, and have 
a valid drivers license. 
 
We are a group of researchers and doctors from the Northern Ontario School of Medicine 
(NOSM) and Lakehead University. The research team includes Dr. Sheryl Wark, Dr. Simon 
Lees, Dr. Paolo Sanzo, Dr. Jane Lawrence-Dewar, Dr. Carlos Zerpa, and Dr. Michael Wesner. 
 

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Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
43
 
 
What is the usual treatment? 
Treatment of concussions usually involves complete physical and mental rest until 
symptoms are no longer present. In many people, symptoms of a concussion can resolve in 7-10 
days. In a minority of people, these symptoms can last longer than 7-10 days and may last 
months or years. In persons who experience long term symptoms, some studies have shown that 
mental and physical rest may not be beneficial. 
 
Why is this study being done? 
Persons with PCS may experience difficulties completing day to day tasks, such as 
driving, concentrating, or exercising. This reduces a person quality of life and puts a strain on the 
healthcare system. The goal of the research study is to determine the effectiveness of an aerobic 
exercise therapy (AET) on PCS, which will include mild aerobic and balance training. An AET 
program has previously been studied for the treatment of PCS, and results have been promising. 
If you are participating, you will complete a few initial assessments over the course of one week. 
These assessments include a computerized concussion test, balance test, reaction test, driving 
test, and a saliva test. Following completion of the assessments, you will complete either an AET 
or standard of care (SC) intervention for eight weeks. After eight weeks you will repeat the 
assessments.  
 
If you would like to participate in this study, an appointment will be set up between you 
and a member of the research team at Lakehead University. The purpose of this appointment will 
be to inform you of your rights as a participant and fill out an informed consent form. Over the 
course of the whole study, you will be asked to participate in up to eight assessment visits, four 
at the beginning, four at the end (described below), including a computerized concussion test, 
simple balance test, reaction tests, and driving simulation. Your saliva will also be collected at 
some point during this week as well. If you are in the AET group, you will also be asked to 
participate in 24 training visits, described below. Additionally, you will be given an activity 
monitor to be worn on your wrist for the duration of the study. 
 
The ImPACT computerized concussion test and simple balance test will be conducted at 
the Sanders building, Lakehead University. For the ImPACT test, you will be seated at a 
computer station, where you will follow on screen instructions designed to evaluate mental 
functioning. The balance test will involve single and double leg stances, with and without your 
eyes closed. The balance test will be performed on a force platform, which will measure how 
much your center of mass and center of pressure moves, as well as the speed at which they move. 
The entire session should last approximately one hour 
 
For the brain imaging, you will meet a member of the research team at the Sanders 
building, Lakehead University, where you will be escorted to Dr. Michael Wesner’s Vision 
Laboratory at Lakehead University. Here, you will complete two computer-based reaction tasks 
while wearing a specialized head cap. This cap will allow us to measure brain activity non-
invasively during tasks. In order for the recording electrodes to monitor brain activity, we will 
place electrode gel at each recording location. The gel may feel slimy and cool at first. Once the 

 
44
recording sites are ready, the experimenter will review the instructions of the computer based 
tasks for you. These tasks will require you to make a button press as quickly and accurately as 
possible when a target image appears on the computer screen. The whole procedure including set 
up and recordings should last approximately two hours. There is shampoo and towels available at 
the lab should you want to wash your hair in a sink following the study. 
 
For the driving simulation, you will meet a member of the research team at the Sanders 
building, Lakehead University, where you will be escorted to the Centre for Research on Safe 
Driving in the Braun building, Lakehead University. The simulation will replicate driving 
conditions of Thunder Bay, and ask you to respond to a series of scenarios including: vehicle 
entering an intersection, pedestrian running on to the road, sudden braking by a vehicle in front 
of you, pedestrian running on to the road in a school zone, braking by a vehicle in front of you, 
and an animal running onto the road. These assessments will also be completed while you are 
required to perform a second task during the scenario, such as pressing a button when your side 
mirror is covered. This visit should take less than an hour. 
 
The saliva draw will be completed in the Sanders building, room SB-1025, Lakehead 
University. For the saliva draw, you will be asked not to brush your teeth, smoke, eat, or drink 
for 2 hours before saliva collection. You will also be asked not to consume alcohol for 12 hours 
before saliva collection. You will passively drool into a tube, which will be collected and 
analysed in a lab for brain-derived neurotrophic factor (BDNF). Higher levels of BDNF have 
been associated with improvements in mental functioning. 
 
Following the baseline assessments, you will be assigned to either the AET group or SC 
group. If you are assigned to the AET group, you will begin a three days per week, eight week 
AET intervention.  If you are assigned to the SC group, you will continue with your current PCS 
treatment. All AET sessions will be completed at the Sanders building, Lakehead University, 
under the supervision of a trainer that has the Canadian Society of Exercise Physiology Certified 
Personal Trainer (CSEP-CPT) certification. For all sessions, you will wear a heart rate monitor to 
measure exercise intensity. The aerobic portion of the session will be completed on a stationary 
bicycle. During week one, you will complete a five minute warmup, followed by 20 minutes of 
cycling at a low intensity. From week to week, the duration and intensity will be adjusted to 
gradually increase difficulty. 
 
 
Following the aerobic portion of each session, you will complete a series of balance 
exercises. These exercises will be the same as completed during the preliminary test. In week 
one, difficulty will be kept low. As with the aerobic portion of the session, difficulty will be 
increased from week to week. Difficulty will be increased by adjusting duration, surface (firm or 
soft), and if your eyes are open or closed during the exercises. Each session will conclude with a 
cooldown consisting of static stretching. 
 
After eight weeks you will repeat the baseline testing. If you were in the SC group, you 
will be offered the AET intervention following completion of the study. You will be able to keep 
the activity monitors following completion of the study.  
 
What will happen during this study? 

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You will be randomly assigned to either the AET or the SC group upon consent. We will 
be using randomization software that will help balance enrolment numbers in each group. 
Because of this, the chance that you will be placed in either group is not exactly 50/50, but it is 
still a random assignment. The participants placed in the SC group will be offered the AET once 
their participation in the study is complete, and this will not be included in data analysis. Below 
you will find an overview of the study for participants assigned to the AET and SC interventions. 
 
 
AET Overview 
Week 
1 & 10 
  
  
  
2-9 
Event 
ImPACT & 
balance 
Reaction 
test 
Driving 
simulation 
Saliva 
AET 
intervention 
Time Required  
1 hour 
2 hours 
1 hour 
15 
minutes 
1 hour, 3x per 
week 
 
SC Overview 
Week 
1 & 10 
  
  
  
2-9 
Event 
ImPACT & 
balance 
Reaction 
test 
Driving 
simulation 
Saliva 
SC intervention 
Time Required  
1 hour 
2 hours 
1 hour 
15 
minutes 
No required 
appointments 
 
 
How many people will take part in this study? 
It is anticipated that 60 participants will be recruited into this study. Recruitment, data 
collection and analysis will continue over the span of 6 months. Your direct participation, 
however, will only last 9-10 weeks depending on scheduling of the preliminary and final 
assessments. 
 
What are the risks or harms of participating in this study? 
No serious side effects or risks such as stroke, heart attack or death are anticipated due to 
participation in this study. During the driving simulation, there is a small chance that you will 
experience dizziness or nausea. If this happens, the simulation will be paused to allow you to 
rest, or stopped completely. 
 
Low intensity aerobic and balance exercise has minimal risk for healthy individuals. Like 
all types of exercise, there is a small risk of experiencing an injury such as a sprain or strain. 
There is a small risk when performing aerobic and balance exercises while experiencing PCS; 
participants may see an increase or worsening of his/her symptoms. In order to reduce this risk, 
exercise will be very easy to begin, and gradually get harder over the eight weeks. All exercise 
sessions will be monitored by a research team member to ensure that the session is being 
completed at the proper intensity. Should you report any signs of PCS during a session, the 
session will be stopped immediately. Furthermore, to ensure that you are healthy enough to 
participate in exercise, all participants will be medically cleared by Dr. Wark prior to 
participating in the study. 

 
46
 
What are the benefits of participating in this study? 
While we are unsure of the direct benefit to you, the participant, there is the 
Possibility that AET and SC will improve your PCS symptoms. The purpose of this study is to 
gather this information and our research may impact how people suffering from PCS are treated. 
Research investigating PCS and AET is important work and this study will serve to expand the 
knowledge in this field.  
 
Can participation in this study end early? 
Your participation in this study may end early if you choose to withdraw for any reason. 
If you wish to withdraw consent from the study, you will be asked to specify if you wish for any 
data or samples collected to be withdrawn as well. Samples and data will be withdrawn in 
accordance with your wishes. We want to assure you that whether you choose to participate or 
not participate in the study, your medical care will not be affected in any way. You are under no 
obligation to participate in this study, and you may choose to withdraw from it at any point by 
contacting Dr. Carlos Zerpa (807-343-8940), the primary contact for this study. Participation, 
refusal to participate, or withdrawal from participation will not in any way affect your care from 
Dr. Wark or your primary care physician/healthcare provider. During the course of the research 
project, you will be given all information that is relevant to your decision to continue or 
withdraw from the study, as well as information on your right to request the withdrawal of 
collected data.  
 
What are the costs of participating in this study?  
There are no fees associated with participation in the research. If you choose to park at 
the assessment locations, there are fees associated with these parking lots. Parking fees at 
Lakehead University for study visits will be reimbursed.  
 
What happens if I have a research related injury?  
There is no compensation or insurance coverage for research-related injuries, however, 
we do not anticipate any to occur during your participation in this study. Please note that by 
consenting to participate in this study, you have not waived any rights to legal recourse in the 
event of research-related harm. 
 
Are study participants paid to participate in this study?  
There will be no prorated payments. Parking costs for study visits at Lakehead University 
will be reimbursed. Upon completion of the study, you will be able to keep the activity monitors. 
 
How will my information be kept confidential?  
As described above, all personal data (test scores and saliva samples) that are collected 
will be de-identified through a coding process, and only the research team will have access to 
this data and the samples. Collected hard copies of the data will be stored in a secure file cabinet 
in a locked office. Computer data will be kept on a secure server on a password protected 
computer. Saliva samples will be stored in a secure laboratory at NOSM until analysis, after 
which they will be securely disposed of. All data/samples will be stored for a minimum of five 
years. When the study is finished, we will write up our aggregate results, that is, data which is 
combined and summarized so that no individual participant can be identified in manuscripts. 

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Post-Concussive Symptoms 
 
 
47
These manuscripts may then be published in academic journals. We will also present our results 
at academic conferences. If you are interested in the results of the study, we can arrange to have 
those results sent to you. Please ask a member of our team; we would be happy to provide them 
to you. Dr. Carlos Zerpa will be the sponsor for this study, and the research team as a whole will 
act as study monitors and auditors. These people, as well as the research ethics boards at 
TBRHSC will be granted access to the information you provide and data collected as a result of 
your participation in this study for verification of clinical trial procedures/data without violating 
your confidentiality to the extent permitted by the applicable laws and regulations. A description 
of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 
Do the investigators have any conflicts of interest? 
There will be no commercialization of the study findings by the researchers. There are no 
real, potential, or perceived conflicts of interest on the part of the researchers, their institutions, 
or the research sponsors. None of the research team members will receive a fee for your 
enrollment.  
 
What are the rights of participants in a research study?  
If you have any questions regarding this study, please feel free to contact the research 
team. The primary contact for this study is Dr. Carlos Zerpa and he can be reached at 807- 343-
8940; czerpa@lakeheadu.ca. This project has been approved by the ethics board at TBRHSC. If 
you have any concerns regarding your rights as a research participant, or wish to speak to 
someone other than a research team member about this research project, you are welcome to 
contact the: 
 
 
Chair, Research Ethics Board  
Thunder Bay Regional Health Sciences Centre 
 Phone: 807-684-6422  
Fax: 807-684-5904  
Email contact for REB: TBR_REO@tbh.net  
 
 
We understand that you may need some time to consider your participation, so you may take at 
least 24 hours to assimilate the information provided, pose any questions you may have, and 
discuss and consider whether you will participate.  
 
We thank you for your time, 
 
Dr. Sheryl Wark, 
           Dr. Simon Lees, 
Dr. Paolo Sanzo, 
Dr. Jane Lawrence-Dewar 
Dr. Carlos Zerpa                    Sarah Niccoli  
Dr. Michael Wesner             
 

 
48
 
 
 
 
16.3 Screening checklists 
 
Inclusion/Exclusion Criteria Screening Checklist- PCS 
Participant number ______________ 
 
o Person aged 18-50 years 
 
o Fluent in English 
 
o Experience injury greater than 2 weeks ago? 
 
o Experienced injury less than 6 months ago? 
 
o Not diagnosed with psychological/neurological disorder 
 
o Not diagnosed with depression 
 
o Not currently seeking counselling/therapy for depression 
 
o Has valid drivers license with 12 months driving 
experience 
 
 
 

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V 1.5: November 30th, 2018                                                                                                                      
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
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Inclusion/Exclusion Criteria Screening Checklist- HC 
Participant number ______________ 
 
o Person aged 18-50 years 
 
o Fluent in English 
 
o Not diagnosed with psychological/neurological disorder 
 
o Not diagnosed with depression 
 
o Not currently seeking counselling/therapy for depression 
 
o Has valid drivers license with 12 months driving 
experience 
 
 
 
 
 
 
 

 
50
 
 
 
 
 
 
 
 
16.4 Data abstraction form 
 
 
 
 
 
 
Participant Number:__________________ 
Consent Date: 
__________________________ 
Sex (male/female) 
  
Height (cm) 
  
Weight (kg) 
  
Age (in years) 
  
  
  
Date of injury 
  
Date of first assessment  
  
Past Medical History 
(Y/N) 
Concussion 
  
How 
many? 
  
Traumatic brain injury 
  
Migraine 
  
ADHD 
  
Motion sickness 
  
 
 
 
 
 

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V 1.5: November 30th, 2018                                                                                                                      
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
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16.5 International Physical Activity Questionnaire
 

 
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V 1.5: November 30th, 2018                                                                                                                      
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16.6 Study budget
 

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V 1.5: November 30th, 2018                                                                                                                      
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
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 RP-506-07112017                                                                                                                                                                                         
V 1.5: November 30th, 2018                                                                                                                      
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
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 RP-506-07112017                                                                                                                                                                                         
V 1.5: November 30th, 2018                                                                                                                      
Multi-modal Evaluation of a Physical Intervention Approach to Treating Persistent 
Post-Concussive Symptoms 
 
 
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