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Cerebral blood flow velocity : does it play a role in symptom exacerbation during exercise in concussed… Marsden, Katelyn Randi Lee 2013

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CEREBRAL BLOOD FLOW VELOCITY: DOES IT PLAY A ROLE IN SYMPTOM EXCAERBATION DURING EXERICSE IN CONCUSSED ATHLETES?   by  Katelyn Randi Lee Marsden   B.H.K., The University of British Columbia, 2011   A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF   MASTER OF SCIENCE   in   THE COLLEGE OF GRADUATE STUDIES   (Interdisciplinary Graduate Studies)   (Health and Exercise Sciences)   THE UNIVERSITY OF BRITISH COLUMBIA    (Okanagan)   October 2013    ? Katelyn Randi Lee Marsden, 2013  ii Abstract  Exercise frequently results in exacerbation of symptoms following a sports-related concussion (SRC). However, the mechanism(s) behind this phenomenon has yet to be determined. It is possible that an inability to regulate cerebral blood flow (CBF) may lead to over-perfusion, and thus cause the exacerbation of symptoms seen during exercise. It was hypothesized that: 1) CBF velocity during exercise will be greater in SRC. 2) Severity of symptoms will be correlated with CBF velocity during exercise and 3) day-to-day variability in CBF velocity will be greater in SRC compared to control subjects. Subjects refrained from caffeine, alcohol and exercise 24hrs prior to testing.  Blood velocity was monitored using transcranial Doppler targeting both the middle and posterior cerebral artery (MCAv and PCAv). Exercise was performed on a stationary bike at 30% and 70% predicted heart rate reserve (HRR) for 2-3 minutes and changes in MCAv and PCAv were compared to baseline at rest. Symptoms were evaluated using SCAT2 pre and post-exercise. Subjects included 6 subjects (5 males and 1 female) diagnosed with sport-related concussion (mean ? standard deviation; age: 17.5?2 years, BMI: 24?1 kg/m2) and 6 healthy control-subjects (5 males and 1 female; age: 20?2 years, BMI: 22?2 kg/m2). Concussed subjects were tested at the same time of day on Day 4?1, Day 8?1, Day 17?3 and Day 29?1 following injury. Assessment of day-to-day variability also conducted using the test-retest method with the inclusion of a subgroup of control subjects (n=12).  Results demonstrated that 1) there was no effect of concussion on resting MCAv or PCAv over the month post-injury. In addition, no effect of concussion was seen on the relative changes in MCAv or PCAv at either 30% or 70% HRR. 2) A linear regression revealed a relationship between the increase in both number and severity of symptoms and MCA velocity response to 70% HRR (R2 = 0.37). 3) Concussion did not significantly change day-to-day  iii variability over the course of testing. Taken together, these results demonstrate that SRC does not significantly impact CBF responses during mild to moderate exercise; however, MCAv response may play a role in symptom exacerbation during exercise.  iv Preface This study was approved by the University of British Columbia Clinical Research Ethics Board (H11-02900). Data were collected at the University of British Columbia (Kelowna, BC), by Dr. Paul van Donkelaar, Dr. Philip Ainslie, Dr. Brad Monteleone help with the design, equipment acquisition and funding for the study.  Kurt Smith, Nicole Strachan and Katelyn Marsden were responsible for the overall implementation and execution of the study. Kurt Smith helped with technical assistance and study implementation. Nicole Strachan and Katelyn Marsden coordinated both subject recruitment and data collection.  Katelyn Marsden was also responsible for study implementation, study promotion, analyzed all of the data, including statistical analyses and was responsible for writing the manuscript.  An abstract based on the preliminary findings discussed in this thesis has been accepted for a poster session at the Neuroscience conference in San Diego, 2013. Katelyn R. Marsden, Nicole C. Strachan, Brad J. Monetelone, Philip N. Ainslie and Paul van Donkelaar. (2013). Is post-concussion symptom exacerbation during exercise related to an inappropriate cerebral blood flow response? Katelyn Marsden was responsible for the data collection, data analysis, writing, and formatting of the abstract and poster.         v Table of Contents Abstract ................................................................................................................................. ii Preface ................................................................................................................................. iv Table of Contents .................................................................................................................. v List of Tables ........................................................................................................................ vii List of Figures ..................................................................................................................... viii List of Equations .................................................................................................................... x List of Abbreviations ............................................................................................................. xi Acknowledgements .............................................................................................................xiv Dedication ...........................................................................................................................xvi  Introduction ....................................................................................................... 1 1    Chapter: Cerebral Blood Flow ........................................................................................................... 2 1.1 Cerebral Circulation ........................................................................................................... 2 1.2 Cerebral Blood Flow Regulation ......................................................................................... 4 1.31.3.1 Cerebral Perfusion Pressure ........................................................................................ 5 1.3.2 Cerebral Vascular Resistance ...................................................................................... 6 1.3.2.1 Partial Pressure of Arterial CO2 .............................................................................. 7 1.3.2.2 Cerebral Autoregulation ......................................................................................... 8 1.3.2.3 Cerebral Blood Flow Regulation during Exercise.................................................... 9  Sport-Related Concussion ................................................................................................ 12 1.41.4.1 Incidence Rates ......................................................................................................... 13 1.4.2 Signs and Symptoms .................................................................................................. 15  Cerebral Pathophysiology following Concussion ............................................................. 16 1.51.5.1   The Neurometabolic Cascade .................................................................................... 17 1.5.2   Alterations in Cerebral Blood Flow and Metabolism................................................. 18 1.5.3   Alterations in Cerebrovascular Reactivity to CO2 ...................................................... 21 1.5.4   Alterations in Cerebral Autoregulation ..................................................................... 22 1.5.5   Role of Cerebral Blood Flow in Symptom Exacerbation during Exercise .................. 24  Purpose ............................................................................................................................ 26 1.6 Aims .................................................................................................................................. 26 1.7 Hypotheses ....................................................................................................................... 27 1.8 Methods ........................................................................................................... 28 2    Chapter: Subject Characteristics ..................................................................................................... 28 2.1 Subject Recruitment and Inclusion Criteria ..................................................................... 28 2.2 Instrumentation ............................................................................................................... 30 2.32.3.1 Cardiovascular Measures .......................................................................................... 30 2.3.2 Cerebral Blood Velocity Measures ............................................................................ 30  Transcranial Doppler Ultrasound ..................................................................................... 31 2.42.4.1 Transcranial Doppler Principles ................................................................................. 32 2.4.2 Vessel Insonation ...................................................................................................... 34 2.4.3 Validity of transcranial Doppler ................................................................................ 35  Pre-testing Guidelines ...................................................................................................... 36 2.5 vi  Experimental Design and Outcome Measures ................................................................ 36 2.62.6.1 Post-Concussion Symptom Evaluation ...................................................................... 36 2.6.2 Cerebral Blood Flow Velocity during Exercise ........................................................... 37  Statistical Analysis ............................................................................................................ 39 2.72.7.1 Day-to-Day Variability Analysis ................................................................................. 40 2.7.1.1 Coefficient of Variation ....................................................................................... 41 2.7.1.2 Intra-class correlation coefficient ....................................................................... 41 2.7.1.3 Technical Error of Measurement ........................................................................ 41  Results ............................................................................................................. 43 3    Chapter: Rest ................................................................................................................................... 43 3.1 Mild to Moderate Exercise ............................................................................................... 47 3.2 Symptoms and MCA and PCA Velocity Response ............................................................ 57 3.3 Day-to-Day Variability ...................................................................................................... 61 3.43.4.1 Between-subject Variations in MCA and PCA Velocity Measures ............................ 61 3.4.2 Within-subject Variation in MCA and PCA Velocity Measures ................................. 65 3.4.3 Technical Error of Measurement .............................................................................. 66  Discussion and Conclusion ................................................................................ 67 4    Chapter: CBF velocity at rest in SRC ................................................................................................ 67 4.1 CBF velocity during exercise in SRC ................................................................................. 68 4.2 Symptom Exacerbation and MCA velocity ....................................................................... 70 4.3 Day-to-Day Variation ........................................................................................................ 73 4.4 Methodological considerations ....................................................................................... 74 4.54.5.1 Subject recruitment, Sample Size on Statistical Power ............................................ 74 4.5.2 Parametric vs. Non-parametric testing ..................................................................... 75 4.5.3 Missing Data .............................................................................................................. 76  Concluding remarks ......................................................................................................... 77 4.6 Future Directions.............................................................................................................. 78 4.7 Significance and Relevance .............................................................................................. 80 4.8Bibliography or References .................................................................................................. 82 Appendices: ......................................................................................................................... 97 Appendix A : Human Research Ethics ....................................................................................... 97 Appendix B : Recruitment Email ............................................................................................. 117 Appendix C : Informed Consent Form .................................................................................... 118 Appendix D : Prescreen Questionnaire .................................................................................. 124 Appendix E : Sport Concussion Assessment Tool 2 ................................................................ 128   vii List of Tables  Table 1.1   The four major features of concussion at determined by the Concussion in Sport Group    in Zurich 2012 (McCrory et al, 2013). ................................................................................. 13  Table 2.1   Individual characteristics of the concussed athletes that participated in the study. ......... 28  Table 3.1   Comparison of anthropometric and resting data of concussed athletes (SRC) and       control subjects (CS) on Day 3. ........................................................................................... 44  Table 3.2   Comparison of cardiovascular and gas exchange variables between controls (CS) and   concussed (SRC) during exercise. ........................................................................................ 49  Table 3.3   Comparison of absolute cerebrovascular variables between controls (CS) and        concussed (SRC) during exercise. ........................................................................................ 50  Table 3.4   Comparison of relative MCA and PCA velocity response to mild-moderate exercise between controls (CS) and concussed (SRC) subjects during exercise. .............................. 51  Table 3.5   Regression analysis between changes in symptoms against relative MCA and PCA velocities during 70% of predicted heart rate reserve in symptomatic concussed      athletes. .............................................................................................................................. 60  Table 3.6   The coefficient of variation of absolute MCA and PCA velocities at rest and during   exercise in a subset control subjects (N=12). ..................................................................... 61  Table 3.7   The coefficient of variation of absolute MCA and PCA velocities at rest and during   exercise for concussed (N=6) and control (N=6) groups across visits. ............................... 63  Table 3.8   Intra-class correlation coefficient of absolute MCA and PCA velocities at rest and        during exercise in a subset control group (N=12). .............................................................. 65                  viii List of Figures  Figure 1.1   Schematic representation of the cerebral arterial system ........................................... 4  Figure 1.2   An adapted schematic representing the main factors in CBF regulation and their relationship with cerebral blood flow within physiological ranges of arterial CO2, arterial BP and neural activity (Adapted from (Willie et al, 2012, Ainslie and Duffin, 2009, Lucas et al, 2010)). The red dashed line represents the ?classical? definition    of CA by Lassen in 1959. ................................................................................................ 7  Figure 1.3   A graphical representation of the normal CBF response during graded exercise (adapted from (Sato et al, 2011)). Middle cerebral artery velocity (MCAv), internal carotid artery flow (ICA), vertebral artery flow (VA), partial pressure of end-tidal carbon dioxide (PETCO2), and maximal oxygen consumption (VO2max). ...................... 12  Figure 2.1   A pictorial representation of equipment instrumentation for the experimental protocol. ...................................................................................................................... 32  Figure 2.2   A diagram of the testing interval used to assess subjects over the course of                 1-month. ...................................................................................................................... 36  Figure 2.3   A depiction of the experimental protocol used to quantify CBF velocity response during sub-maximal exercise in SRC. Middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv), heart rate (HR), blood pressure (BP),       30% and 70% predicted heart rate reserve (30% HRR and 70% HRR). ....................... 39  Figure 3.1   Resting averages of cardiovascular and gas-exchange variables across the four    testing days in concussed athletes (black dots) and controls subjects (white dots). . 45  Figure 3.2   Resting PCA (top) and MCA (bottom) velocities across one month of testing in concussed (black dots) and control (white dots) subjects. ......................................... 46  Figure 3.3   Relative change in MCA (left) and PCA (right) velocities during the exercise         protocol in concussed athletes (black dots) and control group (white dots),     displayed for all four testing days................................................................................ 52  Figure 3.4   Each individual concussed athlete?s (SRC) relative MCA velocity response across      four testing sessions; Day 3, 7, 14 and 30 ................................................................... 53  Figure 3.5   Change in cerebrovascular resistance in the MCA (left) and the PCS (right) during exercise over the four testing days in concussed athletes (black dots) and control subjects (white dots). .................................................................................................. 54    Figure 3.6   Changes in mean arterial blood pressure (MAP; Left), systolic blood pressure (SBP; middle) and diastolic blood pressure (DBP; right) during exercise over the four     ix testing days in concussed athletes (black dots) and control subjects (white dots). Significant difference between groups is indicated by * (p<0.05). ............................. 55  Figure 3.7   Changes in heart rate (HR; left) and partial pressure of end-tidal CO2                   (PETCO2; right) during exercise over the four testing days in concussed athletes     (black dots) and control subjects (white dots). Significant difference between      groups is indicated by *(p<0.05). ................................................................................ 56  Figure 3.8   Reported number of symptoms and symptoms severity pre-testing (black shade)    and post-exercise (grey shade) across the four testing sessions in symptomatic concussed athletes. Significant difference between Day 3 pre-testing score across days is indicated by * and difference between Day 30 post-testing scores across    days is indicated by A (p<0.05). .................................................................................... 59  Figure 3.9   This regression plot shows the relationship between the dependent variable (MCA velocity at 70% HRR) and the standardized predicted values (using the change in number of symptoms and symptom severity) in symptomatic concussed athletes. Significance is indicated by * (p<.05). ......................................................................... 60  Figure 3.10 A graphical representation of the coefficient of variations for both the MCA (top)   and PCA (bottom) velocities at rest, 30% and 70% heart rate reserve (HRR) in a subgroup of control subjects (n=12) over two days of testing. .................................. 62  Figure 3.11 A graphical representation of the coefficient of variations in both the concussed  (top; n=6) and control (bottom; n=6) group for both the MCA (left) and PCA (right) velocities at rest, 30% and 70% heart rate reserve (HRR) over the four days of  testing. ......................................................................................................................... 64  Figure 3.12 Depicted here are the individual data between the two repeated measures for the PCA (top) and MCA (bottom) velocities at baseline, 30% and 70% heart rate reserve(HRR) in a subgroup of controls subjects (n=12) used to calculate the intra-class correlation coefficients. ...................................................................................... 66                x List of Equations Equation 1.1  Ohm?s Law???????????????????.?????????????????????4 Equation 1.2 Cerebral Blood Flow???????????????????????????????????4 Equation 1.3  Cerebral Perfusion Pressure??????????????????????????????.5 Equation 1.4 Poiseuille?s Law??????????????????????????????.???????.6 Equation 2.1 Doppler Shift??????????????????????????????????????.33 Equation 2.2 Predicted 30% Heart Rate Reserve??????????????????????????38 Equation 2.3 Predicted 70% Heart Rate Reserve??????????????????????????38 Equation 2.4 Mean Cerebral Blood Flow Velocity?????????????????????????.39 Equation 2.5 Relative Cerebral Blood Flow Velocity?????????????.??????????..39 Equation 2.6 Cerebrovascular Resistance?????????????????????????????..39 Equation 2.7 Coefficient of Variation????????????????????????????????.41 Equation 2.8 Technical Error of Measurement?????????????????.?????????..42 Equation 2.9 Relative Technical Error of Measurement?????????????..????????.42               xi List of Abbreviations  ACA  Anterior cerebral artery ANOVA Analysis of variance  ATP  Adenosine triphosphate BMI  Body mass index BP  Blood pressure CA  Cerebral autoregulation CBF  Cerebral blood flow CBFv30%HRR Cerebral blood flow velocity at 30% heart rate reserve CBFv70%HRR  Cerebral blood flow velocity at 70% heart rate reserve CBFvbaseline Cerebral blood flow velocity at baseline CCI  Controlled cortical impact CIS  Concussion in Sports Group CMRO2 Cerebral metabolic rate of oxygen CO2  Carbon dioxide CV  Coefficient of variation  CPP  Cerebral perfusion pressure CT  Computed tomography CVR  Cerebrovascular Resistance DBP  Diastolic blood pressure DTI  Diffusion tensor imaging fMRI  Functional magnetic resonance imaging HR  Heart rate  xii HRR  Heart rate reserve ICA  Internal carotid artery ICC   Intra-class correlation coefficients ICP  Intracranial Pressure MAP  Mean arterial pressure MCA  Middle cerebral artery MRI  Magnetic resonance imaging MRS                  Magnetic resonance spectroscopy mTBI   Mild traumatic brain injury O2  Oxygen PaCO2  Partial pressure of arterial carbon dioxide PaO2  Partial pressure of arterial oxygen PCA  Posterior cerebral artery PET  Positron emission tomography PETCO2  Partial pressure of end-tidal carbon dioxide PETO2  Partial pressure of end-tidal oxygen SBP   Systolic blood pressure SCAT2  Concussion-specific symptom evaluation questionnaire SD  Standard deviation SPECT  Single-photon emission computed tomography SRC  Sport-related concussion TBI  Traumatic brain injury VA  Vertebral artery   xiii VA  Alveolar ventilation  VCO2  Production of CO2 VO2max  Maximal oxygen consumption  VO2peak  Peak oxygen consumption    xiv Acknowledgements I would like to acknowledge the National Science and Engineering Research Committee for supporting my academic endeavors here at UBC Okanagan under Dr. Phil Ainslie and Dr. Paul van Donkelaar, as well as my research term abroad, in Ljubljana Slovenia under Dr. Shawnda Morrison and Dr. Igor Mekjavic. I gained invaluable amount of experiences and expertise by being able to be to participate in various research projects here at UBC Okanagan and around the world.  A large thank you goes to my committee for all their hard work and support in completing this project. My committee includes:  Dr. Philip Ainslie, Dr. Paul van Donkelaar, Dr. Brad Monteleone and Dr. Patrick Neary. Thank you Dr. Ainslie for all the amazing opportunities you have given me over the last four years. And to Dr. van Donkelaar for taking me under your wing and giving me a place within your lab.  An especially large thanks also goes to all of the subjects who participated in this study.  I would especially like to acknowledge our concussed athletes, for sticking in there to the end. Without their efforts, this study would have never been able to occur.  In addition, without the efforts of Nicole Strachan, subject recruitment and data collection would have been near next to impossible. Thanks for being a supportive and collaborative friend and colleague.  To all of my peers (Jinelle Gelinas, Nicole Strachan, Collin Wallace, Bobby Hermosillo, Sandy Wright, Kurt Smith, Jon Smirl, Tanis Burnette, Nia Lewis, Graeme Koelwyn, Darian Cheung and Francisco Colino), for the many philosophical and physiological discussions that took place in and around the lab. All of your unique and different takes on life and science has helped to open and broaden my way of thinking.   xv  Last, but definitely not least, I would like to thank all of my friends and family for their enduring support and encouragement. To my parents who always believed in me and to Jinelle Gelinas, for always being there.   xvi Dedication    To the people who have inspired us, whose presence in our lives has changed the paths we have taken. Thank you Mr. Craigen, for opening my eyes to the world of science and for igniting a passion that will live forever.  1  Introduction  1    Chapter:Sport-related concussions (SRC) in young athletes have become both an important individual and public health concern (Halstead et al, 2010, Cohen et al, 2009, Guskiewicz and Valovich McLeod, 2011, Meehan et al, 2011, Schatz and Moser, 2011, Wiebe et al, 2011). In the United States alone, SRC occur approximately 1.6 to 3.8 million times per year (Langlois et al, 2006) and account for 20% of $56 billion spent annually on traumatic brain injuries (Mihalik et al, 2005). In Ontario the calculated incidence rates of hospital treated mild traumatic brain injury (mTBI) were 426/100,000 by expert diagnosis; including family physician diagnoses these rates increased to 653/100,000 (Ryu et al, 2009).  Concussions clinically manifest as one or more neurological, behavioral or physical symptoms. These symptoms are exacerbated during physical exertion (McCrory et al, 2009, McCrory et al, 2013, Majerske et al, 2008). The underlying impairments are likely due to neuropathological changes that occur after the injury. Despite the high incidence rates and well-characterized nature of the symptoms of concussion (Johnson et al, 2011, Lau et al, 2011, Taylor et al, 2010, McClincy et al, 2006), the pathophysiology behind symptom exacerbation is not well understood. As such, a new and emerging area in research on concussion pathophysiology is cerebral blood flow (CBF) and the factors affecting CBF regulation (Len and Neary, 2011). As such, this review will first concentrate on CBF regulation at rest and during exercise in healthy humans. Next, focus will be placed on describing CBF regulation following a concussion and how such changes may be important in the pathophysiology of symptom exacerbation.     2  Cerebral Blood Flow 1.1The brain is a highly metabolically active organ that consumes 3.5 ml/100g tissue/min of oxygen (Rowell, 1993), which is matched by approximately 50 ml/100g tissue/min of blood flow at rest (Lassen, 1985). This makes the brain one of the most highly perfused organs relative to its body weight; as it constitutes about 2% of our total body weight but consumes 15-20% of our total cardiac output (Shulman et al, 2004). Because the brain is highly dependent on oxygen to fuel itself, it can only withstand very short periods of low blood supply. For example, the when there is a lack of oxygen, the brain can only last up to 10 seconds before losing consciousness. Therefore adequate CBF must be maintained to ensure a constant delivery of oxygen and nutrients for full cognitive functioning and cell viability. This is most true in the face of everyday physiological disturbances to the body such as exercise or postural change (i.e. standing up); where there is a rapid change in blood pressure and may cause CBF to be transiently altered. The maintenance of CBF is accomplished through multiple regulatory mechanisms, which include, but are not limited to: neural activity/metabolism, arterial blood pressure (BP) and arterial carbon dioxide (CO2).    Cerebral Circulation 1.2The cerebral circulation encompasses a network of blood vessels that supply the brain with blood. The arterial circulation delivers oxygen (O2) and essential nutrients, while the venous circulation carries away deoxygenated blood and metabolic by-products such as CO2. An overview of the cerebral arterial system is depicted in Figure 1.1.  CBF is supplied to the human brain through two pairs of bilateral arteries; the internal carotid arteries (ICA) and the vertebral arteries (VA); which contribute 70% and 30% of total CBF (Scheel et al, 2000) respectively. In  3 the cerebral venous circulation, blood is drained via the cerebral veins and dural sinuses into the internal jugular veins. The ICA branch off the common carotid arteries in the neck and enter the skull where it branches off into the middle and anterior cerebral arteries (MCA and ACA respectively).  While on the other hand, the VA branch off the subclavian arteries, entering deep to the transverse process of the cervical vertebrae and enter the skull through the foramen magnum and fuses into the basilar artery and then the posterior cerebral arteries (PCA). Ultimately, the basilar artery interconnects to the ICA and other communicating arteries to form the circle of Willis (Cipolla, 2009).  The three main cerebral arteries within the circle of Willis include the: ACA, MCA and PCA.  The ACA and MCA supplies the anterior and lateral portions of the brain including the frontal, temporal and parietal lobes, whereas, the PCA supplies the occipital lobe, cerebellum and brainstem.  These three main cerebral arteries progressively divide into smaller arteries and arterioles and eventually penetrate the brain tissue to supply their respective cortical regions. The configuration of the circle of Willis provides a safe guard in case one artery becomes occluded and therefore diverts possible ischemia.   4  Figure 1.1 Schematic representation of the cerebral arterial system  (Public Source: Wikipedia).   Cerebral Blood Flow Regulation 1.3Blood flow is governed by many physical properties, which are the same that govern flow of any fluid under steady-state conditions and are based on Ohm?s Law.  Ohm?s law states that blood flow is the difference between pressure gradient (?P; also called perfusion pressure) and the resistance to flow (R).  This relationship can be summarized by the following equation:                         F = (?P)/ R                                                    Equation 1.1 Where: F = flow, ?P = pressure gradient and R = resistance. Based on the Ohm?s Law, CBF under steady state conditions can be broadly described by two groups of factors: those affecting cerebral perfusion pressure (CPP) and those affecting cerebrovascular resistance (CVR).                                                            CBF = CPP/ CVR                                               Equation 1.2   Middle Cerebral Artery  Anterior Cerebral Artery  Internal Carotid Artery   Posterior Cerebral Artery  Posterior Communicating Artery Basilar Artery  Vertebral  Artery   5 1.3.1 Cerebral Perfusion Pressure The cerebral circulation provides blood distribution within the brain; however, to adequately supply blood to the brain tissue there must be sufficient pressure within the system. In the brain, CPP is the gradient between the arterial and venous systems. CPP is calculated as the difference between mean arterial pressure (MAP) and central venous pressure; where central venous pressure is approximated by intracranial pressure (ICP) as ICP reflects the surrounding pressure within the skull and may buffer changes in venous pressure.                                                                CPP = MAP ? ICP                                                   Equation 1.3 CPP is approximated to be around 80 millimeters of mercury (mmHg) in healthy adults. Clearly, any changes in either MAP or ICP could affect CPP and hence CBF.  However, an increase in CPP is usually a result of an increase in MAP, as any contribution made by ICP usually is accompanied by a pathological state (hematoma), vasospasm or trauma.  On a daily basis, the brain is subjected to changes in MAP during exercise or postural changes for example. Despite these regular surges in MAP, however, CBF remains relatively constant over a wide range of CPPs (Lassen, 1959, Paulson et al, 1990). This is achieved by a process called cerebral autoregulation (discussed below; section 1.3.2.2). The maintenance of CPP and CBF through autoregulation is made possible through altering resistance, primarily changes through vessel radius.  Although most segments of the arterial system seem to react to various physiological stimuli (large arteries; (Willie et al, 2012), intracranial cerebral arteries; (Giller et al, 1993), and pial arterioles; (Kontos et al, 1978)), vascular resistance is primarily mediated by the pial arterioles. However, there is substantial evidence in animal models that the large arteries may actually contribute up to 50% of cerebrovascular resistance (Heistad et al, 1978, Faraci et al, 1987) under resting conditions. A recent human study by Willie and colleagues (2012) also  6 demonstrated that both the ICA and VA were reactive to changes in PaCO2 (15-65mmHg) with a 20% change in ICA diameter.   1.3.2 Cerebral Vascular Resistance Resistance exists because of friction and can be induced by a multitude of factors. Based on the relationship described by Poiseuille?s law (Equation 1.4) where; F=flow, ?P = pressure gradient, r=radius, ?= viscosity of the fluid, L=length, it emphasizes that the radius of a vessel (r); which is to the fourth power, is the most influential factor on flow dynamics. The large effect of radius compared to other variables described in Poiseuille?s law has important physiological implication, as it allows for enough time for adequate gas and nutrient exchange to occur in the capillary networks (Cipolla, 2009).                  F = ?P ?r4/8?L                                                   Equation 1.4 The principle factors regulating CBF through alterations in vascular tone include; arterial partial pressure of CO2 (PaCO2), arterial BP and neural/metabolic activity (Figure 1.2). However, it is important to stress that while most pressure-flow relationships are characterized by using the steady-state equations such as Ohm?s (Equation 1.1) and Poiseuille?s law (Equation 1.4), these equations may not be sufficient to describe non-steady state conditions (reviewed in (Tzeng and Ainslie, 2013), because these equations do not consider other variables such as cardiac output (Ogoh et al, 2005a).   7            Figure 1.2 An adapted schematic representing the main factors in CBF regulation and their relationship with cerebral blood flow within physiological ranges of arterial CO2, arterial BP and neural activity (Adapted from (Willie et al, 2012, Ainslie and Duffin, 2009, Lucas et al, 2010)). The red dashed line represents the ?classical? definition of CA by Lassen in 1959.  1.3.2.1 Partial Pressure of Arterial CO2  The cerebrovasculature is highly sensitive to changes in the partial pressure of arterial carbon dioxide (Kety and Schmidt, 1948). For example, an elevation in PaCO2   (hypercapnia) causes vasodilation and accompanies an increase in CBF, while a reduction in PaCO2 (hypocapnia) leads to vasoconstriction and a subsequent reduction in CBF (Ainslie and Duffin, 2009, Kety and Schmidt, 1948, Wasserman and Patterson, 1961). The main purpose for altering CBF for a given change in PaCO2 helps to ?wash-out? CO2 in order to regulate and maintain central pH within the brain (Ainslie and Duffin, 2009, Chesler, 2003). It is thought that the cerebrovascular responsiveness to changes in PaCO2 is mediated directly by H+ or pH variations (Pannier et al, 1971), rather than PaCO2 itself. Cerebrovascular reactivity to CO2 may differ between the hyper- and hypocapnic ranges (Ide et al, 2003), but on average CBF typically increasing 4-5% for a given 1 mmHg rise in partial pressure of end-tidal CO2 [PETCO2; (Willie et al, 2012, Ogoh et al, 2008, Hurn and Traystman, 2002, Claassen et al, 2007)].     8 1.3.2.2 Cerebral Autoregulation Cerebral autoregulation (CA) is the intrinsic ability of the cerebrovasculature to alter vascular resistance in order to adjust CBF levels to match metabolic demands in response to changes in CPP (Tiecks et al, 1995, Aaslid et al, 1989, Zhang et al, 1998). Such CA can be described on a continuum of static to dynamic terms. Static CA refers to the relationship between CPP and CBF under steady state conditions, whereas, dynamic CA refers to the transient response of CBF to changes in CPP (i.e. standing up).  Lassen (1959) was the first to describe CA as the tendency of CBF to remain relatively constant over a wide range of mean arterial pressures of 60-150mmHg (Lassen, 1959, Paulson et al, 1990, Panerai, 2009). For example, as arterial blood pressure is increased, the cerebrovasculature reacts by vasoconstricting and therefore maintaining CBF.  However, more recently this classic definition of CA has been challenged. New evidence shows that CBF is more dependent on BP fluctuations than previously thought (Lucas et al, 2010).  Lucas and colleagues reported MCA velocity changes 8% per 10mmHg change in BP. This was found across both ranges of hypertension and hypotension. Another study by Tan and colleagues (2012) using a different non-linear based model (projection pursuit regression) to assess the pressure-flow relationship in healthy individuals and were able to consistently produce the same relationship between BP and CBF across individuals and testing days. The relationship Tan (2012) observed, similar to Lucas (2010), found an autoregulatory phase where slow pressure fluctuations are effectively dampened and pressure-dependent regions on both the left and right side of the autoregulatory phase (Tan, 2012) where pressure fluctuations became too fast to be effectively dampened by the vasculature. When CA becomes impaired or abolished, CBF becomes even more pressure-dependent and therefore even the smallest change in MAP can have a profound  9 effect on CBF and therefore the brain (i.e. hypotension- ischemic damage and hypertension- hemorrhage).    1.3.2.3 Cerebral Blood Flow Regulation during Exercise   While exercising, CBF becomes elevated between 10-30% during sub-maximal intensities (Ogoh and Ainslie, 2009, Secher and T, 2008, Ogoh et al, 2009, Sato et al, 2011) to meet the rising metabolic demand and neuronal activity within the brain (Linkis et al, 1995, Herholz et al, 1987). For example, Linkis and colleagues (1995) found the greatest increase in left MCA and ACA velocities during right-hand contractions and foot movement, suggesting there is a relationship between cortical activation and regional distribution of CBF.    Although CBF is partly determined by CPP, the increase in CBF during sub-maximal exercise cannot be explained by increases in MAP (Secher and T, 2008). Pott and colleagues (1997), for example, found that MCA velocity returned to baseline values despite an exercise pressor reflex-induced increase in MAP. Studies have shown that more dynamic fluctuations in MAP during the stroke phase of rowing (Pott et al, 1997) or rhythmic resistance exercise (Edwards et al, 2002) might be too rapid to be effectively countered by CA. Zhang and colleagues (1998) were the first to describe the relationship between CBF and CPP using transfer function analysis (within a frequency range of 0.07-0.3 Hz), which showed that dynamic CA is a frequency-dependent phenomenon. Recent studies have begun to use transcranial Doppler and transfer function analysis to assess dynamic CA during exercise (Brys et al, 2003, Ogoh et al, 2005c, Ogoh et al, 2005b). Brys and colleagues (2003) demonstrated that CBF variability remained stable during progressive elevations in exercise workload, while arterial BP variability increased. This was interpreted as implying that dynamic CA remains intact during exercise.  Two years  10 later, Ogoh and colleagues reported a loss of dynamic CA during the diastolic phase of exercise (Ogoh et al, 2005c) and during exhaustive exercise (Ogoh et al, 2005b); however, physiologically speaking, it is unclear how relevant a selective change in diastolic CA is when mean MCA velocity was not impaired. Based on the evidence available, it is most likely that dynamic CA is modified by exercise intensity, as not all exercise induces such a dramatic change in MAP (i.e. rowing, resistance training). For example, cycling exercise increases MAP and systolic blood pressure (SBP) by 20-30% with a slight decrease or no change in diastolic blood pressure (DBP; (Rowell, 1974)).  Remarkably, even with a progressive increase in MAP and SBP during graded exercise, CBF only increases 10-30% until approximately 60-70% of their peak oxygen consumption (VO2Peak). When an individual reaches between 60-70% VO2peak, CBF begins to return towards baseline values (Moraine et al, 1993, Hellstrom et al, 1996), regardless of the rise in cerebral metabolism, neural activation and MAP with increasing exercise intensity. As a result, it appears that the cerebrovasculature is well adapted in protecting the brain from over perfusion due to a rise in MAP that accompanies exercise.   The reduction in CBF is a result of exercise-induced hyperventilation at higher intensities, causing a reduction in PaCO2 and hence cerebral vasoconstriction.  This has important implications as it appears that PaCO2 may become the primary factor driving CBF at intensities >60-70% V02 peak (Moraine et al, 1993, Hellstrom et al, 1996, Rasmussen et al, 2006). However, low to moderate exercise intensities are also accompanied by an increase in PETCO2, which could explain, in part, the elevation seen in CBF. A relatively recent study reported a significant correlation between PETCO2 and MCA velocity at low work rates (R2= 0.79), however, this correlation was much stronger during moderate-high work rates (R2=0.91) as PETCO2 and MCA velocity decreased (Subudhi et al, 2008). The authors explained that the weaker correlation  11 between PETCO2 and MCA velocity at lower exercise intensities might be a product of a more integrative modulation of CBF (i.e. by-products of metabolism, PETCO2 and cardiac output) than at higher exercise intensities (i.e. primarily driven by changes in CO2). However, not all arteries are found to follow this trend in CBF. Sato and colleagues (2011) found that despite the gradual decrease in CBF in ICA and MCA velocity at intensities >60% VO2max, blood flow in the VA progressively increased (Figure 1.3). These findings indicate that there are regional differences in CBF distribution during graded exercise.  Although this review does not cover the exhaustive list of all the factors that have been shown to play a role in CBF regulation at rest (Peterson et al, 2011, Rudzinski et al, 2007) or during exercise (Ogoh and Ainslie, 2009, Secher and T, 2008, Querido and Sheel, 2007), the complexity of CBF regulation can be appreciated.  Nevertheless, these mechanisms are sensitive to both disease and trauma, where they can become blunted or abolished altogether. As a result, this can create cerebral instability and injury to the brain. In the case of concussion, the trauma translated through the brain is quite substantial and has been shown to affect both CBF and CBF regulatory mechanisms (i.e. reactivity to CO2 and CA; reviewed in (Len and Neary, 2011)). This next section of the literature review will provide an overview of SRC and the effect of concussion on cerebral physiology.  12  Figure 1.3 A graphical representation of the normal CBF response during graded exercise (adapted from (Sato et al, 2011)). Middle cerebral artery velocity (MCAv), internal carotid artery flow (ICA), vertebral artery flow (VA), partial pressure of end-tidal carbon dioxide (PETCO2), and maximal oxygen consumption (VO2max).     Sport-Related Concussion 1.4SRC are the most common form of traumatic brain injury (TBI).  However, concussions are much more complex injuries than previously thought and are not as ?mild? in nature as its interchangeable synonym ?mild traumatic brain injury? (mTBI) might imply (Slobounov et al, 2012, McCrea et al, 2004). Despite the increasing incidence of concussion, there is still no universally accepted definition. This poses a problem in uniformly evaluating athletes and determining if a concussion has been sustained. Notwithstanding the lack of consensus, it has not stopped researchers and health professional alike to attempt to define this complex condition. The most success has been achieved by the Concussion in Sports Group (CIS) who have held four international conferences over the last 11 years (Vienna 2001, Prague 2004, Zurich 2008 and Zurich 2012). The most recent definition put forth by the CIS in Zurich (2012) stated that a concussion is ?a brain injury and is defined as a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces? and includes four major  13 features described in Table 1.1. The same consensus noted that the vast majority (80?90%) of concussions resolve between 7-10 days; however, recovery time may take longer in younger athletes (high school versus collegiate; (Guskiewicz and Valovich McLeod, 2011, McCrory et al, 2013, Lovell et al, 2004).   Table 1.1 The four major features of concussion at determined by the Concussion in Sport Group in Zurich 2012 (McCrory et al, 2013).  1) Concussion may be caused either by a direct blow to the head, face, or neck or elsewhere on the body with an ?impulsive? force transmitted to the head.  2) Concussion typically results in the rapid onset of short-lived impairment of neurologic function that resolves spontaneously. However, in some cases, symptoms and signs may evolve over a number of minutes to hours.  3) Concussion may result in neuropathological changes, but the acute clinical symptoms largely reflect a functional disturbance rather than a structural injury and, as such, no abnormality is seen on standard structural neuroimaging studies.  4) Concussion results in a graded set of clinical symptoms that may or may not involve loss of consciousness. Resolution of the clinical and cognitive symptoms typically follows a sequential course. However, it is important to note that in some cases symptoms may be prolonged.   1.4.1 Incidence Rates  The incidence of high-school athletes sustaining a concussion has increased by 16.5% per year (Bakhos et al, 2010, Lincoln et al, 2011). SRC are 3-8% of all sport-related injuries presenting in young athletes in Canadian emergency departments (Boyce and Quigley, 2003). In the US, out of approximately 30-45 million adolescents participating in organized sport (Cohen et al, 2009), SRC account for 9% and 6% of all injuries incurred by high school and collegiate athletes respectively (Gessel et al, 2007). All sports contain some inherent risk of injury, including concussion, but the sports with the highest risk of concussion include male football  14 and girls? soccer and basketball (Gessel et al, 2007). For example, incidence of concussions in high-school and collegiate football are 0.47 and 0.61 per 1000 athletic exposures, respectively (Gessel et al, 2007). These incidence rates, however, are most likely underestimated due to under-reporting. McCrea and colleagues (2004) backed this premise by showing that only 47.3% of high-school football players who had sustained a concussion actually reported it. The most common responses for not reporting their injury was: 1) they believed that their injury was not serious enough to warrant medical attention (66.4%); 2) they did not want to leave the game (41%); 3) they did not recognize that a concussion had occurred (36.3%); and finally 4) they did not want to disappoint their teammates (22.1%; (McCrea et al, 2004)). This latter statistic leaves cause for concern, as the risks of playing with a concussion far outweigh the benefits of staying in the game. Although the acute effects of SRC are relatively shorted lived (7-10 days) in 90% of athletes (McCrory et al, 2013, McCrea et al, 2003), those athletes who have sustained a single concussion are still 3 times more likely of sustaining a second concussion within the same season (Guskiewicz et al, 2000, Guskiewicz et al, 2003b).  There is evidence that multiple concussions have both cumulative and long-term effects which include: greater severity of symptoms (Iverson et al, 2004, Collins et al, 2002), longer recovery times(Guskiewicz et al, 2003a, Gronwall and Wrightson, 1975), decreased threshold for future injury (Guskiewicz et al, 2003a), late-life cognitive impairment(Guskiewicz et al, 2005, De Beaumont et al, 2009), and depression (Guskiewicz et al, 2007). The most severe consequence of sustaining a second concussion prior to full recovery from the first has been shown to result in death and is termed second impact syndrome (Cantu, 1998). Interestingly, Gueskiewicz and colleagues (2007)  15 conducted a survey on approximately 2500 retired professional football players from the US and found that 11.1% had clinical depression, which seemed to be positively correlated with the number of concussions sustained. With such significant consequences both acute and chronic in nature, it is important to properly assess and diagnosis a concussion.   1.4.2 Signs and Symptoms The majority of the research centered on concussion assessment has focused on characterizing the signs and symptoms of the injury (Johnson et al, 2011, Lau et al, 2011, Taylor et al, 2010, McClincy et al, 2006). Most concussions manifest clinical signs over hours and even days following concussion. Presentation of symptoms can widely vary between individuals, with some presenting with cognitive impairments (difficulty remembering) or with more physical signs such as headache, dizziness and fatigue.  The CIS panel in Zurich 2012 agreed that diagnosis of concussion can include one or more of the following manifestations: 1) symptoms (i.e. headache); 2) physical signs (i.e. loss of consciousness); 3) behavioral changes (i.e. irritability, anger); 4) cognitive impairments (i.e. slowed reaction times); and 5) sleep disturbances (i.e. lower sleep efficiency and more awakenings). Despite the range of possible manifestations of symptoms, the most commonly reported symptom by high-school athletes is headache (Gessel et al, 2007, Collins et al, 2003a). Meehan and colleagues (2011) found that in over 1000 incidences of high-school concussion, headache was the most commonly reported symptom, with other studies showing the same trend (Collins et al, 2003a, Blinman et al, 2009). Similarly, a recent study which monitored concussion rates in the National Hockey League during the regular season 1997-2004, found the most commonly reported symptoms were headache (71%), dizziness (34%), nausea (24%) and neck pain (23%; Benson et al. 2011).   16 Headaches resulting from concussion have been described as having a ?pressure? sensation located within the skull. A loss of consciousness use to be a primary indicator that a concussion had resulted; however, new evidence has shown that loss of consciousness occurs in less than 10% of concussions sustained (Meehan et al, 2011, Guskiewicz et al, 2000, Collins et al, 2003b).  Symptoms, especially headache, are exacerbated during physical exertion (McCrory et al, 2009, McCrory et al, 2013, Majerske et al, 2008, McCrory et al, 2005). As such, symptom exacerbation is used as part of the process of evaluating when a player is ready to return back to play, by employing a standardized exercise test to determine physiologic recovery.  For example, if athletes are asymptomatic at rest but present with symptoms during light exercise, then the athlete would be returned to rest. If the athlete is asymptomatic during light exercise, but symptomatic during moderate exercise, then the athlete returns to sustaining light exercise and so on (McCrory et al, 2013).  However, despite the use of this protocol to ?determine physiological recovery?, the mechanisms responsible for symptom exacerbation during exercise have yet to be elucidated, but in a recent review it was suggested that symptom exacerbation may be linked to altered CBF and impaired CBF regulation (Leddy et al, 2012).   Cerebral Pathophysiology following Concussion  1.5The manifestation of concussive symptoms and cognitive impairments are both complex and highly variable between individuals in part due to the regional nature of the injury. These underlying impairments are likely due to neuropathological changes that appear to be both physiological and anatomical in nature; however, conventional magnetic resonance imaging (MRI) and computed tomography (CT) scans show no evidence of structural alterations in concussions (McCrory et al, 2009, McCrory et al, 2013). Other functional neuroimaging  17 techniques such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) have produced more positive results, while emerging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) are just in their infancy in assessing changes in concussion (Khurana and Kaye, 2012, Ellemberg et al, 2009).  The outcome of traumatic brain injuries can be determined by two stages: 1) primary injury which originates from the initial impact of biomechanical forces translated through the head; and 2) secondary injury which constitutes all of the pathological processes that occur right after impact (Werner and Engelhard, 2007). A well described phenomenon that occurs directly from mechanical disruption of the brain tissue is called the neurometabolic cascade (Giza and Hovda, 2001), which has been shown to alter both cerebral metabolism and blood flow.  1.5.1 The Neurometabolic Cascade  The neurometabolic cascade begins with axonal stretching and mechanical deformation of the neuronal membrane, which causes an immediate and indiscriminate flux of ions (e.g. efflux of potassium; (Farkas et al, 2006). This causes depolarization of the cell, leading to a widespread release the excitatory amino acid glutamate (Katayama et al, 1990). In order to restore ionic balance, adenosine triphosphate (ATP)-dependent sodium-potassium pumps are activated. The sodium/potassium pumps work at maximal capacities, requiring a high level of glucose metabolism (Yoshino et al, 1991, Sunami et al, 1989). Ultimately, the neurometabolic cascade results in changes in cerebral glucose and oxidative metabolism, which are discussed in greater detail below (sub-heading 1.5.2).   18 1.5.2 Alterations in Cerebral Blood Flow and Metabolism Under normal circumstances, CBF is tightly matched to meet the metabolic demand and neuronal activity within the brain (Fox and Raichle, 1986, Fox et al, 1988). Following TBI in animal models, cerebral metabolic rates for glucose uptake rise up to 30-46% above normative values (Yoshino et al, 1991, Sunami et al, 1989, Kawamata et al, 1992) and these elevations can last between 30 minutes up to 4 hours (Yoshino et al, 1991). This elevation in glucose metabolism is to match the rising demand for ATP by the Na+/K+ pumps working to establish ionic balance. However, this state of hyperglycolysis cannot be sustained indefinitely. Yoshino and colleagues (1991) found cerebral glucose metabolism to be diminished below control group levels 24 hours post-injury and lasted for 5-10 days in rats. These results have been further supported in human subjects, where PET was used to measure the reduction in global cerebral glycolysis lasting 2-4 weeks following TBI (Bergsneider et al, 1997).  What is most disconcerting, however, is that the state of hypermetabolism occurs concurrently with a 50% reduction in both global and regional CBF following TBI (Yuan et al, 1988, Yamakami and McIntosh, 1989, Forbes et al, 1997, Hovda et al, 1995, Muir et al, 1992), and regional CBF changes have also been found following mTBI (Golding et al, 1999b). Yuan and colleagues (1988), who used radiolabeled microspheres to measure regional CBF in rats, found a heterogeneous reduction in CBF across the brain with the cerebral hemispheres showing the largest reduction compared to the brainstem and cerebellum.  The same study showed that global CBF was 78%, 71% and 65% lower than baseline at 15mins, 30mins and 60mins respectively. This reduction in CBF following severe TBI (Martin et al, 1997, Maugans et al, 2012, McQuire et al, 1998) and mTBI (Maugans et al, 2012) has also been observed acutely in human studies. These studies have employed various techniques including 133Xe clearance,  19 phase MR contrast angiography and transcranial Doppler. A pediatric study (11-15yrs) by Maugans and colleagues (2012) used phase-contrast MR angiography to show a significant 21% reduction (on first day of testing) in CBF that persisted (17% reduction) beyond 30 days of initial impact.   One study has even reported a chronic depression in regional CBF (measured by SPECT) in individuals still suffering from post-concussive symptoms approximately five years after their mTBI (Bonne et al, 2003). However, this reduction in CBF has not been reflected in transcranial Doppler assessment of MCA velocity in TBI; with the current literature showing no changes in MCA velocity in mTBI (Len et al, 2011, Len et al, 2013) or increase in MCA velocity in severe TBI 4 days after injury (Martin et al, 1997). The discrepancy between measures of CBF and CBF velocity are mostly likely a result of methodological limitations, as transcranial Doppler is an index of flow and assumes the diameter remains constant. Martin and colleagues (1997) reported that the elevation in MCA velocity on Day 4-15 following severe TBI was attributed to an increase in distal vascular resistance (as indicated by increase in pulsatility index). The differences found between measures of MCA velocity between Len (2013) and Martin (1997) could be reflective of injury severity, as Len?s population was considered mild, where Martin?s group of TBI had mean Glasgow Coma Scale of 6, indicating a very severe injury.    Just as cerebral glucose metabolism has been shown to have a biphasic response following TBI, CBF has been seen to follow a triphasic response following TBI.  Using the 133Xe clearance technique to measure CBF, Martin and colleagues (1997) described this phenomenon in severe TBI in humans with hypoperfusion (32 mL/100g/min) occurring on day of injury (Day 0), then a phase of hyperemia (46.8 mL/100g/min) between Days 1-3, followed by another reduction in CBF (36 mL/100g/min) on Day 4-15. Martin and colleagues postulated that the initial cause of low CBF appeared to be an increase in cerebrovascular resistance due to altered  20 vessel diameter. Their own findings demonstrated this by increased pulsatility index values for both the ICA and MCA. Other studies have attributed the phase of hyperemia to raised ICP (Bruce et al, 1973, Obrist et al, 1984); however, these were in comatose subjects and these findings have not been universally confirmed (Robertson et al, 1992). Interestingly, Martin and colleagues (1997) reported a 50% reduction in the cerebral metabolic rate of oxygen (CMRO2; 1.77 ? 0.18 ml/100 g/minute) during the first phase of hypoperfusion (began day of injury) and remained depressed over the course of two weeks (Martin et al, 1997). It is therefore very unlikely the hyperemia was induced by an increase in CMRO2.  This depression in CMRO2 has not been shown in mTBI in humans, but has been reported in milder experimental injury in rats (Pasco et al, 2007). Notwithstanding, hyperemia may occur to meet the rising demands of cerebral glucose metabolism initiated by the neurometabolic cascade, described above. Finally, the final phase of hypoperfusion is thought to finally couple the cerebral hypometabolism as demonstrated by the 50% reduction in CMRO2 by Martin and colleagues (1997).    As the evidence suggests, CBF does not remain depressed throughout the entire time-course of injury; rather, hypoperfusion occurs in the setting of hypermetabolism.  The discrepancy between the demand for glucose and the supply of CBF causes an energy crisis within the brain, which increases the chance secondary injury to the brain tissue (i.e. ischemia; (Werner and Engelhard, 2007)) and places additional stress on the regulatory mechanisms of CBF such as CA and cerebrovascular reactivity to CO2 (discussed below; subheading 1.5.3 and 1.5.4).      21 1.5.3 Alterations in Cerebrovascular Reactivity to CO2  The majority of the research investigating the effects of TBI on CO2 reactivity has been primarily completed in moderate to severe animal models, with a handful of studies looking at mTBI. However, all have reported CO2 reactivity to be impaired or abolished all together, depending on the injury severity (Forbes et al, 1997, Golding et al, 1999b, Enevoldsen and Jensen, 1978a).  Forbes and colleagues (1997) found that rats who had been subjected to a controlled cortical impact had a 30% reduction in CO2 reactivity compared to control group. An estimation of CO2 reactivity (via laser-Doppler flowmetry) after milder controlled cortical impact (CCI) in rats found that the response for both hypercapnia and hypocapnia were significantly blunted (Golding et al, 1999b). They showed that during the hypercapnic stimulus (10% CO2) the sham-injured animals had a 68% increase in CBF, while those with mTBI only had a 13% increase.  The authors proposed that the loss of cerebrovascular reactivity to CO2 was caused by changes in the cellular environment within the injured cortex, rather than due to damage of the blood vessel itself (Golding et al, 1999b). They supported this claim by demonstrating that when the blood vessels supplying the injured cortex were isolated (removed from the traumatized environment) and tested in vitro, the vasculature reacted normally to the CO2 stimulus. Thus, the authors concluded that cerebrovascular impairment to CO2 was not a direct result of damaged blood vessels, but a by-product of inappropriate signaling following the neurometabolic cascade (i.e. changes in ionic balance, neurotransmitter release (Giza and Hovda, 2001, McIntosh, 1994)).     Only two studies have examined cerebrovascular reactivity to CO2 following mTBI in humans (Len et al, 2011, Len et al, 2013). The most recent study found that mTBI subjects have blunted cerebrovascular response to CO2 as indexed via a 20sec breathe hold on Day 2; changes  22 that were resolved by Day 4 following mTBI (Len et al, 2013). These first attempts to assess cerebral reactivity to CO2 in mTBI in humans seem to indicate transient impairment that resolve by Day 4. Such findings remain consistent with the typical resolution of symptoms in athletes [i.e. 7-10 days following; (McCrory et al, 2009, McCrory et al, 2013)].   1.5.4 Alterations in Cerebral Autoregulation Disrupted CA has been well described in severe TBI in both animal and human studies (reviewed in: (Rangel-Castilla et al, 2008, Golding et al, 1999a)) even when CPP and CBF have been shown to be normal (Lewelt et al, 1980, Czosnyka et al, 2001). There is also evidence in animal models that CA is impaired following mTBI (Lewelt et al, 1980, Proctor et al, 1988, DeWitt et al, 1992). Lewelt and colleagues (1980) subjected 24 cats to hemorrhagic hypotension in 10mmHg stages; 16 of which received fluid percussion injury (8 mTBI and 8 severe TBI). Although they found that the degree of impairment in CA was more pronounced in the severe TBI group, it was nevertheless impaired in mTBI.  Static CA in severe TBI (analyzed based on spontaneous fluctuations in CPP and MCA velocity) has been shown to be impaired in humans (Enevoldsen and Jensen, 1978a, Czosnyka et al, 2001, Lang et al, 2003). To date there have been three human studies to measure of CA in mTBI (Junger et al, 1997, Strebel et al, 1997, Vavilala et al, 2004). In a case study, Strebel and colleagues (1997) assessed static CA by increasing MAP from 80 mmHg to 100 mmHg using a phenylephrine infusion with continuous BP and MCA velocity (via transcranial Doppler) in one patient. They reported that MCA velocity became completely pressure-dependent in response to the drug-induced change in MAP, concluding the absence of CA. However, this study did not did have a control subject for comparison and based their results on the classical definition of CA by Lassen (1959). The most  23 current perspective on CA, as assessed by phenylephrine infusion, shows that CBF is much more pressure-dependent than the classical definition of CA implies (Lucas et al, 2010).  Junger and colleagues (1997) used thigh-cuff inflation to induce a rapid but moderate reduction in MAP and found 28% of subjects to have impaired or even absent dynamic CA, which was considered significantly different compared to controls (p=0.008). The third study, conducted in a pediatric population (<15yrs), found only 17% of those with mTBI to have impaired static CA (stimulus was 20mmHg increase in MAP by phenylephrine infusion; (Vavilala et al, 2004)). These data indicate some level of heterogeneity in the physiological dysfunction that accompanies mTBI. Similar to CO2 reactivity, impaired CA has been found to resolve itself following mTBI. CA in particular has been shown to take around 14 days to normalize following an mTBI (Junger et al, 1997, Strebel et al, 1997). Impaired CA has been shown to correlate with poorer outcomes in patients with severe TBI (Czosnyka et al, 1996), this trend was also found in mTBI in pediatrics (Vavilala et al, 2004), but not observed in mTBI in adults (Junger et al, 1997).  Intact CA deals with situations of decreased or increased CPP by altering vascular tone (e.g. increased CPP results in vasoconstriction and therefore decreases CBF). When CA becomes impaired, any increase in CPP will result in an increase in CBF, potentially inducing further injury. For example, when CPP suddenly increases, all that pressure is passively transmitted into the brain, potentially damaging the microvasculature, inducing minor maladies such as headache or related-symptoms and on a much more severe level cause hemorrhage or edema (Simard and Bellefleur, 1989).   As discussed above there is evidence that even in milder cases of TBI regulatory mechanism such as CO2 reactivity and CA are impaired; however, their resolution or phasic patterns have been shown to vary between studies. This is a result of the lack of  24 methodological uniformity amongst the studies, which has limited the ability to compare or confirm these findings. The methodological differences include model type (animal vs. human), measurements (transcranial Doppler vs. 133Xe clearance method), injury severity (mild vs. severe) and timing of observations (hours vs. days). Much is yet to be elucidated about the cerebral pathophysiology following mTBI and when approximately these mechanisms resolve themselves. However, what the research does emphasize is that the cerebral vasculature isn?t able to appropriately respond to various physiological stimuli that is placed upon it (i.e. changes in arterial CO2 and BP).   1.5.5 Role of Cerebral Blood Flow in Symptom Exacerbation during Exercise  Despite the high incidence rates and well characterized nature of the symptoms and neuropsychological impairments of concussion (Johnson et al, 2011, Lau et al, 2011, Taylor et al, 2010, McClincy et al, 2006), the pathophysiology is not well understood. Within the wide range of post-concussion symptoms, headache is often the most commonly experienced.  The pathology of headaches in the general population has yet to be elucidated, let alone the pathogenesis responsible for headache following concussion. There exists many hypotheses regarding the mechanisms behind headaches, however it seems to be a mix of vascular and neurogenic origins (Edvinsson, 2011, May and Goadsby, 1999, Nowak and Kacinski, 2009).  Asymmetrical alterations in both regional and hemispheric CBF (via 133Xe inhalation technique) have been reported 6-8 months after TBI in chronically symptomatic individuals suffering from persistent headache (Gilkey et al, 1997).  However, a recent review clearly showed that CBF examinations in migraneurs are so far, contradictory, with studies showing increases, decreases or no changes at all (Nowak and Kacinski, 2009). Just to highlight the variability seen in CBF  25 measures within the same study, Totaro and colleagues (1992) examined CBF velocity in the ACA, MCA, PCA and basilar artery. They found that during a migraine attack with aura they found both an increase and decrease in CBF velocity in the same arteries in different patients (Totaro et al, 1992). In contrast, no changes were seen in these arteries during migraneurs (with or without aura; (Haring and Aichner, 1992)). However, between studies, methodology varies a great deal in regards to type of migraneurs, control group, timing of observations etc.  Whether alterations in CBF play a primary role in the pathogenesis of headache in concussed individuals still remains unclear.  It has also been postulated that head pain or migraines may be due to the activation of the trigeminal nerves, which innervates the cerebral circulation (i.e. pial, dural and major cerebral arteries within the circle of Willis (May and Goadsby, 1999)). One case-study looking at the mechanisms behind idiopathic intracranial hypertension and symptom manifestation (i.e. headache) postulated that direct compression of the trigeminal nerves by the surrounding cerebral tissue caused traction of the nerve (Davenport et al, 1994). Thus, the activation of these sensory nerve fibers are likely to play a role in the manifestation of head pain and other related maladies (i.e. migraine). Despite that dynamic CA has been shown to be impaired in asymptomatic healthy individuals during exhaustive exercise (Ogoh et al, 2005b), the cerebrovasculature is extremely well adapted to protect the healthy brain against modest elevations in MAP during sub-maximal exercise. However, in a situation where the concussive brain is dealing with a number of physiological disruptions, it is possible that the ?exercising concussed brain? may be less capable of buffering even the modest rises in in MAP. Therefore it would be expected that a greater relative increase in CBF velocity during exercise would occur, which could lead to mild over-perfusion and therefore cause symptom exacerbation. Therefore  26 it is reasonable to postulate that the uninterrupted increase in CPP during exercise causes the trigeminal nerves to become compressed, which would cause the initiation of pain signals. Until now, there has been no study that has examined the CBF response during exercise following SRC.    Purpose 1.6The main purpose of this study was to address the current knowledge gap in assessing CBF as a potential mechanism for symptom exacerbation during physical exertion in recently concussed athletes.  There is evidence to support changes in resting CBF and that mechanisms of CBF regulation are impaired or abolished following concussion.  However, to date, the responsiveness of CBF during any type of exercise has never been evaluated following SRC, let alone an assessment linking CBF and symptom exacerbation.  In addition, it is important to elucidate any temporal variation in the CBF response to exercise in each concussed subject, therefore each subject with be monitored over the course of one month. A better understanding of the mechanisms behind the exacerbation of symptoms may help to better monitor recovery more objectively compared to the current method of self-reporting of symptoms.    Aims 1.7The primary aim was to assess the CBF velocity response during sub-maximal exercise following concussive injury in both the anterior and posterior cerebral circulation. The secondary aim was to assess the relationship between symptom exacerbation and CBF velocity  27 response to sub-maximal exercise. The third aim was to examine the between and within-subject variability in CBF velocity response to exercise in those with and without concussion.     Hypotheses 1.81) The changes in CBF velocity during exercise will be greater in recently concussed athletes compared to control subjects.  2) Severity of symptoms in concussed athletes will be correlated with a greater relative increase in CBF velocity during exercise.  3) Measurement variability in CBF velocity during exercise will be greater in concussed athletes compared to control subjects.  28  Methods 2    Chapter: Subject Characteristics 2.1Six concussed athletes (5 male, Age: 17 ? 3 years, body mass index (BMI): 24 ? 1.5 kg/m2 and 1 female, Age: 18, BMI 23 kg/m2) and six control subjects (5 male, Age 20: ? 2, BMI: 22 ? 2 and 1 female, Age: 21, BMI: 22 23 kg/m2) volunteered for this study. Individual SRC subject characteristics are summarized in Table 2.1. This study was approved by the University of British Columbia Ethics Board (H11-02900; Appendix A) and conformed to the Declaration of Helsinki. Subjects were informed of the experimental protocol and associated risks involved with the study and provided written informed consent (Appendix B). If subjects were minors (<18yrs; n=2) informed consent was obtained from both the subject and legal guardian.    Table 2.1 Individual characteristics of the concussed athletes that participated in the study.     Subject Recruitment and Inclusion Criteria 2.2Subject recruitment emails (Appendix C) were sent throughout the Okanagan, specifically targeting local physicians, coaches, and trainers amongst both the university and local sporting organizations (i.e. Kelowna Suns Football team, Kelowna?s Pursuit of Excellence program). Subject recruitment included both male and female athletes participating in contact sports between 14-25 years of age. Two groups of subjects were recruited: recently concussed  Sex Age (yrs) Sport BMI (kg/m2) Education Returned Back to Play (day post-injury) SRC001 M 14 Football 24.2 Grade 9 24 SRC002 M 18 Varsity Soccer 22.5 2nd year  15 SRC003 M 19 Jr. B Hockey 26.5 1st year  12 SRC004 M 21 Skiing 25.3 4th year  ? SRC005 M 15 Batam Hockey 23.4 Grade 10 6 SRC006 F 18 Cycling 23.8 1st year  ?  29 (?3 days following injury) and control subjects. The SRC group was diagnosed by a physician or athletic therapist as having incurred a concussion from sport-related events. Concussions in sport are considered a single entity encompassing a range of different factors that may modify the injury (McCrory et al, 2009). In classifying all concussions as a single entity, the consensus panel from Zurich 2008 replaced the simple versus complex terminology with a ?list? of modifying factors which, if present at the time of injury may influence both investigation and management of concussion (McCrory et al, 2009). These modifying factors include age, gender, previous concussions, injury specifics (i.e. prolonged loss of consciousness, amnesia) and type of sport or position played. Considering the potential for a vast number of different combinations of injuries, athletes were excluded from the study, if they lost consciousness during the direct impact or their symptoms are severe enough to prevent them from comfortably managing data collection on Day 3 post-injury (n=1). Likewise, subjects were excluded, if they have suffered a previous concussion within 12-months of their current concussion (n=2). The control group consisted of individuals with no previous history of concussion and who were matched for age, sex and physical activity level. In order to establish a time course to recovery for SRC, all subjects were required to fulfill four testing sessions over the course of one month (Days 3, 7, 14, and 28).  A pre-screen questionnaire (Appendix D) was distributed prior to testing to assure the subjects were not taking any medications, were non-smokers and had no prior history of neurological, respiratory, cardiovascular or metabolic disorders and any upper or lower extremity injuries that would prevent them from performing exercise. All individuals were required to have a BMI of less than 30 kg/m2. Subjects meeting the above criteria were invited to participate in this study.  30  Instrumentation 2.32.3.1 Cardiovascular Measures  Heart rate (HR) was monitored via the R-R intervals from a 3-lead electrocardiography. Blood pressure (BP) was obtained using an automated BP machine (SunTech Tango, SunTech Medicals, Morrisville NC, USA). The Tango measures BP in the arm by electrosphygmomanometry with a microphone placed over the brachial artery and the Korotkoff sounds gated to a 3-lead ECG. In order to make sure the automated machine was correct, two manual BP were taken. Parameters of gas exchange were measured using the partial pressures of end-tidal carbon dioxide (PETCO2) and oxygen (PETO2), which were collected from a sampling line attached to a two way mouth piece and an O2 and CO2 gas analyzer pod (ADInstruments, Colorado Springs, CO 198, USA). The analyzer was calibrated against a standard gas of a known concentration (i.e. 16% oxygen, 4% carbon dioxide and balanced nitrogen) and converted into millimeters of mercy (mmHg) using the daily barometric pressure.  2.3.2 Cerebral Blood Velocity Measures CBF velocities in both the MCA and PCA were obtained through transcranial Doppler. The respective arteries were insonated by placing a 2-MHz Doppler probe (Spencer Technologies, Seattle, WA, USA). Ultrasound gel was liberally applied on both the probe and over the zygomatic arch to help with signal conduction. The probes were held in place using a Marc 600 transcranial Doppler fixation head frame to ensure the probe remained fixated on the same portion of the vessel throughout the entire protocol. Search techniques outlined elsewhere (Moppett and Mahajan, 2004, Willie et al, 2011a, Aaslid et al, 1982) were used to increase the likelihood of insonating the same portion of vessel between and within subjects,   31 All data were sampled continuously at 1000 Hz using an analogue digital converter (Powerlab/8SP ML 795; ADInstruments, Colorado Springs, CO, USA)  interfaced with a computer. A pictorial example of instrumentation for this study is shown in Figure 2.1.     Transcranial Doppler Ultrasound 2.4CBF velocity can be measured in a variety of ways; however, the skull makes performing these assessments non-invasively quite difficult due to its thickness. The first studies evaluating CBF invasively used the inert gas method following arterial and jugular venous cannulation (developed by Kety and Schmidt 1948) and the indicator dilution method (Gibbs et al, 1947).  These techniques lack temporal resolution, which do not allow for the transient changes in CBF to be recorded during physiological stimuli. However, great advances have been made over the past 20 years in this research area by the introduction of techniques exhibiting high temporal resolution such as transcranial Doppler ultrasound, near-infrared spectroscopy or high spatial resolution such as magnetic resonance imaging. Each technique has its own advantages and disadvantages (reviewed in: (Willie et al, 2011a). Therefore, choosing a technique to assess CBF is highly dependent on the scientific question and the experimental design. Transcranial Doppler is more than effective for answering the proposed hypotheses, because it is non-invasive, reproducible, has a high temporal resolution and can be used during an exercise stimulus (Willie et al, 2011a). Lastly, transcranial Doppler is able to assess bilateral CBF velocities in two different cerebral arteries, the left middle and right posterior cerebral artery, which are of interest as they perfuse different regions of the brain.   32   Figure 2.1 A pictorial representation of equipment instrumentation for the experimental protocol.   2.4.1 Transcranial Doppler Principles Transcranial Doppler ultrasound uses the same principles and assumptions as other Doppler ultrasound applications to measure blood flow velocity through blood vessels (DeWitt and Wechsler, 1988). Ultrasound waves are generated by alternating a current across  piezoelectric crystals, which are set within the transducer. The transducer transmits ultrasound waves at a given frequencey (i.e. transcranial Doppler 2 MHz, breast ultrasound 7.5-10 MHz) through a medium and this  signal is then reflected back to the transducer. In the case of  blood flow quantification, the signal is reflected off the moving red blood cells within the isnonated vessel. The change in frequency from what was sent to  what was reflected back, is known as 3-lead ECG to measure HR Mouthpiece with gas analyzer port to measure PETCO2 and PETO2 Transcranial Doppler to measure MCA and PCA velocity Automated BP Cuff  33 the Doppler shift. The Doppler shift is directly proportional to the velocity of the moving object (i.e. red blood cells; (DeWitt and Wechsler, 1988)) and is calculated as:                                      (Angelsen and Brubakk, 1976)              Equation 2.1 Where v is the blood flow velocity, c is the sound velocity in a tissue (i.e. for blood c=1540m/s), f0 is the transmitted frequency, fD is the Doppler shift of reflected ultrasound and  is the insonation angle, between the ultrasound beam and the direction of flow.  As depicted from the equation above, both the transmitted frequency and speed of sound through a tissue are constants, therefore the frequency of the Doppler shift is dependent upon two variables; the velocity of the red blood cells and the angle of insonation. The blood flow velocity through a vessel with laminar flow is not uniform and the velocities across the vessel?s diameter are parabolic in nature. Thus, the Doppler shift consists of a distribution of frequencies (i.e. range of red blood cell velocities) from across the vessel from which the sample volume is taken (Angelsen and Brubakk, 1976). The fast Fourier transformation algorithm helps to consolidate this range of frequencies by taking 5ms segments of the raw signal to create a spectral distribution (reviewed in (Panerai, 2009)). From this spectral distribution, either a maximum (?peak?) velocity or an intensity-weighted mean velocity can be extracted.  The other component of the Doppler shift equation that is not constant is the angle of vessel insonation. It is recommended that the angle of insonation be kept less than 30?, which gives a maximum error of less than 15% (Aaslid et al, 1982). However, the angle between the beam and the respective vessel can range from 0? to 30?, which can lead to underestimation of CBF velocity. As there is no way of assessing the insonation angle, it is assumed and therefore remains a limiting factor of transcranial Doppler.    34 2.4.2 Vessel Insonation An accurate assessment of cerebral vascular function via transcranial Doppler relies heavily on the technical skills and knowledge of the examiner. Once there is successful insonation of an artery and a clean sonogram, a number of steps can be taken to help standardize measures of CBF velocity. The examiner must be familiar with cerebral vascular anatomy and normative insonation depths (i.e. depth; MCA 50-58mm and PCA 60-70mm), velocities (i.e. MCA 50-75 cm/s and PCA 30-45 cm/s), direction of flow and response to carotid compression (Aaslid et al, 1982). All of these parameters help to increase the likelihood that the appropriate vessel is being insonated and helps with reproducibility within and between subjects (Moppett and Mahajan, 2004, Willie et al, 2011a, Aaslid et al, 1982, DeWitt and Wechsler, 1988, Arnolds and von Reutern, 1986). During instrumentation of subjects in this study, MCA velocity was measured on the left side 10mm distal to the MCA and ACA bifurcation. MCA was confirmed using ipsliateral carotid compression with the intention to observe a reduction in MCA velocity and an increase in contralateral PCA velocity (Willie et al, 2011a, Aaslid et al, 1982). The PCA, on the other hand, was located first by finding the MCA. Then the probe was tilted and aimed at a location posterior to that of the MCA signal. In this area the P1 segment of the PCA was located on the right side, unless a better signal was found on the left (this occurred in n=3 of our subjects). To ensure we had located the right vessel, we initiated a visual/non-visual stimulus (Lindegaard et al, 1987, Aaslid, 1987) to evoke a response in the PCA, which feeds the occipital cortex of the brain.      35 2.4.3 Validity of transcranial Doppler Transcranial Doppler is advantageous in both the clinical and research setting for several reasons: it is non-invasive, has high resolution, allows for continuous monitoring and allows for repeated measures (Willie et al, 2011a). However, transcranial Doppler only provides a measure of CBF velocity. CBF velocity can reflect changes in CBF with acceptable accuracy as long as the diameter of the insonated artery remains constant. There have been several studies to validate that CBF velocity is a reliable index of global CBF under various conditions including changes in PaCO2 or BP (Bishop et al, 1986, Peebles et al, 2008, Poulin and Robbins, 1996, Serrador et al, 2000, ter Minassian et al, 1998, Valdueza et al, 1997). In addition, Sato and colleagues (2011) showed that measures of internal carotid artery flow were closely followed by measures of MCA velocity during graded exercise (from rest to 80% of VO2peak (Sato et al, 2011)). Moreover, studies have directly compared changes in transcranial Doppler MCA velocity against other validated techniques such as magnetic resonance imaging during hyperventilation (Serrador et al, 2000, Valdueza et al, 1997), using arteriovenous oxygen difference under hypercapnic conditions in those with severe closed head injury (ter Minassian et al, 1998) or Xenon133 clearance technique under hypercapnic conditions (Bishop et al, 1986). However, Bishop and colleagues (1986) cautioned that transcranial Doppler should only be used to reflect changes in CBF, because absolute values of CBF velocity had a poor correlation with absolute values of CBF at rest. Ultimately, transcranial Doppler data should be interpreted carefully when comparing between studies using different measurement modalities and experimental design. In order to evaluate the CBF velocity response to exercise, transcranial Doppler was used to quantify the relative change in CBF velocity in two different arteries (MCA and PCA) over different exercise intensities and across multiple visits.   36  Pre-testing Guidelines 2.5Prior to each testing session, each subject had their anthropometric measurements (height, weight, BMI) taken and a brief interview to confirm that pre-testing guidelines were followed (e.g. adequate hydration, no consumption of alcohol and caffeine or physical exertion within 24 hours). All of these parameters are known to affect cerebrovascular function (reviewed in: (Ainslie and Duffin, 2009)) and therefore need to be tightly controlled.  In addition, to maximize internal validity for each subject, the experimental protocol was conducted by the same personnel, with the same equipment and completed at the same time of day.    Experimental Design and Outcome Measures 2.6Subjects were tested 4 times over the course of 1 month. Concussed subjects were tested on average on Day 4?1, Day 8?1, Day 17?3 and Day 29?1 following injury. The control group was tested at similar intervals. The experimental protocol is depicted in Figure 2.2 and described below.       Figure 2.2 A diagram of the testing interval used to assess subjects over the course of 1-month.   2.6.1 Post-Concussion Symptom Evaluation Immediately following the anthropometric measures, all subjects completed a baseline concussion symptom evaluation questionnaire (SCAT2; Appendix E) to document specific concussion-related symptoms and their severity (McCrory et al, 2009, Shehata et al, 2009). In  Day of Injury = Day 1 Visit 1 Day 3 following injury Visit 2 Day 7 following injury Visit 3 Day 14 following injury Visit 4 Day 30 following injury  37 addition, the SCAT2 was administered right after exercise as a way to measure symptom exacerbation following the physiological stress. Symptom exacerbation was quantified in two ways: 1) the number of symptoms present and 2) the severity of those symptoms on a scale of 0-6, with 0 being not present and 6 being the most severe. The symptom evaluation portion of the SCAT2 consists of 22-item post-concussion symptoms using a 7-point Likert scale.  This scale has been applied in a variety of concussion-related settings (Roe et al, 2009, Covassin et al, 2012) and been shown to be a valid and reliable form of assessing which symptoms are being presented and their severity (Lau et al, 2011, Broglio et al, 2007, McLeod and Leach, 2012, Mailer et al, 2008, Alla et al, 2009, Lovell et al, 2006).    2.6.2 Cerebral Blood Flow Velocity during Exercise This is the first attempt to experimentally assess CBF velocity during exercise in concussed individuals. However the most important issue at hand was that the exercise protocol needed to be conservative considering the implications of exercise on the concussed brain is unknown. Therefore, two steady-state exercise intensities at 30% and 70% of estimated heart rate reserve (HRR; Equation 2.2 and 2.3) were examined. These intensities are typically encountered during everyday activities such as brisk walking, stair-climbing or jogging. Moreover, by being conservative, it increased the likelihood that subjects would be able to complete these stages before becoming symptomatic and terminating the protocol. HRR is the difference between the measured or predicted maximum heart rate and resting heart rate (Karvonen et al, 1957) and is often used to gauge exercise intensity. However, HRR is flawed, as the equation was not developed to incorporate VO2max data. Therefore, a  38 given percentage (%) of HRR is not equivalent to percentage of VO2max (Swain and Leutholtz, 1997).                       Target 30% HRR = ((HRmax ? HRrest)*0.30) + HRrest                                         Equation 2.2                      Target 70% HRR = ((HRmax ? HRrest)*0.70) + HRrest                                         Equation 2.3 Nevertheless, despite the limitations, HRR is a good way to apply the same relative exercise intensity consistently across subjects, especially over a short time frame e.g., <1 month. In addition, HRR considers a person?s relative fitness (resting HR), which can account for the possible deconditioning that could occur over 4 weeks of inactivity.  The protocol is depicted in Figure 2.3. The protocol began with a 5-minute baseline during which MCA and PCA velocity and HR and PETCO2 were continuously measured in an upright and seated position. Manual BP was taken twice over the baseline period.  Following the completion of baseline measurements, subjects commenced pedalling on a stationary upright bike (ErgoSelect 200P, Ergoline, Bitz, Germany) at a fixed rate between 60-70 rotations per minute (rpm) and then were slowly ramped up to predicted 30% HRR. Once a steady state was achieved a 2-3 minute interval was recorded. If subject remained symptom free, they were then ramped up (by adding watts) until they reached 70% HRR. The 2-3 minute interval commenced once a steady state had been reached. Two automated blood pressures were also taken during each exercise interval. To reduce the confounding influence of exercise-induced hyperventilation (and because HRR is not a proximate indicator of VO2peak) careful consideration was taken to monitor PETCO2 to make sure subjects had not starting to hyperventilate at 70% HRR. On completion of steady-state 70% HRR, subjects were cooled down for at least 5 minutes. During each workload, subjects were asked to rate their perceived rate of exertion on a 10-point Borg scale (Borg, 1970).   39        Figure 2.3 A depiction of the experimental protocol used to quantify CBF velocity response during sub-maximal exercise in SRC. Middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv), heart rate (HR), blood pressure (BP), 30% and 70% predicted heart rate reserve (30% HRR and 70% HRR).  Baseline mean MCA and PCA velocity (Equation 2.4), MAP, systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, PETO2, and PETCO2 were averaged over 5 minutes. Both MCA velocity and PCA velocity waveforms were acquired from the spectral envelope displayed in LabChart. From the waveform both systolic and diastolic values were obtained to extrapolate mean MCA and PCA velocity.  Mean CBF velocity for each artery was calculated as:            Mean CBF velocity = 1/3 systolic CBF velocity + 2/3 diastolic CBF velocity         Equation 2.4 Relative change in mean CBF velocity for both MCA and PCA was calculated as follows:                    Relative CBF velocity = (((CBFv%HRR ? CBFvbaseline)/CBFvbaseline)*100)           Equation 2.5 Cerebrovascular resistance (CVR) for each artery was calculated as follows:                                                 CVR  = MAP/CBF velocity                                                         Equation 2.6    Statistical Analysis 2.7Statistical analysis was performed using SPSS 16.0.2 (SPSS, Chicago, IL). As there was a mix of normally and non-normally distributed data (as assessed via Shapior-Wilk test), non-parametric tests were run to assess the effects of concussion (concussed vs. healthy controls) Continuous measurement of MCAv, PCAv, HR and PETCO2. BP will be taken regularly.                                            5-minute Baseline in an Upright and Seated position ? Wattage Cool Down Start cycling  Cycling at 30% HRR for 2-3minutes  Cycling at 70% HRR for 2-3minutes   40 or testing day (3, 7, 14, 30 days) on CBF velocity during exercise. For the non-parametric tests, between group differences was assessed by using the Kruskal-Wallis test and between days comparisons were run using the Friedman?s ANOVA (Field, 2009).  Post-hoc analysis was conducted using the Mann-Whitney test (i.e. independent sample) and the Wilcoxon signed-rank test (i.e. related samples).  Relationships between symptom severity and CBF velocity response was determined by linear regression, as this data were normally distrubted. Data were presented as means ? standard deviation (SD), and a level of p? 0.05 was considered statistically significant.  2.7.1 Day-to-Day Variability Analysis Repeatability of a measure may be measured with the test-retest method, whereby the same measure is executed upon the same subjects at two separate time points.  Reliability testing is used to help evaluate the variable of interest as well as the precision of the measurement tool or rater. In order to assess the amount of variation that occurs in the main outcome measures (MCA and PCA velocity) across days due to intra-rater variability, a subgroup of control subjects (n=12) were recruited for two testing sessions (protocol as described above). The coefficient of variation, intra-class correlation coefficient, and technical error of measurement were calculated to establish day-to-day variation of CBF velocities in the MCA and PCA at rest and during exercise. The use of more than one test is necessary because it has been suggested that no reliability test is comprehensive enough alone (Atkinson and Nevill, 1998).      41  2.7.1.1 Coefficient of Variation  The coefficient of variation (CV) calculates the dispersion of the data within a data series around the group mean. The CV is defined as:  CV = Standard Deviation/ Group Mean                           Equation 2.7 When there is a greater dispersion within the variable, the higher the CV. The lower the CV, the less dispersion and is suggestive of better reliability. In order to assess if the variation between subjects was the same between days a repeated measures ANOVA was run with the adjusted-absolute deviations.  2.7.1.2 Intra-class correlation coefficient The intra-class correlation coefficient (ICC) is used to assess within-subject differences by using an analysis of variance, which allows for calculation of error variances from each source. It is a preferred method over the Pearson?s correlation in that ICC is sensitive to the presence of systematic bias in the data (Atkinson and Nevill, 1998). There are different interpretations of ICC, but a standard scale indicates that ICC less than 0.7 is weak, 0.7-0.8 good and greater than 0.9 showing excellent reproducibility (Rosner, 2005).  2.7.1.3  Technical Error of Measurement The technical error of measurement (TEM) is another method used to assess measurement accuracy; it is used more commonly to assess the degree of accuracy of an intra-rater who is repeating measurements. The lower the TEM obtained the better precision of the  42 intra-rater in measuring the desired outcomes.  TEM was calculated as follows (Goto and Mascie-Taylor, 2007):                                               TEM = Square Root (? Diff2 / 2N)                             Equation 2.8 Where: Diff2 is the difference between the two means for each subject squared, N is sample size.                                         % TEM = ((TEM x100)/((Mean1+Mean2)/2))                     Equation 2.9 Where: Mean1 is the group mean for visit 1 and Mean2 is the group mean for visit 2.                   43    Results  3    Chapter: Rest 3.1A total of 12 concussed subjects were originally recruited; however, 6 did not complete the study for various reasons including: 1 facial injury (could not hold mouth-piece), 2 had received previous SRC within the last 12-months, 1 could not perform cycling (due to bad knees), and 2 dropped out. Of the subjects that completed the one month of testing, one subject could not complete 70% HRR on Day 3 and 7 due to being too symptomatic and one subject missed Day 14 completely due to a family vacation. Subject characteristics are depicted in Table 3.1. The average age of SRC was 17.5?2 years old with an average BMI of 24?1 kg/m2.  Control subjects (CS) were 20?2 years old and had a BMI of 22?2 kg/m2. There was a significant difference for age and BMI between groups (Table 3.1, p <0.05). However, resting cerebrovascular (MCA and PCA velocity, cerebrovascular resistance in MCA and PCA; CVRMCA, CVRPCA), cardiovascular (HR, MAP, SBP, DBP) and gas exchange (PETCO2) variables were not significantly different between groups or across any day of testing (Table 3.2 and Figure 3.1). MCA and PCA velocities were both within normative reported ranges (Figure 3.2; (Moppett and Mahajan, 2004, Willie et al, 2011a)). When averaged across the four visits, MCA velocities were 60.0?8 cm/s for controls and 61?12 cm/s for SRC.  While, PCA velocities were 38?6 cm/s for controls and 41?6 cm/s for SRC.      44           Table 3.1 Comparison of anthropometric and resting data of concussed athletes (SRC) and control subjects (CS) on Day 3.  CS              Mean ? SD SRC Mean ? SD Demographics:   Age (years) 20 ? 2 17.5 ? 2* Height (cm) 182 ? 10 172 ? 8 Body Mass (kg) 73 ? 10 73 ? 9 BMI (kg.m-2) 22 ? 2 24 ? 1* Cardiovascular:   MAP(mmHg) 84 ? 7 86 ? 7 SBP(mmHg) 118 ? 6 123 ? 6 DBP(mmHg) 68 ? 9 67 ? 10 HR(beats ?min-1) 64 ? 9 66? 7 Cerebrovascular:   MCA Vmean (cm?s-1) 60 ? 7 63 ? 8 CVRMCAV (mmHg?cm?s-1) 1.4 ? 0.25 1.4 ? 0.17 PCA Vmean (cm?s-1) 41 ? 6 39 ? 6 CVRPCAV (mmHg?cm?s-1) 2.2 ?0.5 2.1 ?0.3 Gas Exchange:   PETCO2 (mmHg) 37 ? 4 40 ? 2 PETO2 (mmHg) 107 ? 7 105 ? 4 There was no significant difference in resting cardiovascular, cerebrovascular or gas-exchange variables across days, the resting averages reported here is the average across days. BMI Body Mass Index, MAP Mean Arterial Pressure, SBP Systolic  Blood  Pressure, DBP Diastolic Blood Pressure, MCA Vmean Mean Middle Cerebral Artery Velocity, PCA Vmean Mean Posterior Cerebral Artery Velocity, CVR cerebral vascular resistance, PETCO2  End-tidal carbon dioxide, PETO2  End-tidal oxygen. Significance between groups * p<.05.         45    Figure 3.1 Resting averages of cardiovascular and gas-exchange variables across the four testing days in concussed athletes (black dots) and controls subjects (white dots).  46  Figure 3.2 Resting PCA (top) and MCA (bottom) velocities across one month of testing in concussed (black dots) and control (white dots) subjects.     47  Mild to Moderate Exercise 3.2  The absolute values for the exercise variables are summarized in Table 3.2 and Table 3.3. Table 3.4 and Figure 3.3 depict the relative changes in MCA and PCA velocities during exercise across the four testing days. There was a significant effect of exercise intensity within-subjects for the majority of variables in both groups (Table 3.2 and 3.3; MCA, PCA, MAP, SBP, PETCO2 and HR; p<0.05) except DBP, which remained unchanged throughout exercise. There was no significant effect between groups or testing day in any of the variables, except in PETCO2, MAP and SBP (discussed below).    Throughout mild-to-moderate exercise, both groups had significant increases in relative MCA and PCA velocity (Figure 3.3, Table 3.4).   Interestingly, when looking at the individual data, four of the six concussed subjects (SRC001, SRC002, SRC004 and SRC006) had their largest increase in relative MCA velocity on Day 3 (Figure 3.4) with a range of 30-48% increase from baseline at 70%HRR. Day 3 was also when these subjects reported a greater number and severity of symptoms (discussed in more depth below). There was a significant reduction in CVRMCA and CVRPCA from baseline to 30%HRR in the control group (p<0.05) on all days except Day 30 (Figure 3.5). The concussed subjects only had a significant reduction in both CVRMCA and CVRPCA on Day 30 at 30%HRR.  Whilst DBP was maintained in both groups, there was a progressive increase in absolute SBP and MAP (Figures 3.6).  Absolute MAP did not significantly increase from baseline to 30% HRR in either group on any day of testing; however, there was a significant increase at 70% HRR, except on Day 7 in SRC (p=0.08).  There was a group difference in MAP on Day 3 at 30%HRR (U=3, z=-2.191, p<0.05). SBP significantly increased from baseline to 30% HRR and 70%HRR in both groups. There was a group difference in SBP (U=4, z=-2.246), with a significant  48 difference between groups on Day 30 at 30% HRR (p <0.05). There was no difference in the averaged predicted HRR for 30% and 70% between groups, and both groups had a significant increase in HR over each exercise interval and across all days (Figure 3.7). There was an increase in absolute PETCO2 in both groups from rest to 30% HRR (Figure 3.7; p<0.01), but there was no increase between 30% and 70% HRR across all days.  Although there was a trend for the concussed athletes to have a higher PETCO2 values that control group (Figure 3.7), PETCO2 was only significantly different between groups on Day 7 at 30% HRR (U=4, z=-2.242, p<0.05). There was no change in PETCO2 from 30% HRR to 70% HRR in either group on any testing day. Both groups on average reported perceived rate of exertion on a 10-point Borg Scale and on average reported 3.5 out of 10 at 30% HRR and 7 out of 10 at 70% HRR. There were no between groups differences.                               49    Table 3.2 Comparison of cardiovascular and gas exchange variables between controls (CS) and   concussed (SRC) during exercise.  MAP  (mmHg) SBP    (mmHg) DBP (mmHg) PETCO2    (mmHg) HR (bpm)  CS SRC CS SRC CS SRC CS SRC CS SRC Day 3           Baseline 84?8 86?8 121?8 126?5 66?13 66?12 37?4 41?4 66?9 69?7 30%HRR 87?8 95?12 143?10A 154?13A 59?12 65?14 43?2A 46?6A 106?8A 106?4A 70%HRR 107?7A 105?11A 175?21A 182?12A 68?15 67?17 45?4A 47?7A 156?6A 152?15A  Day 7           Baseline 84?5  89?11 117?6 127?6 68?8 68?16 36?4 40?2 62?9 64?3 30%HRR 90?9 94?5 140?16A 161?19A 65?14 61?7 42?4A 48?3A* 106?7A 107?3A 70%HRR 106?8 104?7A 183?20A 188?10A 68?13 60?13 44?4A 49?5A 153?7A 156?6A  Day 14           Baseline 84?7 84?6 121?4 124?7 66?11 64?9 36?4 40?3  67?11 71?8 30%HRR 85?7 93?7* 138?7A 155?18A 62?9 63?2 43?1A 47?4A 105?7A 102?7A 70 HRR 105?7A 107?3A 179?17A 195?18A 68?9 62?7 43?3A 46?6 157?6A 146?25A  Day 30           Baseline 84?9 85?8 116?4 121?4 71?8 68?11 38?3 40?2 62?14 64?5 30%HRR 83?11 86?7 132?12A 150?11A* 59?15 58?10 43?2A 47?3A 104?8A 107?4A 70%HRR 102?11A 99?9A 175?21A 183?19A 66?16 57?10 44?3A 46?4A 155?9A 158?4A MAP Mean Arterial Pressure, SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure,   PETCO2 Partial Pressure of End-tidal CO2, HR Heart Rate, 30% and 70%HRR Predicted Heart Rate Reserve.  All values are means ?SD. Difference between group is indicated by * (p<.05). Difference from baseline is indicated by A p<.05.    50    Table 3.3 Comparison of absolute cerebrovascular variables between controls (CS) and concussed (SRC) during exercise.  MCA Vmean (cm?s-1) CVRMCAV (mmHg?cm?s-1) PCA Vmean (cm?s-1) CVRPCAV (mmHg?cm?s-1)  CS SRC CS SRC CS SRC CS SRC Day 3         Baseline 60?8 61?10 1.4?0.3 1.4?0.2 40?6 39?6 2.1?0.5 2.2?0.3 30%HRR 71?7A 74?10A 1.2?0.2A 1.3?0.2 49?9A 46?5A 1.8?0.5A 2.0?0.3 70%HRR 80?10A 82?10A 1.3?0.2 1.3?0.2 54?12A 55?10A 2.1?0.5 1.9?0.2  Day 7         Baseline 61?7 63?11 1.4?0.2 1.4?0.2 38?9 40?7 2.4?0.8 2.2?0.4 30%HRR 74?8A 74?12A 1.2?0.1A 1.3?0.2 47?13 47?4A 2.1?0.7A 2.0?0.2 70%HRR 84?8A 81?12A 1.3?0.1 1.3?0.2 54?13A 52?6A 2.0?0.5 2.0?0.2  Day 14         Baseline 60?8 66?5 1.4?0.3 1.3?0.1 39?5 44?4 2.2?0.4 2.0?0.2 30%HRR 75?6A 74?5A  1.1?0.1A 1.3?0.1 45?6A 48?7 1.9?0.3A 2.0?0.3 70 HRR 84?9A 82?10A 1.3?0.2 1.3?0.1 50?6A 51?6 2.1?0.3 2.1?0.3  Day 30         Baseline 59?6 64?9 1.5?0.3 1.4?0.2 39?6 40?4 2.2?0.5 2.1?0.3 30%HRR 69?7A 74?5A 1.2?0.2 1.2?0.1A 44?8A 50?7A 2.0?0.4 1.7?.2A 70%HRR 77?9A 78?8A 1.3?0.3 1.3?0.1 49?9A 52?8A 2.1?0.4 1.9?0.2 MCA Vmean Mean Middle Cerebral Artery Velocity, CVRMCAV Cerebral Vascular Resistance in the MCA, PCA Vmean Mean Posterior Cerebral Artery Velocity, CVRPCAV Cerebral Vascular Resistance in the PCA, 30% and 70% HRR Predicted Heart Rate Reserve.  All values are means ?SD. Difference between group is indicated by * (p<.05). Difference from baseline is indicated indicated by A p<.05.     51           Table 3.4 Comparison of relative MCA and PCA velocity response to mild-moderate exercise between controls (CS) and concussed (SRC) subjects during exercise.            MCA Vmean Mean Middle Cerebral Artery Velocity and PCA Vmean Mean Posterior Cerebral Artery Velocity.  All values are means ?SD. Difference from baseline (within-group) is indicated by A (p<.05). MCA Vmean (%?SD) PCA Vmean (%?SD)  CS SRC CS SRC Day 3     30% HRR 19?15A 19?9A 20?16A 18?15A 70% HRR 34?26A 35?11A 32?27A 40?15A  Day 7     30% HRR 24?17A 18?6A 24?29A 17?10A 70% HRR 41?21A 29?4A 47?32A 28?12A  Day 14     30% HRR 26?17A 11?4A 17?10A 8?11A 70% HRR 43?26A 25?7A 28?16A 17?10A  Day 30     30% HRR 18?10A 15?9A 11?9A 24?13A 70% HRR 33?20A 24?7A 25?18A 29?14A  52     Figure 3.3 Relative change in MCA (left) and PCA (right) velocities during the exercise protocol in concussed athletes (black dots) and control group (white dots), displayed for all four testing days.  53           Figure 3.4 Each individual concussed athlete?s (SRC) relative MCA velocity response across four testing sessions; Day 3, 7, 14 and 30.  54  Figure 3.5 Change in cerebrovascular resistance in the MCA (left) and the PCS (right) during exercise over the four testing days in concussed athletes (black dots) and control subjects (white dots).  55    Figure 3.6 Changes in mean arterial blood pressure (MAP; Left), systolic blood pressure (SBP; middle) and diastolic blood pressure (DBP; right) during exercise over the four testing days in concussed athletes (black dots) and control subjects (white dots). Significant difference between groups is indicated by * (p<0.05).          *  *  56   Figure 3.7 Changes in heart rate (HR; left) and partial pressure of end-tidal CO2 (PETCO2; right) during exercise over the four testing days in concussed athletes (black dots) and control subjects (white dots). Significant difference between groups is indicated by * (p<0.05).           *  57  Symptoms and MCA and PCA Velocity Response 3.3There was a significant effect of day on both number of symptoms (F= 9.75, p<0.005) and symptom severity (F=10.15, p<0.006). The number of symptoms and symptom severity reported pre-testing gradually decreased over the course of one month (Figure 3.8). For example, by Day 14 two of the six SRC subjects were asymptomatic at rest and only three of the six were reported as asymptomatic during rest by Day 30. On Day 3 SRC reported the most number of symptoms and highest severity with average 10?6 symptoms (out of a possible 22) with a severity of 25?23 (out of a possible score of 132). For the remaining testing days, symptoms presentation was reported as: Day 7, 7?4 symptoms with a severity of 11?7; Day 14, 4?4 symptoms with a severity of 5?5; and finally on Day 30, 3?5 symptoms with a severity of 5?7.  There was a significant difference between Day 1 and Day 30 in both number of symptoms (p<0.05) and symptom severity (p<0.05) reported pre-testing. The most commonly reported symptoms were; headache, pressure in head, dizziness, balance problems and more irritable than normal.  Although there was a trend of an increase in reported number of symptoms and severity between pre and post-testing, this was not significant (p= 0.5 and p=0.6 respectively; Figure 3.8). However, most subjects reported that they felt worse following exercise than prior to testing. For example, on Day 3, SRC reported 11?6 symptoms severity at rest with a severity of 27?23 following exercise at 70% HRR. In particular, 4 of the 6 subjects had the greatest increase in MCA velocity on Day 3 (Figure 3.4) at 70% HRR compared to any other day.  This was in conjunction with the largest severity of symptoms reported for these subjects across all four visits. For the remaining testing days, symptoms at 70% HRR were reported as: Day 7, 10?6 symptoms with a severity of 18?13, Day 14 6?5 symptoms with a severity of 9?9 and  58 finally on Day 30 3?4 symptoms with a severity of 4?6. By Day 14 only one of six subjects was asymptomatic during exercise and only three of six on Day 30.  The number of symptoms reported post-testing was significantly different between; Day 3 and Day 30 (p<0.05), Day 7 and Day 30 (p<0.05) and Day 14 and Day 30 (p<0.01). Symptom severity followed a similar trend, with each day being significantly different from Day 30 post-testing (p<0.05).  On average (across all visits), symptomatic subjects had a 51% increase in the number of symptoms reported and a 50% increase in the severity of symptoms reported after exercise. There was no correlation between the change in scores of symptoms or symptom severity and the relative change in MCA or PCA velocities at 70% HRR (Table 3.5). However, when a multiple linear regression was run between the changed scores of both 1) number of symptoms and 2) symptom severity (which were converted to a standardized predicted values) against relative change in MCA velocity; a significant relationship (R2 =0.367; Table 3.5, Figure 3.9, p<0.05) was revealed. Interestingly, when the changed score of headache severity was run against relative MCA velocity at 70% HRR there was a significant relationship (p<0.001) with an R2 value of 0.60.      59                      Figure 3.8 Reported number of symptoms and symptoms severity pre-testing (black shade) and post-exercise (grey shade) across the four testing sessions in symptomatic concussed athletes. Significant difference between Day 3 pre-testing score across days is indicated by * and difference between Day 30 post-testing scores across days is indicated by A (p<0.05).             * * A A A A A A  60 Table 3.5 Regression analysis between changes in symptoms against relative MCA and PCA velocities during 70% of predicted heart rate reserve in symptomatic concussed athletes.   ? Number of Symptoms ? Severity of Symptoms Multiple Regression ? MCAv70%HRR           R2 = 0.05 R2 =0.15 R2 =0.37* ? PCAv70%HRR                    R2 = 0.15 R2 = 0.02         R2 =0.21 Relative change in middle and posterior cerebral artery velocity at 70% predicted heart rate reserve, respectively; ? MCAv70%HRR and ? PCAv70%HRR. The multiple regression was run with the both the change in symptom severity and symptom number against relative MCA and PCA velocity at 70%HRR.  Significance is indicated by *p<0.05.      Figure 3.9 This regression plot shows the relationship between the dependent variable (MCA velocity at 70% HRR) and the standardized predicted values (using the change in number of symptoms and symptom severity) in symptomatic concussed athletes. Significance is indicated by * (p<.05).   R2= 0.37*  61  Day-to-Day Variability  3.4 3.4.1 Between-subject Variations in MCA and PCA Velocity Measures  The coefficients of variations (CV) for both MCA and PCA velocity during exercise are summarized in Table 3.6.  The between subject variation for both visits in MCA velocity at rest and during exercise ranged from 9-12%, which was consistent across the two visits (p>0.05). The variation between subjects was much higher in the PCA compared to the MCA. However, there were no significant differences in CV between the two visits in either MCA or PCA within the subgroup of control subjects (n=12; Figure 3.10). This indicates that despite high variation of the measures between subjects, the variation stayed the same across days. The CV was also calculated in the study groups (concussed; n=6 and controls; n=6) over the four days of testing (Table 3.7). The concussed athletes had greater variation in their measures, however there was no day or group differences (MCA F= 0.24, p=0.62, PCA F=0.21, p=0.80; Figure 3.11).    Table 3.6 The coefficient of variation of absolute MCA and PCA velocities at rest and during exercise in a subset control subjects (N=12).  Visit 1 CV (%) Visit 2 CV(%)      P-Value MCA velocity                                 Resting 12 12 >0.05 30% HRR 9 11 >0.05 70% HRR 11 12 >0.05  PCA velocity     Resting 15 20 >0.05 30% HRR 17 22 >0.05 70% HRR 21 23 >0.05 MCA Middle Cerebral Artery Velocity, PCA Posterior Cerebral Artery Velocity, CV Coefficient of Variation. Between-subject variations in CBF velocities at rest and during exercise were not statistically different between days.   62  Figure 3.10 A graphical representation of the coefficient of variations for both the MCA (top) and PCA (bottom) velocities at rest, 30% and 70% heart rate reserve (HRR) in a subgroup of control subjects (n=12) over two days of testing.      63          Table 3.7 The coefficient of variation of absolute MCA and PCA velocities at rest and during exercise for concussed (N=6) and control (N=6) groups across visits.  Day 3 CV (%) Day 7 CV (%) Day 14 CV (%)  Day 30         CV (%) P-Value Controls      MCA velocity                                   Resting 14 14 13 10 >0.05 30% HRR 9 11 8 11 >0.05 70% HRR 12 11 11 12 >0.05  PCA velocity       Resting 15 24 14 15 >0.05 30% HRR 18 28 13 19 >0.05 70% HRR 23 25 12 18 >0.05  Concussed      MCA velocity                                   Resting 17 17 9 14 >0.05 30% HRR 14 15 9 7 >0.05 70% HRR 14 14 13 10 >0.05  PCA velocity       Resting 15 19 9.5 10 >0.05 30% HRR 30 12 20 14 >0.05 70% HRR 13 13 11 12 >0.05 MCA Middle Cerebral Artery Velocity, PCA Posterior Cerebral Artery Velocity, CoV Coefficient of Variation, HRR Predicted Heart Rate Reserve. Repeated measures ANOVA was run for each group across the four days, there was no significant difference in CV between different testing days in either group (i.e. controls or concussed).         64  Figure 3.11 A graphical representation of the coefficient of variations in both the concussed (top; n=6) and control (bottom; n=6) group for both the MCA (left) and PCA (right) velocities at rest, 30% and 70% heart rate reserve (HRR) over the four days of testing.  65 3.4.2 Within-subject Variation in MCA and PCA Velocity Measures   Within-subject variation of both MCA and PCA velocity during exercise was assessed using intra-class correlation coefficient (ICC; Table 3.8) in the subgroup of control subjects (n=12). All MCA and PCA velocity measures at rest and during exercise at 30% and 70% HRR ICC?s were >0.7, indicating good reliability. Within-subject variation for MCA and PCA velocities across the exercise protocol for each individual subject is depicted in Figure 3.12.     Table 3.8 Intra-class correlation coefficient of absolute MCA and PCA velocities at rest and during exercise in a subset control group (N=12).   95% C.I.    ICC Lower Upper F Sig. MCA velocity                                     Resting 0.92 0.750  0.976 12.440 <0.001 30% HRR 0.92 0.709  0.976 11.209 <0.001 70% HRR 0.96 0.860  0.988 23.099 <0.001  PCA velocity        Resting 0.88 0.478  0.967 12.664 <0.001 30% HRR 0.80 0.262  0.945 4.793 <0.01 70% HRR 0.79 0.223  0.943 4.578 <0.05 MCA Middle Cerebral Artery Velocity, PCA Posterior Cerebral Artery Velocity, HRR Predicted Heart Rate Reserve, ICC Intra-Class Correlation Coefficient.                      66    Figure 3.12  Depicted here are the individual data between the two repeated measures for the PCA (top) and MCA (bottom) velocities at baseline, 30% and 70% heart rate reserve(HRR) in a subgroup of controls subjects (n=12) used to calculate the intra-class correlation coefficients.     3.4.3 Technical Error of Measurement  Test re-test resting MCA and PCA velocities were 4% and 5%, respectively, in the subset of control subjects (n=12). Test re-test for 30% HRR and 70% HRR in the subgroup of control subjects (n=12) was 4% and 5% for the MCA respectively, and 11% and 13% for the PCA.   67  Discussion and Conclusion 4    Chapter:  This is the first study to monitor serial changes in MCA and PCA velocity at rest and during exercise in SRC. In relation to the stated hypotheses, the main findings of this preliminary study were: 1) there was no significant between group differences in the relative change in MCA or PCA velocity following SRC during exercise. 2) There was a moderate but significant relationship between the change in number of symptoms and the severity of symptom scores and relative MCA velocity at 70% HRR. 3) Day-to-day variation in CBF velocity measures within the concussion group showed large variation (9-17% at rest) across the four testing days; with no differences across days or between controls and concussed.   CBF velocity at rest in SRC 4.1Majority of the CBF literature in TBI have found a significant reduction in CBF in both animal and human models at rest (Yamakami and McIntosh, 1989, Golding et al, 1999b, Martin et al, 1997). However, the present study found no significant difference in the relative change in MCA or PCA velocity in SRC at rest or during exercise. Whilst previous studies have indicated that velocity is a reliable index of global CBF during exercise (reviewed in (Ogoh and Ainslie, 2009)), interpretation of resting CBF should be interpreted with caution (Bishop et al. 1986), as it assumes the diameter remains constant. One study showed an increase in vascular resistance distal of the MCA following severe TBI (Martin et al, 1997) suggesting that vessel diameter may not remain constant. This substantiates the use of CBF velocity as an index of flow by assessing the responsiveness of CBF rather than using absolute values (Bishop et al, 1996).  On the other hand, the present findings that showed no change in MCA velocities at rest following SRC supports previous work in acute concussion (Len et al, 2011, Len et al, 2013) but not following  68 severe TBI (Martin et al, 1997).  This discrepancy between studies could be explained in part by the large differences in injury severity, as Martin?s (1997) subjects averaged a 6 on the Glasgow Coma Scale; indicating severe disability and poor prognostic outcome (Teasdale and Jennett, 1976)).   CBF velocity during exercise in SRC 4.2There was no significant group difference in the relative changes in MCA or PCA velocity following SRC during mild-moderate exercise intensity. Nevertheless, it should be highlighted that the ?concussed brain? was able to effectively increase both MCA and PCA velocities in response to mild-moderate exercise intensity (Figure 3.3), with concurrent increases in MAP, HR and PETCO2. This indicates that the concussed brain is still capable of meeting the rise in the metabolic demands, BP and CO2 placed upon it during exercise. It also indicates that autoregulation is not compromised during exercise in the SRC individuals studied. If it were, a greater elevation in MCA/PCA velocity would be anticipated for a given change in MAP (Tzeng and Ainslie, 2013). Another possible explanation of why there was no difference between MCA and PCA velocities during exercise could be explained by not evaluating out athletes acutely enough following injury. When looking at individual data within the concussion group (Figure 3.4), there was a trend (p=0.09) toward the largest MCA velocity response in four of the six subjects on Day 3, which was accompanied by the largest change in reported symptoms (Figure 3.8). Len and colleagues (2013) found a change in CO2 reactivity on Day 2, with recovery being established on Day 4. These observations support the notion that the current study did not measure enough days in the acute phase of the injury. On average, our subjects had returned  69 back-to-play by an overseeing physician on Day 13, with two subjects being returned to play as early as 4-6 days after injury. In general terms, returning a player back-to-play indicates he/she is sufficiently recovered enough to resume maximal level of activity.  With a majority of our subjects being returned so soon, it may indicate that the injuries were quite mild in nature and therefore resolved quickly. This may be supported as the vast majority (90%) of SRC has been reported to resolve with 7-10 days following injury (McCrory et al, 2009, McCrory et al, 2013). However, this has not been a universal finding, as a study by Maugans and colleagues (2012) showed following SRC in a pediatric population (11-15yrs) that CBF (133Xe clearance method) remained significantly reduced in 36% of the group 30 days after injury, with an average return back to play on Day 14.  The current study was not only novel in being the first study to assess CBF velocity response to exercise, but also to examine regional differences within the cerebral circulation. Only a handful of studies in healthy individuals have examined CBF in the posterior circulation during exercise (Sato et al, 2011, Smith et al, 2012, Willie et al, 2011b), with the vast majority reporting changes only in the anterior (i.e.,MCA) circulation only (Moraine et al, 1993, Hellstrom et al, 1996, Marsden et al, 2012). There is relevance of including the posterior circulation in examination as it supplies the brainstem, which contains the areas responsible for cardiac, vasomotor and ventilatory control, all parameters that are considerably altered with exercise.  One other noteworthy observation is that there was a trend for the concussed group to have higher PETCO2 values at rest and throughout exercise compared to the control group (Figure 3.7).  This trend following SRC might suggest a small degree of hypoventilation. Hypoventilation occurs when alveolar ventilation (VA) is inadequate to meet the requirements  70 of gas exchange and is characterized by a rise in PaCO2; where PaCO2 reflects the relationship between VA and CO2 production (VCO2; PaCO2 = VCO2/VA).  However, it should be noted that PETCO2 has been shown to slightly overestimate PaCO2 during exercise (Jones et al, 1979, Peebles et al, 2007). Despite this methodological limitation, there is still a ?relative? difference in PETCO2 between groups, indicating a similar ?relative? difference within the PaCO2. As described in Chapter 1 (subheading 1.3.2.1), the cerebrovasculature is highly sensitive to any changes in PaCO2 in ensuring the maintenance central pH within the brain. Previous literature indicating that cerebrovascular reactivity to hypercapnia may be blunted following mTBI in humans (Len et al, 2013); however, reactivity to CO2 was not assessed in the current group of concussed athletes.    Symptom Exacerbation and MCA velocity 4.3We found a relationship between the increase in symptoms at 70% HRR the increase in MCA velocity in SRC (R2= 0.37; P<0.05). This finding indicates that elevations in MCA velocity (and hence CBF) may play a role in symptom exacerbation during exercise in SRC.  Our study also validated previous studies that found the most commonly reported symptom reported by athletes was headache or pressure in the head (Meehan et al, 2011, Gessel et al, 2007, Collins et al, 2003a, Blinman et al, 2009, Benson et al, 2009) and was the most prominent symptom to be reported as exacerbated during exercise. Despite the well-documented rates and characterization of post-concussive symptoms (Johnson et al, 2011, Lau et al, 2011, Taylor et al, 2010, McClincy et al, 2006), the pathophysiology responsible for the presentation and exacerbation has yet to be well defined.   71 Interestingly, when a regression was run using the changed score in headache severity against relative MCA velocity at 70% HRR, there was found to be a very strong relationship (R2=0.60) between the two variables. This is consistent with the current theories on headache pathology; where researchers believe that headaches may stem from a mix of both vascular and neurogenic origins (Edvinsson, 2011, May and Goadsby, 1999, Nowak and Kacinski, 2009). The role of CBF and CBF velocity has been studied extensively in headache/migraine pathophysiology (Nowak and Kacinski, 2009) with mixed results.  However, this research has been based in the general population presenting with headache with no direct pathophysiological origins, such as TBI. One study has compared chronic post-traumatic headaches in migraneurs and healthy controls. Subjects with post-traumatic headache were found to have abnormal regional CBF (133Xe clearance technique) characterized by lower initial slope index and significant regional and hemispheric CBF asymmetries (Gilkey et al, 1997). The authors postulated that the massive upheaval of cellular homeostasis following the neurometabolic cascade would naturally interfere with many of the regulatory processes that occur within the brain, including CBF regulatory processes such as CA.  Although Gilkey and colleagues (1997) did not directly measure CA in their subjects, there is strong evidence to support that following TBI, CA is impaired (Enevoldsen and Jensen, 1978a, Lewelt et al, 1980, Czosnyka et al, 2001).  In the introduction the possibility of CA playing a role in symptom exacerbation was outlined. Potentially, the loss of CA during exercise could allow for a pressure-dependent relationship to occur between the increasing MAP and CBF velocities and hence ultimately increasing CPP and possibly causing traction of the trigeminal nerves (Davenport et al, 1994). Certain evidence supports the hypothesis of impaired CA through observations in autonomic  72 and cardiovascular uncoupling following mTBI (Hilz et al, 2011, Gall et al, 2004, Goldstein et al, 1998). This is interesting because dynamic CA appears to be in part mediated by neural mechanisms (Zhang et al, 2002). For example, Zhang and colleagues (2002) removed autonomic neural activity with a ganglion blockade, causing an impaired dynamic CA, which resulted in a more pressure-passive cerebral circulation. Two follow-up studies using an ?-adrenergic blockade (Hamner et al, 2010) and a cholinergic blockade (Hamner et al, 2012) during oscillatory lower-body negative pressure to induce changes in MAP, revealed that both sympathetic and parasympathetic activity contribute to CBF regulation. This evidence suggests that part of CBF regulation is controlled by autonomic neural activation and mTBI might be a strong enough perturbation to disrupt it.  The calculation of CVR crudely quantifies the extent to which the input signal (MAP) is reflected in the output signal (CBF velocity) according to Ohm?s law.  Even though the calculation of CVR in the upright position has been extensively used in previous studies (as MAP is likely the major determinate of CPP at rest (Ainslie and Tzeng, 2010)); MAP is not likely reflective of CPP under all circumstances in the upright posture. For example, the effects of exercise creating large changes in intrathoracic pressure, intracranial/venous pressures, and/or potentially cerebral blood volume and PaCO2, all of which may affect CPP.  Regardless of the methodological or physiological limitations of assessing solely MAP and CVR under dynamic conditions such as exercise, our data analysis showed CVRMCA and CVRPCA to be significantly reduced from baseline to 30% HRR in control subjects (Table 3.2, Figure 3.5) and then returned to baseline values at 70% HRR. This is consistent with previous findings (Marsden et al, 2012), where young individuals had a significant reduction in MCA CVR at 50% VO2peak and then progressively increased until the termination of exercise at VO2peak.  However,  73 this was not the case in the concussion group, who showed no change in CVR in either the MCA or PCA throughout the exercise protocol, with the exception of Day 30 (Table 3.2).  Unfortunately, these differences in CVR trend between groups occurred without any group differences in MAP, MCA or PCA velocity indicating very robustly that the concussed brain remains relatively effective in protecting itself from damage due to over-perfusion. This is supported by recent research indicated that CA may be more adept at compensating for hypertension rather than hypotension in both animal (Cassaglia et al, 2009) and healthy humans (Tzeng et al, 2010). However, it should be reiterated that the present study did not measure CA directly and therefore these changes remain relatively unknown in SRC. It is clear so far that there is still much to be determined about the extent of which CBF and CBF dysregulation contribute to symptom presentation following post-concussive injury; however, there is evidence CBF plays a role in what seems to be a very complex and integrative pathophysiology.     Day-to-Day Variation 4.4Reliability testing is used to help evaluate the variable of interest as well as the precision of the measurement tool or intra-rater. The present experimental design used a repeated-measures design to examine the consistency of the measures across days. This was addressed by using a test-retest method both at rest and during exercise in a subgroup of controls subjects (n=12), whereby the same measures were executed in the same subjects at two separate time points. Between-subject variation, as indicated by CV (Table 3.6) within the MCA was approximately 12% and 15-20% for the PCA at rest. The largest variation was seen in the PCA in CV, ICC and TEM.  This may be explained in part by the difficulty of locating the vessel; its  74 smaller size and greater depth compared to the MCA, and susceptibility to movement, especially during cycling. However, despite large variation between healthy control subjects, intra-rater reliability was shown to be consistent across testing days. This finding indicates that the majority of variation in measures is most likely attributable to physiological variation. The TEM for both MCA and PCA velocity at rest was within 5%. Although there has been no set standard for what is deemed acceptable variation in a measurement by intra-rater for transcranial Doppler, other peer-reviewed articles from this laboratory have reported test- retest reliability to be between 2-3% (Willie et al, 2012).    Due to the large variation between controls subjects, a sample size calculation based on a power of 0.80 and significance criterion of p=0.05 indicated that to measure the effect of concussion on CBF velocities during exercise we would need a sample size of 25 or more to see the effect size of 0.60 (i.e. calculated from MCA velocity data using Cohen?s D; (Field, 2009)).  Therefore, when considering our small sample size, it is realistic to expect that any population difference that may exist between our concussed and control subjects was ?wash-out? due to the large between-subject variability.   Methodological considerations  4.54.5.1 Subject recruitment, Sample Size on Statistical Power  The present study encountered many difficulties during the subject recruitment process, despite the best efforts of the research team. The original goal was to recruit between 25-30 subjects per group. Since February 2011, we have personally contacted sporting professionals from a variety of different associations of varying levels of competition (i.e. UBC Heat, WHL, BCHL, Kelowna Minor Hockey, Senior High-School Football) across the Okanagan  75 Valley (Vernon to Penticton). However, due to a variety of constraints (i.e. new program, campus location, attitudes towards concussion research, time commitment of study, inclusion criteria, lack of interest), we were only able to recruit/include 6 SRC. Such a small sample size is usually accompanied by a significant loss of statistical power. When interpreting results, it is important to consider the statistical power of the test as it represents the probability that the null hypothesis will be accepted, when the null hypothesis is false (Field, 2009).  There are several factors that can affect a test?s statistical power and they include; choice of significance level, the size of the effect of interest and the sample size. The reason why sample size has such an influence is because small sample size can result in wide confidence intervals with a greater degree of variation, making it very difficult the statistical test to distinguish between the tests effects from random chance. A power of 0.80 and greater is considered statistically ?powerful? (Cohen, 1992); however, the calculated power of the current study was 0.29. Altman and Bland (1995) expressed that in underpowered studies, the lack of statistical significance does not necessarily mean that there was no effect (Altman and Bland 1995) because small sample sizes are unlikely to yield reliable and precise estimates of the true population. Therefore, it is important not to make strong conclusions, whether the alternative hypothesis was accepted, or in this case rejected. The only recommendation in cases such as these is to follow up small studies with larger ones to confirm results.    4.5.2 Parametric vs. Non-parametric testing  The data from this project had a mix of both normally and non-normally distributed. Parametric statistical analyses are based on assumptions that the data is normally distributed and that there is equal variance. Whereas, nonparametric statistical analyses are based on no  76 assumptions about the shape of the populations distribution from which the sample was drawn.  However, the vast majority (80%) of the collected data were normally distributed, with a few exceptions in each variable (i.e. MCA velocity at Day 14 at 30% HRR). Because this study had a small sample size, and to be as comprehensive as possible, both parametric (ANOVA, t-tests) and non-parametric tests were run. The results yielded from both types of statistical analysis showed the same overall trends, with no major group differences or overall day effects, with the exception of exercise. However, as there was non-normally distributed data, the non-parametric results were reported. It should be noted that there were no p-values below 0.05 for any of the exercising variables following non-parametric analysis, which when run using parametric t-tests ranged mostly between p= 0.01-0.001. When conducting multiple t-tests it is important to correct the alpha to reduce the possibility of inflating type-1 error (Field, 2009); this is usually corrected by using the Bonferroni?s correction. However in the case of our non-parametric results, we would have lost any significant changes with exercise. This would have, however, not been a true reflection of the data; therefore, p-values of 0.05 were considered significant.   4.5.3 Missing Data   Although the researchers on this project worked very hard to minimize missing data, not all subjects were able to make testing on appropriate day or finish the entire protocol. For example, we had one subject who was not able to tolerate 70% HRR for the first two visits and one subject?s Day 14 was right in the middle of a two week spring break. These are the main reasons for the missing data in the study. Although a consensus for the percentage of missing data that is acceptable to run transform (Schlomer et al, 2010), the standard cut-off to air on  77 the side of caution is recommended at 5%. Unfortunately, due to the small sample size, the missing data constituted more than 5% of our data therefore numerical imputation or substitution was not an option. In addition, the assumptions of imputing or substituting missing data relies on the fact that the missing data in completely random, which is not the case here in the present study.  Nonetheless, as the statistical analysis was done using non-parametric tests, our statistical analysis was not limited to the only four subjects who had complete data sets, keeping the analyses as complete and statistically valid as possible.    Concluding remarks 4.6Due to the constraints of our limited sample size and missing data, this made statistical analysis with the present data set difficult to properly assess. Therefore, it should be re-iterated that this study is a summary of the preliminary findings of what is hope to be a much larger study, which would allow for a more thorough and appropriate statistical analysis. Despite these limitations presented here, they do not de-value what has been accomplished and the findings that have been summarized here.   The data were collected with much dedication and precision as possible to eliminate as much random error as possible. This was made possible for example by have very strict pre-testing and testing guidelines; to limit the confounding influences of; caffeine, pre-testing exercise, alcohol, use of anti-inflammatory drugs for headache and other related symptoms. If there was a breach of pre-testing guidelines or a subject could not make testing at the same time of day, testing was re-scheduled. The analysis of day-to-day variation in our outcome measures also helped to analytically evaluate how much of our measurement variation is due to physiological variation or source error (i.e. the rater).  78 The use of transcranial Doppler made it possible to accurately track continuous MCAv and PCAV changes during upright exercise over the course of 1-month. Other CBF techniques are difficult to ascertain beat-to-beat changes, and those that can (i.e. duplex ultrasonography) are difficult to execute during exercise in the typical upright position.  Moreover, because CBF velocities increased significantly from 30% to 70%HRR this indicates that we successfully exercised our subjects at two different exercise intensities. Notwithstanding the limitations of HRR (discussed in subheading 2.6.3) HRR was a good way to apply the same predicted exercise intensity consistently across subjects; accounting for individual differences and possible deconditioning that could occur over 4 weeks of inactivity in concussed athletes.  Overall, the dedication to pre-testing guidelines and the structure of our testing protocol and assessment of day-to-day variation, it is fair to conclude that our data reflects our concussion population. Moreover, the protocol utilized was able to appropriately assessing CBF velocity response to both mild and moderate exercise intensity in a uniform manner without previous baseline data, while remaining as conservative as possible in such a vulnerable population.    Future Directions 4.7This preliminary study marks the first attempt to elucidate the response of CBF velocity to exercise as well as the potential role of CBF velocity in post-concussion symptom exacerbation.  Although the current study was restricted to a small clinical population, it has provided the starting blocks for further investigation into this area of concussion research. It is important that research continues in this area, as there is currently significant methodological difference between the studies and hence inherent difficulties to appropriately  79 contrast/compare between them. These differences include; severity of injury, timing of observations, measurement tool and protocol (drug infusion vs. cuff-inflation). Future research into CBF velocity should include direct measures of cerebrovascular reactivity to CO2, and dynamic CA following SRC both at rest and during exercise. There is strong evidence that CBF, CA and cerebrovascular reactivity CO2 to be altered following moderate-severe TBI (Enevoldsen and Jensen, 1978a, Lewelt et al, 1980, Czosnyka et al, 2001, Enevoldsen and Jensen, 1978b); however there is mixed results in mild TBI research (Len et al, 2011, Junger et al, 1997). This research is needed to help further explain the preliminary findings presented here in the current study as well as to help with better comparisons of current concussion literature revolving around CBF regulation and concussion.  An additional note, no study to date has assessed all parameters of CBF regulation simultaneously in the same sample population. Willie and colleagues (2011) highlighted in their review that integrative assessment of cerebrovascular function is severely lacking, and suggested that future studies endeavoring to assess cerebrovascular function should take a holistic approach and incorporate the assessment of multiple mechanisms (i.e. dynamic CA, CO2 reactivity, neurovascular coupling etc.).  Future studies may also want to consider using dual measures of CBF and velocity by including duplex B-mode ultrasound imaging of the ICA and VA.  Including these complimentary measures will help to more closely approximate changes in CBF, CBF velocities, and if these changes are accompanied by changes in vessel diameter. Current guidelines contradict normal exercise immediately following concussion and until the concussed subjects are completely asymptomatic at rest and during maximal exertion (McCrory et al, 2009, McCrory et al, 2013). There are some issues with these guidelines. First, the main reason for this recommendation to prevent any possibility of subsequent concussion  80 (McCrory et al, 2009), which could cause the development of the fatal and devastating consequence, second impact syndrome. Second, the associated risks of subjecting the brain to that kind of physiological stress so early on after injury (i.e. increased CPP, edema) are unknown. However, returning back-to-play and returning back to physical activity are two separate entities. A recent review has questioned the recommendation that athletes should remain at rest until asymptomatic (Silverberg and Iverson, 2012). This is based on their observations that inactivity can contribute to increased reporting of symptoms. Studies have emerged using physical activity as a treatment, to aid recovery from concussion (Leddy et al, 2011, Baker et al, 2012). However, sub-symptom exercise therapy in these studies was executed in chronically symptomatic athletes. This highlights the need for more clarification surrounding concussion pathophysiology, which may or may not validate exercise as risky or a viable recovery method for mTBI. More research is needed in this area.    Significance and Relevance 4.8This preliminary study has set a new precedent to highlight the feasibility of concussed subjects to exercise safely and to simultaneously assess cerebrovascular parameters in the process. The most important aspect of the current study was that it is the first study to address the potential role of regional CBF velocity as a mechanism behind symptom exacerbation post-concussion. Moreover, the majority of the studies evaluating CBF in this field have been principally in moderate to severe forms of TBI (i.e. car accidents, falls), therefore the current study has addressed the need for more observations in SRC. The assessment of post-concussion symptoms is important, as it is easy on-field concussion assessment tool. However, there are increasing reports that athletes may not be completely honest in reporting their symptoms  81 (McCrea et al, 2004) so they can be returned back-to-play sooner.  There are obvious concerns associated with returning an athlete back to play while still being symptomatic, for example the fatal and devastating consequence of second impact syndrome. For that reason, elucidating the mechanisms driving symptom exacerbation will be the first step in being able to objectively monitor and establish recovery in athletes, helping to make the safest return-to-play decisions possible. Moreover, there is evidence to suggest that symptoms may resolves despite the underlying physiology remaining impaired. For example, studies by Gall and colleagues (2004) have observed an increase in HR variability during sub-maximal exercise in junior hockey players suffering from mTBI, despite no differences observed at rest. This establishes that although subjects may present asymptomatic at rest, strong physiological stressors such as sub-maximal exercise may reveal the presence of continual physiological disruption in concussion. Lastly, the present study conducted serial monitoring of both the MCA and PCA velocities, providing detailed documentation over the course of 30 days following injury. This will help create a reference point for future studies. Future endeavors of this research will not only provide answers about the nature and potential mechanisms behind post-concussion symptoms, but may also provide a more objective measure of recovery.                 82 Bibliography or References Aaslid, R (1987). Visually evoked dynamic blood flow response of the human cerebral circulation. Stroke 18, 771-775.  Aaslid, R, Lindegaard, KF, Sorteberg, W & Nornes, H (1989). Cerebral autoregulation dynamics in humans. Stroke 20, 45-52.  Aaslid, R, Markwalder, TM & Nornes, H (1982). 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Appendices: Appendix A  : Human Research Ethics        The University of British Columbia Office of Research Services Clinical Research Ethics Board Room 210, 828 West 10th Avenue Vancouver, BC V5Z 1L8    H11-02900   Concussions and Brain Blood Flow during Exercise   (Version 4.0) Principal Investigator: Paul van Donkelaar 1. Principal Investigator & Study Team - Human Ethics Application [View Form] 1.1. Principal Investigator Please select the Principal Investigator (PI) for the study. Once you hit Select, you can enter the PI's name, or enter the first few letters of his or her name and hit Go. You can sort the returned list alphabetically by First name, Last name, or Organization by clicking the appropriate heading. Last Name First Name Employer.Name Email van Donkelaar Paul UBCO Health and Exercise Sciences paul.vandonkelaar@ubc.ca   Enter Principal Investigator Primary Department and also the primary location of the PI's Institution: Health and Exercise Sciences, UBCO  1.2. Primary Contact Provide the name of ONE primary contact person in addition to the PI who will receive ALL correspondence, certificates of approval and notifications from the REB for this study. This primary contact will have online access to read, amend, and track the application. Last Name First Name Rank Strachan Nicole Cecelia Graduate Student   1.3. Co-Investigators List all the Co-Investigators of the study. These members WILL have online access which will allow them to read, amend and track the application. These members will be listed on the certificate of approval (except BC Cancer Agency Research Ethics Board certificates). If this research application is for a graduate degree, enter the graduate student's name in this section. Last Name First Name Institution/Department Rank Burnett Tanis UBC/UBCO Health & Social Development/UBCO Health and Exercise Sciences Graduate Student Marsden Katelyn UBC/UBCO Health & Social Development/UBCO Health and Exercise Sciences Graduate Student Strachan Nicole Cecelia UBC/UBCO Health & Social Development Graduate Student Monteleone Brad UBC/Medicine, Faculty of/Family Practice Clinical Instructor Smith Kurt UBC/UBCO Health & Social Development Graduate Student van Donkelaar Paul UBC/UBCO Health & Social Development/UBCO Health and Exercise Sciences Professor    98 1.4. Additional Study Team Members - Online Access List the additional study team members who WILL have online access to read, amend, and track the application but WILL NOT be listed on the certificate of approval. Last Name First Name Institution/Department Rank   1.5. Additional Study Team Members - No Online Access Click Add to list study team members who WILL NOT have online access to the application and will NOT be listed on the certificate of approval. Last Name First Name Institution / Department Rank / Job Title Email Address    Tri Council Policy Statement2 (TCPS2) Tutorial All undergraduate and graduate students and medical residents are required to complete the TCPS2 Tutorial (CORE) before submission. This tutorial provides an essential orientation to Canadian human research ethics guidelines. The Principal Investigator and all Co-Investigators must be familiar with the TCPS2. Indicate completion of the TCPS2 (CORE) tutorial below: 1.6.A. All Undergraduate/Graduate Students: Yes  1.6.B. All Medical Residents: N/A (no medical residents participating in this study)  Comments:   1.7. Project Title Enter the title of this research study as it will appear on the certificate. If applicable, include the protocol number in brackets at the end of the title. If this is a class-based project, see guidance on the right. Using cerebrovascular biomarkers to better diagnose adolescent sports concussion  1.8. Project Nickname Enter a nickname for this study. What would you like this study to be known as to the Principal Investigator and study team? Concussions and Brain Blood Flow during Exercise  2 Study Dates and Funding Information - Human Ethics Application [View Form] You plan to start collecting data immediately after obtaining ethics and any other required approvals (the start date on the ethics certificate will reflect the approval date), no  You plan to start data collection at a later date i.e., 2 months or more after approvals are obtained. Click the calendar icon below to select the dates (Internet Explorer) or enter the dates manually using the format yyyy-mm-dd. Estimated start date: November 23, 2012  2.1. B. Estimated end date: November 22, 2013   99 2.2.A. Types of Funds Please select the applicable box(es) below to indicate the type(s) of funding you are receiving to conduct this research. You must then complete section 2.3 and/or section 2.4 for the name of the source of the funds to be listed on the certificate of approval. Grant  2.2.B. For Industry Sponsored studies, please provide a sponsor contact.   2.3. Research Funding Application/Award Associated with the Study that was Submitted to the UBC Office of Research Services Please click Add to identify the research funding application/award associated with this study. Selecting Add will list the sources of all research funding applications that have been submitted by the PI (and the person completing this application if different from the PI). If the research funding application/award associated with this study is not listed below, please enter those details in question 2.4. UBC Number Title Sponsor  F12-04140 Using cerebrovascular biomarkers to better diagnose adolescent sports concussion Canadian Institutes of Health Research (CIHR)  F12-01963 Executive function deficits following concussion in adolescents UBCO Faculty of Health and Social Development    2.4. Research Funding Application/Award Associated with the Study not listed in question 2.3. Please click Add to enter the details for the research funding application/award associated with this study that is not listed in question 2.3. When you press Add you can do a search for your funding award by doing a search in the Sponsor box - over 7000 options are listed UBC Number Title Sponsor    2.5.A. Is this a DHHS grant? (To view a list of DHHS funding agencies click on add in 2.5.B below) no  2.5.B. If yes, please select the appropriate DHHS funding agency from the selection box, and attach the grant to box 9.8. of the application. DHHS Sponsor List: Order: Active:   Attach DHHS Grant Application for each sponsor listed above   2.6. Conflict of Interest Do any of the following statements apply to the Principal Investigator, Co-Investigators and/or their partners/immediate family members? Receive personal benefits in connection with this study over and above the direct cost of conducting this study. For example, no   100 being paid by the funder for consulting. (Reminder: receiving a finders fee for each participant enrolled is not allowed). Have a non-financial relationship with the sponsor (such as unpaid consultant, advisor, board member or other non-financial interest). Have direct financial involvement with the sponsor (source of funds) via ownership of stock, stock options, or membership on a Board. Hold patent rights or intellectual property rights linked in any way to this study or its sponsor (source of funds). 4. Study Type - Human Ethics Application [View Form] 4.1. UBC Research Ethics Board Indicate which UBC Research Ethics Board you are applying to and the type of study you are applying for: UBC Clinical Research Ethics Board  N/A no  4.2.A. Institutions and Sites for Study Institution Site UBC Okanagan   4.2.B. Please enter any other locations where the research will be conducted under this Research Ethics Approval (e.g., private physician's office, community centre, school, classroom, participant's home, in the field - provide details). Lifemark Health Sports Medicine Centre, Kelowna, B.C.  Community-based facilities (e.g., hockey arenas, schools, football facilities) in the Kelowna, B.C. region.  4* Clinical Study Review Type [View Form] 4.3. Relationship with other proposals 4.3.A. If this proposal is closely linked to any other proposal previously/simultaneously submitted, enter the Research Ethics Board number of that proposal.   4.3.B. If applicable, please describe the relationship between this proposal and the previously/simultaneously submitted proposal listed above.   4.3.C. Have you received any information or are you aware of any rejection of this study by any Research Ethics Board? If yes, please provide known details and attach any available relevant documentation in question 9.7.   4.4. Level of Risk After reviewing the minimal risk guidance notes and the criteria for minimal risk, does yes   101 this study qualify for minimal risk review? Note that all studies which do not fall into the minimal risk category will undergo full board review. Peer Review If this research proposal has received any independent scientific/methodological peer review, please include the names of committees or individuals involved in the review. State whether the peer review process is ongoing or completed. All above minimal risk studies generally require a peer review. 4.5.A. External peer review details: None  4.5.B. Internal (UBC or hospital) peer review details: None  4.5.C. If this research proposal has NOT received any independent scientific/methodological peer review, explain why no review has taken place. It is a new project hence first submission to CREB  4.6. Harmonized review of multi-jurisdictional studies Please read and review the guidance note on the right prior to completing this question. Is this study a multi-jurisdictional study that will also require REB review/approval at one or more of the following institutions with which UBC has a collaborative review agreement? (See the guidance to the right for details about the harmonized process.) Simon Fraser University University of Alberta University of Northern British Columbia University of Saskatchewan University of Victoria (Note: If submitting an amendment for an already approved study, you must respond No to this question) no  4.7.A Creation of a Research Database, Registry or Tissue Bank Does this study involve the creation of a research database, registry or tissue bank? [if no, skip to 4.8] no  4.7.B Is the purpose of this application exclusively to obtain approval for the creation of a research database, registry or tissue bank? [Note if the creation of the database or registry or tissue repository is part of a bigger project also included in this application, you must answer no below.]   Clinical Chart Review 4.8.A. Is this an application for research using the no   102 review of clinical charts? 4.8.B. Insert the date range of the charts to be included in this research.   4.8.C. Is this a retrospective chart review where the only source of data will be medical charts/records that are currently in existence? (i.e., will pre-date the date of your ethics approval?)   4.8.D. Is this a retrospective chart review study that will involve the collection of NO personally identifiable information of any sort?   4.8.E. Is this a retrospective chart review study for which you are requesting a waiver of consent   5. Summary of Study and Recruitment - Human Ethics Application for Clinical Study [View Form] 5.1. Study Summary 5.1.A Provide a short summary of the project written in lay language suitable for non-scientific REB members. DO NOT exceed 100 words and do not cut and paste directly from the study protocol. Concussions are a common injury in contact sports and pose a serious threat to long-term neurological and mental health. The primary screening protocol for return to sport is cognitive functioning and exercise tests, which often results in a return of concussion symptoms. Advanced imaging techniques have failed to provide an accurate and identifiable cause. To date, no study has linked concussion symptom exacerbation with cerebral auto-regulation, despite known instances of cerebral auto regulation impairment during exercise. It is our belief that in looking at cerebral auto regulation, we may be able to identify an objective physiological tool in diagnosing concussions.   5.1.B Summarize the research proposal: Purpose: There is no direct evidence to support the putative relationship between dysfunctional CA and exercise-induced symptom exacerbation in concussion. The studies proposed in this application will be the first to directly measure the physiological correlates of this phenomenon and to quantify how these correlates are related to the return of symptoms and associated executive function deficits.  Hypothesis: The proposed study lead us to suspect that in subjects suffering from a concussion or mild traumatic brain injury will have an impaired cerebral auto regulation compared to age and activity matched control subjects. Furthermore, with the common use of exercise as a concussion diagnostic tool, it is believed that the common return of concussion symptoms a further impairment in executive functioning, cerebral blood flow regulation compared to control data will follow.   Justification: Mild traumatic brain injury or concussion is defined as a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces. Following a brain injury event there is a rapid onset of one or more graded neurological impairments that may or may not involve loss of consciousness and that usually resolve spontaneously over the course of a few days to weeks. The underlying cause of these impairments is due to neuropathological changes that appear to be both physiological and anatomical in nature. Moreover, the microstructural changes associated with physiological and  103 anatomical damage accompanying concussion injuries are not always detected on static brain images using expensive imaging techniques (e.g. fMRI, CT, PET). Given the subtle nature of the deficits following a concussion, it is quite often difficult to determine when a patient has recovered sufficiently to return to normal activities. Therefore, to quantify and identify if cerebrovascular functioning as indicated by dynamic CA and exercise cerebral perfusion, might be an acceptable method of determining return to exercise and sport readiness in the treatment of concussion. Provided that CA and executive function are appropriate outcome measures, they may provide an invaluable objective tool in assessing concussion at all levels of contact sport. The second control group, the asymptomatic and previously concussed subjects group will be used to explore the long term effects of concussions on CA and executive functioning.  Objective: To directly monitor CA processes at rest and during exercise in concussed individuals and correlate the resulting changes with the level of symptom exacerbation and executive dysfunction.   Research Method: The protocol will be a longitudinal design, covering a period of 1 month, with four consecutive testing sessions. Our experimental group will be athletes from a variety of contact sports who have recently suffered a concussion, and our two separate control groups will be age, gender, education and activity matches with our experimental group and have either have never suffered a concussion or have suffered a concussion in the past and are no longer symptomatic. Subjects will be tested 4 times over the course of 1 month. The concussion group will be tested within 3 days of experiencing a concussion, 1 week, 2 weeks, and 1 month after the injury. The control groups will be tested at similar intervals, approximately within the same time line. On the final testing session, subjects who have remained asymptomatic throughout all the protocols, may be asked to partake in a running gait analysis on a specially designed treadmill.  Statistical Analysis:The aim of this study is to generate the data needed to identify physiological and cognitive markers associated with post concussion syndrome. In order to generate and design a study with adequate power we estimated the required sample size based on previous data (Leddy et al. 2007, NeurRehabilitation; Aries et al., 2010, Stroke; van Donkelaar et al., 2005, Brain Injuries) from our laboratories in both healthy and disease populations, including concussed subjects. Power calculations are based on the desired endpoint to detect a change in cerebrovascular and executive function. Therefore, assuming our published standard deviations for these measures, a sample size of 20-30 subjects in each group would provide >90% probability that the study will detect a group difference at a two sided 5% significance level. However, accounting for potential dropouts (~10%), we will recruit 30 subjects per group for a total sample size of 60. All variables will be explored for parity with a normal distribution. At this time no sex difference measurements are planned, as it will be difficult to plan for a specific number of male and female concussed subjects. An amendment may be done if we feel that we will have an equal representation by each of the sexes. Relationships and differences between variables will be evaluated using multiple regression analysis or  104 linear mixed model analysis. Alpha value will be set a priori at P=0.05. All data will be analyzed using SPSS 16.0.2 (SPSS, Chicago, IL).   5.2. Inclusion Criteria Inclusion Criteria. Describe the participants being selected for this study, and list the criteria for their inclusion. For research involving human pluripotent stem cells, provide a detailed description of the stem cells being used in the research. Participants ( male or female) will be recruited and separated into one of three groups; 1) normal healthy individuals (n=30) who have never suffered from a concussion, 2) asymptomatic athletes (n=30) with a prior history of concussions (1 or more), and 3) athletes who have recently (<3days) suffered a concussion (n=30). Subjects will be carefully screened during each visit to the laboratory (e.g., cardio vascular disease history, spirometry, carotid screening, and exercise stress test). Participants recruited will be young individuals and between the ages of 11-25. All individuals will have a body mass index (BMI) <30 kg/m2.   5.3. Exclusion Criteria Exclusion Criteria. Describe which potential participants will be excluded from participation, and list the criteria for their exclusion. Exclusion criteria will include any history or signs of history, cardio-respiratory or cerebrovascular disease (specifically ischemic or other heart disease, carotid or other vascular disease, previous transient ischemic attack or stroke, previous head injury complicated by long term neurological sequelae, epilepsy),lower body injury limiting exercise performance, or who are smokers or pregnant. Subjects will have BMIs <30 kg/m2. All participants who cannot speak or read English will be excluded.   5.4. Recruitment Provide a detailed description of the method of recruitment. For example, describe who will contact prospective participants and by what means this will be done. Ensure that any letters of initial contact or other recruitment materials are attached to this submission on Page 9. Availability for the opportunity to volunteer in this study will be displayed on local community and university notice-boards, along with verbal invitation within the School of Health and Social Development at the University of British Columbia Okanagan campus. An email detailing the study will also be emailed among the university community, and local sports teams organizations. Additionally, Dr Monteleone, via his sports medicine clinic and involvement with local athlete clubs, will have access to a number of concussed subjects, who would satisfy the study inclusion. Subject recruitment will be completed using the informed consent application ( page 9), as well as, the recruitment email sent out to the local sports teams and organizations (Kelowna Suns Football team, Kelowna?s Pursuit of Excellence program).  No undue influence will be exercised in the recruitment of subjects, which will emphasize their volitional involvement. Upon recruitments participants will be given a unique subject number for identification purpose. Contact information will be collected by the principle investigator for scheduling purposes only (i.e. if a test needed to be cancelled/rescheduled).    5.5. Recruitment of Normal/Control Participants Describe how prospective normal/control participants will be identified, contacted, and recruited, if the method differs from the above. Same as above. Additionally, through Dr Monteleone's extensive involvement in the athletic community and personal contacts, he will be able to provide prospective normal/control subjects for our study. However, Dr. Monteleone will not be recruiting prospective normal/control subjects from his clinical practice.   5.6. Use of Records If existing records (e.g. health records, clinical lists or other records/databases) will be used to IDENTIFY potential participants, please describe how permission to access this information, and to collect and use this information will be obtained. Not applicable   105 5.7. Summary of Procedures Experimental Procedures ? Prior to and after each testing session, each subject will complete the SCAT2 symptom evaluation questionnaire to document specific symptoms and their severity. Dr Monteleone has extensive experience of assessing and using the SCAT2 symptom evaluation questionnaires.  Each testing session will be approximately two hours in duration. The subjects, upon arrival will have all anthropometric measurements taken (height, weight, BMI), as well as, a brief interview to confirm that pre protocol steps were followed (e.g. adequate hydration, no consumption of alcohol and caffeine within 12 hours, no strenuous physical activity). Immediately following the anthropometrics, the subjects will complete a concussion symptom evaluation questionnaire (SCAT2) and perform two neurocognitive tasks (Task Switching and The Stroop test) before the subject is set-up with all the instrumentation (listed above). After set-up, subjects will be asked to perform a second round of the Task Switching and The Stroop test (described later on).   Task Switching Protocol - Executive function will be assessed prior to the bout of exercise using a task-switching protocol. During the protocol, subjects will be comfortably seated in front of a computer monitor on which visual targets consisting of a circle (subtending ~1 degree of visual angle) appearing either at the top or the bottom of a vertically oriented rectangle (subtending ~5 x 2 degrees of visual angle) will be presented. Throughout the different components of the protocol either compatible or incompatible responses to the position of the circle will be required: compatible responses to the circle appearing at the top and bottom require the participant to press the ?7? and ?1? key, -respectively on the numeral keypads on the right hand side of a standard computer keyboard. By contrast, incompatible responses require the opposite mapping. We will assess performance in two different conditions (each with six blocks of 48 trials). In the single-task condition participants will perform either the compatible or incompatible versions of the protocol alone. This condition serves as a baseline for the general control demands of the task-switching condition. The task-switching condition requires switching between the two tasks in alternating runs of two trials. Participants will perform the alternating sequence without any external guidance (however, with feedback in case of errors that allows participants to realign themselves with the appropriate sequence. The interval between the response to the previous trial and the next stimulus will be 100 ms. Data collection will take approximately 15 minutes. The dependent variables for the task switching protocol include the reaction time and response accuracy. Reaction time is defined as the time period from the presentation of the visual stimulus to the pressing of the key by the participant. Response accuracy is defined as the percentage of trials within a condition in which the participant pressed the correct key. The ?global cost? of switching will be computed by calculating the relative change in reaction time during repeat trials in switch blocks compared to average single task reaction times. The ?switch cost? will be computed by calculating the relative change in reaction time during switch trials compared to repeat trials within the switch blocks.  Neurovascular Coupling: Neurovascular coupling will be  106 measured using a Visual Stimulation protocol while seated. The subject will be asked to close their eyes for 2 minutes, then open their eyes read an emotionally neutral article from a computer screen for another 2 minutes. This is immediately followed by 5 cycles of; eyes closed (20-seconds), and open while reading same document (40-seconds).  Cerebral Reactivity: Assessment of cerebrovascular reactivity in both hypercapnic and hypocapnic ranges will be carried out only at rest in an upright and seated position. The hypercapnic range will consist of 4 mins of an inspired fraction of CO2 5% with the intention of raising PETCO2 up 10mmhg. After a break to allow the subject to regain baseline values, the subject will be asked to stimulate the hypocapnic range, which will consist of 4 mins of volitional hyperventilation with the intention of reducing PETCO2 approximately 10mmHg. Safe ranges for human experimentation for hypocapnia should be 20mmHg, similarly marked subject discomfort is apparent with administration of 8% CO2 (15mmHg PaCO2 above rest); thus changes in PaCO2 under this range is recommended for safety and subject related comfort. However, mild changes in CO2 can be followed by minor headache or dizziness during increases in CO2 . Subjects will be closely monitored throughout the protocol, however, and in our experience of conducing greater than 2000 of these tests there have been no ill effects reported21. The tight controlling of the CO2 and O2 levels used in the technique will be performed using a closed circuit re-breathing system (Respiract, Thornhil Research, Toronto). In normal healthy humans PETCO2 and PETO2 provide accurate estimates of PaCO2 and PaO222. The use of this device has been approved by a previous CREB ethics board (H11-01105).  Dynamic CA: Assessment of dynamic CA is accomplished by combining beat-by-beat cerebral blood flow measurements (transcranial Doppler ultrasound) and blood pressure (finger photoplethysmography) recordings using spectral transfer function techniques 13,14. Impairment in dynamic CA is strongly linked to adverse clinical outcomes 4. The two measures we propose for dynamic CA are Stand-Squat and Lower Body Negative Pressure.  Squat-stand technique: The dynamic CA protocol will incorporate what is referred to as the squat and stand technique. Following a 5 min resting baseline subjects are asked to stand while being spotted at all times by two individuals. Once subjects are comfortable and a new steady state standing baseline is achieved, subjects will begin the repeated squat-stand maneuvers, attempting to mimic the lead researchers movements and a metronome as best as possible. The subjects will perform two randomized sets the squat-stand technique with five minutes of resting between each set. The two different sets will differ by the frequency rate the subject is moving from the squat position to the standing position. The two frequencies are a 0.05 Hz (10 second squat-10 second stand) or a 0.10 Hz (5second squat-5 second stand) for 5 minutes. Careful attention is paid to the depth of the squat obtained, as it is imperative to avoid a valsalva maneuver, which is known to increase brain blood flow, which may influence the results.  Lower Body Negative Pressure: The second method for determining dynamic CA is by using a lower body negative  107 pressure chamber. This chamber allows for the loading and unloading of a supine subject?s heart by methods of negative pressure oscillations. The typical protocol used is a 10 minute resting period, followed by 10 minute pressure fluctuation ranging from 0 mmHg to -40 mmHg.  The above techniques for dynamic CA have been approved or are in review by the CREB ethics board (H09-02682, H11-01105).  Force Platform and Centre of Pressure- Subjects will be asked to stand perfectly still with feet shoulder width apart on a 2x2 foot platform, that stand approximately 6 inches off the floor for 5 minutes while a computer software program analyzes postural changes. These postural changes will allow for the computer to perform a series of calculations and return a value of the subject?s centre of pressure. This value will be used as an index of balance, and is safe.   Exercise Protocol - Once subjects finish the stand and squat protocol, subjects will be seated on a specially designed upright bicycle to regain baseline values, before commencing the exercise protocol. Completion of baseline measurements will lead into the start of a 16-minute bout of progressive incremental exercise. In particular, subjects will cycle for 8-minutes at 30% estimated heart rate reserve and provided they remain symptom free; will be ramped up (by adding watts) and attempt to exercise at 70% of estimated heart rate reserve for the final 8-minutes. At each given HRR ( 30% and 70%), once the subject reaches a steady state for at least 5 minutes, they will then perform the Stroop test while continuing to exercise.   Stroop Task Protocol - During the bout of exercise, the Stroop task will be administered at during the final 2 minutes of each exercise stage. This will allow us to monitor the putative effects of disrupted CA during exercise on a simple probe of executive function. In the Stroop task, a 20-item list of color names are presented either in compatible (e.g. ?blue? written in blue ink) or incompatible (e.g. ?blue? written in red ink) configurations. The participant is required to read through the list of names as quickly and accurately as possible. The time required to complete the list and the accuracy of the responses are the dependent variables of interest. At each testing period within the exercise bout the incompatible or compatible list will be presented in a counterbalanced order.   Symptomology will be recorded throughout exercise, and ended if symptoms increase to performance impairing effects. Exercise will finish following a 5-minute warm-down with subjects resting for 10 minutes while remaining seated on the bike before completing a final SCAT2 form. All tests will be terminated at the onset of any returning concussion symptoms (e.g. headache, dizziness, nausea, and fatigue) or on yours (the subjects) request without any discourse or repercussions.  For a time course and order of each protocol please see the attached protocol (pg. 9) for a depiction of the experimental design.   6. Participant Information and Consent Process - Human Ethics Application for Clinical Study [View Form]  108 6.1. Time to Participate How much time will a participant be asked to dedicate to the project beyond that needed for normal care? 4 visits of 2.5 hours over a one month period.  6.2. Time to Participate ? Normal/Control Participants If applicable, how much time will a normal/control volunteer be asked to dedicate to the project? Same as above  6.3. Risks/Harms Describe what is known about the risks (harms) of the proposed research. Exercised induced exacerbation of concussion symptoms (ie; headache, nausea, dizziness) are possiblities. At all times a physician will be present when testing concussion patients who are expected to present symptoms during testing. The presentation of these symptoms without subsiding will be the primary determinant for testing cessation. Upon standing from a resting stage, or during the squat stand protocol, the individuals may experience symptoms associated with fainting or may possible faint. These movements are incorporated into everyday life and have previously used in other studies that have gained ethical approval. Subject will be made aware of these symptoms and if the experience any or they progress rapidly then they will be instructed to inform us and individuals will be returned to the laying position. Also visual recordings of blood pressure will be available, this will allow blood pressure to be monitored, a drop in blood pressure below 80mmHg for more than 10s this is an indication that fainting may occur, if any individuals experience this, they will be rapidly returned to the laying down position. This has been employed in previous studies. There are no major risks associated with the mild changes in PaCO2, however participants may experience light headedness or dizziness during the inspiration of the gas mixture, in which case the gas mixture will be removed and subjects inspire normal room air. Patients will be closely monitored throughout the protocol, however, and in our experience of conducing >2000 of these tests there have been no ill effects reported.   6.4. Benefits Describe any potential benefits to the participant that could arise from his or her participation in the proposed research. There are no benefits to participants of this study.   6.5. Reimbursement Describe any reimbursement for expenses (e.g. meals, parking, medications) or payments/incentives/gifts-in-kind (e.g. honoraria, gifts, prizes, credits) to be offered to the participants. Provide full details of the amounts, payment schedules, and value of gifts-in-kind. Subjects will not be reimbursed for this study.   6.6. Obtaining Consent Specify who will explain the consent form and consent participants. Include details of where the consent will be obtained and under what circumstances. Subjects will be free to contact any of the investigators if they wish to discuss the procedures of the experiment following notification either by recruitment, flyers or word of month. A meeting will be arrange between the intending volunteer and the investigator, where the study will be presented and experimental procedure and equipment will be explained in detail. After which subjects will decide if they would like to take part in the study. It the participant wants to take part in the study, verbal and written consent will be obtained by one of the  109 investigators, at the research lab on the UBCO campus or at the community-based facility.   6.7.A. Waiver/Alteration of Consent If you are asking for a waiver or an alteration of the requirement for participant informed consent, please justify the waiver or alteration and explain how the study meets all the criteria on the right. Please address each criterion on the right individually. Not applicable   6.7.B. Waiver of Consent in Individual Medical Emergencies If you are asking for a waiver or an alteration of the requirement for participant informed consent in individual medical emergencies, please justify the waiver or alteration and explain how the study meets all the criteria on the right. Please address each criterion on the right individually.   6.8. Time to Consent How long after being provided with detailed information/consent form about the study will the participant have to decide whether or not to participate? Provide your rationale for the amount of time given. Subjects will have as long as they need to decide whether they do or do not want to participate.   6.9. Capacity to Consent Will every participant have the capacity to give fully informed consent on his/her own behalf? Please click Select to complete the question and view further details. Will the participant have the capacity to give fully informed consent? Details of the nature of the incapacity If not, who will consent on his/her behalf? If not, will he/she be able to give assent to participate? If Yes, explain how assent will be sought.  No Teenage children aged 14 to 18 will be asked to participate. Parent or Gaurdian yes Under CREB guidelines the informed consent will be readable by all participants 14 years or older and individual will be able to provide assent alongside parent or guardian signatures. [Details]   6.10. Renewal of Consent Describe    110 any situation in which the renewal of consent for this research might be appropriate, and how this would take place. 6.11. Provisions for Consent What provisions are planned for participants, or those consenting on a participant's behalf, to have special assistance, if needed, during the consent process (e.g. consent forms in Braille, or in languages other than English). Not Applicable  6.12. Restrictions on Disclosure Describe any restrictions regarding the disclosure of information to research participants (during or at the end of the study) that the sponsor has placed on investigators, including those related to the publication of results. Also, indicate any plans for communicating study results to participants. Not Applicable  7. Number of Participants and Drugs - Human Ethics Application For Clinical Study [View Form] 7.1. Multi-Centre Studies 7.1.A. Is this a multi-centre study (involves centres outside of those applied for under this Approval?) no  If known, please list the other sites below:   7.1.B. Is this study being submitted for ethical approval to any other BC or Canadian Research Ethics Board? Description: No   If yes, please provide the name of the REB(s) and if available, contact information:   7.2. Number of Participants 7.2.A. How many participants (including controls) will be enrolled in the entire study? (i.e. the entire study, world-wide) 90  7.2.B. How many participants (including controls) will be enrolled at institutions covered by this Research Ethics Approval? (i.e. only at the institutions covered by this approval) 90  Of these, how many are controls? 60  7.3. Drug approvals Enter the generic name of any investigational drug(s) not yet approved or any marketed drug(s) used outside of its approved indication. Not Applicable  7.4. Marketed Drugs Enter the name of any marketed drug(s) used within its approved indication. Not Applicable   111 7.5. Natural Health Products Enter the name of any Natural Health Products used: Not Applicable  7.6. Experimental Drugs and Devices Enter the name of any new investigational devices, or marketed devices used in experimental mode, that will be used outside of their approved indication. Not Applicable  7.7. PERs Enter the name of any positron-emitting radiopharmaceuticals (PERs). Not Applicable  7.8. Health Canada Regulatory Approvals 7.8.A. Health Canada Regulatory Approvals Is this study a clinical trial or investigational test requiring Health Canada regulatory approval (If this study does not require Health Canada approval, skip to 7.10) no  7.8.B. If Yes, check all that apply from the list below. Description Regulatory Approval:   7.8.C. Name the sponsor/institution/investigator responsible for filing a Clinical Trial Application (CTA) or Investigational Testing Authorization (ITA) with Health Canada or Other.   7.9. Details of Health Canada Regulatory Approvals If regulatory approval from a Health Canada directorate is required for this study, your certificate of ethical approval will not be released until the regulatory approval certificate, approval date and control number are received by REB administration. Click Add to enter the name of the regulatory agency, the date of the application (if pending) or the date of the approval, and the control number and the date of approval, for either the initial application or subsequent amendments. A copy of the approval (NOL, ITA, NOA) must also be attached in question 9.1. Name of Agency Date of Approval Date of Pending Application:    Health Canada NOL Control Number Health Canada NOL Control Number Date of Approval    7.10. Stem Cell Research Does this research fall within the categories of pluripotent stem cell research that need to be submitted to the CIHR Stem Cell Oversight Committee (SCOC)? no  7.11. Registration for Publication of Clinical Trials 7.11.A. Does this clinical study fall within the definition stated on the right (in the no   112 guidelines)? 7.11.B. If Yes, click Add to enter the following information. (Please note that registration by UBC ORS administration requires the prior ethical approval of the study. In that case, registration information should be added when it becomes available.) Has it been registered? Indicate the Authorized Registry used: Enter your Clinical Trial unique identifier:    7.12. US Regulatory Requirements 7.12.A. Is there a requirement for this research to comply with United States regulations for research ethics? no  7.12.B. If yes, please indicate whether or not FDA (Investigational New Drug) number (drug studies) or an FDA Investigational Device Exception (IDE) is required for the research and provide documentation from the Sponsor or the FDA verifying the IND/IDE number, or explaining the study exemption status, in Question 9.1.C.   8. Data Monitoring- Human Ethics Application For Clinical Study [View Form] 8.1. Unblinding in an Emergency Describe the provisions made to break the code of a double-blind study in an emergency situation, and indicate who has the code. This is not a Double blinded study  8.2. Data Monitoring Procedures Describe data monitoring procedures while research is ongoing. Include details of planned interim analyses, Data and Safety Monitoring Board, or other monitoring systems. There are no planned interim analysis. Data will only be analyzed on completion of the study.   8.3. Study Stoppage Describe the circumstances under which the study could be stopped early. Should this occur, describe what provisions would be put in place to ensure that the participants are fully informed of the reasons for stopping the study. We do not envision any reason why the study would be stopped early.  8.4. Personal Identifiers 8.4.A. Describe how the identity of the participants will be protected both during and after the research study, including how the participants will be identified on data collection forms. The identity of the subject will be protected by providing a unique, non-identifying numerical subject code for each individual that is not derived from a personal identifier, such as SIN, DOB, initials etc.   8.4.B. Will any personal health information or personal identifiers be collected? yes  If yes, please describe what Only information required for safety screening purposes will be  113 personal identifying information will be collected, and justify the need for it to be collected. collected such as past medical conditions, disease history, medications and known allergies.   8.5. Data Access and Storage 8.5.A. Explain who will have access to the data at each stage of processing and analysis, and indicate whether a current list of the names of study personnel (including co-investigators) and their delegated tasks will be maintained in the study file. If a list will not be maintained, please explain. Only the researchers associated with the study (Ainslie, Burnett, Monteleone, Marsden, Smith, and van Donkelaar) will have access to the data. A list of study personnel and their tasks will be kept with the file at all times  8.5.B. Describe how the data will be stored (e.g., computerized files, hard copy, video-recording, audio recording, personal electronic device, other). Paper-based data will be stored in a locked filing cabinet and electronic data will be stored on a password controlled computer with both firewall and virus protection.   8.5.C. Describe the safeguards in place to protect the confidentiality and security of the data. Paper-based data will be stored in a locked filing cabinet and electronic data will be on a password controlled computer with both firewall and virus protection. Subjects will not be identified by name but by a numeric subject code which will not be connected or linked to the data.   8.5.D. If any data or images are to be kept on the Web, what precautions have you taken to prevent it from being copied? No data or images will be kept on the web.   8.6. Disposition of Study Data 8.6.A. Describe what will happen to the data at the end of the study (including how long the study data will be retained, when and how the data will be destroyed), and what plans there are for future use of the data, including who will have access to the data in the future and for that purpose. If this study involves the creation of a research database or registry for the purpose of future research, please refer to the Guidance note linked on the right and provide the requisite information. Original data will be retained in the unit of origin for at least 5 years after the work has been published or presented. There are no future plans for using this data after the initial analysis of the study and the preparation and publication of manuscripts have been achieved. All paper data will also be shredded at the time of destruction and any electronic data will be permanently deleted and removed from any hard drive.   8.6.B. If applicable, describe what will happen to the study samples at the end of the study, including how long the study samples will be retained and where, when and how the samples will be destroyed, and what plans there are for future use of the samples, including who will have access to the data in the future and for what purpose.   8.7. Data Transfer to Other Institutions Will data be sent outside of the Institution where it is being collected?: no  If yes, please describe the type of    114 data to be transferred, who the data will be transferred to, where the data will transferred, and how the data will be sent. 8.8. Data Transfer to Institution Will the researchers be receiving data from other sites?: no  If yes, please describe the type of data that will be received, who it will be received from, where it will be received from, and how the data will be received.   8.9. Data Linkage 8.9.A. Will the data be linked to any other data source (including a biorepository)? no  8.9.B. Identify the data set, how the linkage will occur, and explain how confidentiality regarding the shared information will be preserved.   9. Documentation - Human Ethics Application for Clinical Study [View Form] 9.1.A. Protocol Examples of types of protocols are listed on the right. Click Add to enter the required information and attach the documents. Name Version Date  Cerebral blood flow and concussions during exercise 3 November 15, 2012 [View]  Cerebral blood flow and concussions during exercise 2 December 6, 2011 [View]  Cerebral blood flow and concussions during exercise  October 28, 2011 [View]  Cerebral blood flow and concussions during exercise 4 May 4, 2013 [View]    9.1.B. Health Canada regulatory approval (receipt will be acknowledged) Name Version Date    9.1.C. FDA IND or IDE letters (receipt will be acknowledged) Name Version Date    9.2. Consent Forms Examples of types of consent forms are listed on the right. Click Add to enter the required information and attach the forms. Name Version Date  Controls Informed Consent 4 November 15, 2012 [View]  Concussion Informed Consent 2 December 6, 2011 [View]  Controls Informed Consent  October 28, 2011 [View]  Concussion Informed Consent  October 28, 2011 [View]  Concussion Informed Consent 3 May 14, 2012 [View]  Controls Informed Consent 3 May 14, 2012 [View]  Control Informed Consent 5 May 4, 2013 [View]  Concussion Informed Consent 4 November 15, 2012 [View]  Concussion Informed Consent 5 May 4, 2013 [View]   115 Control Informed Consent 2 December 6, 2011 [View]    9.3. Assent Forms Examples of types of assent forms are listed on the right. Click Add to enter the required information and attach the forms. Name Version Date  Concussion Assent 1 May 4, 2013 [View]  Control Assent 1 May 4, 2013 [View]    9.4. Investigator Brochures/Product Monographs Please click Add to enter the required information and attach the documents. Name Version Date    9.5. Advertisement to Recruit Participants Examples are listed on the right. Click Add to enter the required information and attach the documents. Name Version Date  Concussion Cerebral Blood Flow Recruitment Email 4 May 4, 2013 [View]  Concussion Cerebral Blood Flow Recruitment Email 3 November 15, 2012 [View]  Concussion Cerebral Blood Flow Recruitment Email 2 December 6, 2011 [View]  Concussion Cerebral Blood Flow Recruitment Email  October 28, 2011 [View]    9.6. Questionnaire, Questionnaire Cover Letter, Tests, Interview Scripts, etc. Please click Add to enter the required information and attach the documents. Name Version Date  Concussion cerebral blood flow pre screen questionairre  October 28, 2011 [View]  Concussion cerebral blood flow pre screen questionaire 4 May 4, 2013 [View]  Concussion cerebral blood flow pre screen questionaire 3 November 8, 2012 [View]  Concussion cerebral blood flow pre screen questionairre 2 December 6, 2011 [View]    9.7. Letter of Initial Contact Please click Add to enter the required information and attach the forms. Name Version Date    9.8. Other Documents 9.8.A. Other documents: Examples of other types of documents are listed on the right. Click Add to enter the required information and attach the documents. Name Version Date    9.8.B. If a Web site is part of this study, enter the URL below. Since URL's may change over time or become non-existent, you must also attach a copy of the documentation contained on the web site to this section or provide an explanation.   10. Fee for Service - Human Ethics Application for Clinical Study [View Form] Please indicate which of the following methods of payment will be used for this application. N/A (Not funded by an Industry For-Profit Sponsors)  Enter information stating when the fee will be sent:    116 12. Save Application - Human Ethics Application [View Form]                                               117 Appendix B  : Recruitment Email   RE: Integrative Sports Concussion Research Group Dear _____________________   The School of Health and Exercise Sciences, located in the new Health Sciences Centre on the UBC-Okanagan campus is conducting an experiment that is aimed at investigating the progression of post-concussion symptoms on cognitive functioning and cerebrovascular functioning before, during, and after exercise. This is a novel research area that has the potential to generate positive health and economic benefits to all individuals engaged in contact sports, or active people who have suffered a concussion. In addition, further information on the clinical implications and potential screening ability for people who have had a concussion will be attractive to all family and sports physicians across Canada who are currently limited in their ability to objectively diagnose concussion and prescribe a safe and valid return to sport or physical activity. We are looking to recruit healthy volunteers between the ages of 14-25 years of age as well as similar aged athletes who have recently suffered a concussion. If you would like to participate in this study, please contact any member of research team listed at the end of this email, and please read the accompanying participant information sheet for further information on the investigation and the involvement that is required. Participation in the study is voluntary and you would have the right to withdraw at any point, with no explanation. If you would still like to participate in this investigation after reading the informed consent, we will ask that you come to the laboratory to discuss the project and the next steps of action. If you have any questions regarding the research study or the procedures involved, please do not hesitate to contact us. We will be happy to answer any questions. If you do not wish to take part in this study, thank you for your time. Yours sincerely,  Dr. Bradley Monteleone #104, 1634 Harvey Avenue Kelowna, B.C. Email: bmontele@telus.net Work: 250-860-4122  Dr. Paul van Donkelaar Room 113 Health Science Centre University of British Columbia Email: paul.vandonkelaar@ubc.ca Work: 250-807-8858     Kurt Smith Room 108 Health Science Centre University of British Columbia Email: kurt.smith@ubc.ca Cell: 250-863-8528 (24hr Contact)  Katelyn Marsden Room 108 Health Science Centre University of British Columbia Email: kit_marsden@hotmail.com Cell: 250-928-0273 (24hr Contact) 118 Appendix C  : Informed Consent Form  INFORMED CONSENT FORM ? CONCUSSION PARTICIPANTS  Title of Project: Cerebral Blood Flow Response to Exercise following Concussion   Principal Investigator: Dr. Paul van Donkelaar, PhD                                      UBC Okanagan, School of Health and Exercise Sciences                                        Health and Science Centre                                                                                           Work: 250-807-8980                  Co-investigators:  Dr. Brad Monteleone, MD, PhD    Dr. Philip Ainslie, PhD    Mr. Kurt J Smith, PhD Candidate    Ms. Katelyn R. Marsden, MSc Candidate    Ms. Nicole Strachan, MSc Candidate        Institution:  School of Health and Exercise Sciences    University of British Columbia, Okanagan Campus  You are being invited to participate in this research study because you have recently received a concussion. Please take time to read this document carefully and to discuss it with the investigator, your family, your doctor, or others before you decide to participate in this study. Participants:  Your participation is completely voluntary. You have the right to refuse to participate in this study. If you decide to participate, you will be required to sign the consent from at the end of this document. Also, if you do decide to participate, you may still choose to withdraw from the study at any time without any negative consequences to the medical care, education, or other services to which you are being entitled or are presently receiving.  Before you decide, it is important for you to understand what the research involves.  This document will provide you with all the necessary information regarding why the research is being done, what will happen to you during the study and the possible benefits, risks and discomforts. Who is conducting the study: You are being invited to take part in a study within the School of Health and Exercise Sciences in the Faculty of Health and Social Development within the University of British Columbia Okanagan.  This study will be conducted and overseen by Dr. Phil Ainslie, Dr. Brad Monteleone, Dr. Paul van Donkelaar, Mr. Kurt Smith, and Ms. Katelyn Marsden.   The purpose of this study: The purpose of this study is to understand how the brain responds to exercise and how this response is affected by a concussion. To do so, we need to compare subjects with concussion to healthy people.  Who can participate in this study? You can participate in this study as a concussed subject if you are 1) between the ages of 14-25 years of age, and 2) have recently (within the first 3 days) received a concussion. You must be able to speak and read English fluently.     Who should NOT participate in this study?  You will not be able to participate in this study if you 1) are over 25, 2) have a history of multiple concussions within the past six months, 3) have a previous history of cardiorespiratory/ cerebrovascular/neurological illness or events, 4) are taking any medication that might alter your blood pressure or brain blood  119 flow, 5) have a body mass index above 30 kg/m2, 6) if you are pregnant, or 7) are a smoker.  What does this study involve? : You will visit the lab on 4 separate occasions each lasting about 2 hours and spaced 1-2 weeks apart. During each session, we will 1) measure your height and weight, 2) ask you questions about what you ate and drank, how much physical activity you have had in the last 12 hours, and whether you have any concussion symptoms, 3) Immediately following, you will complete a concussion symptom evaluation questionnaire (SCAT2) and remain seated for a 5-minute baseline. 4) Afterwards you will be asked to breathe in 5% carbon dioxide for 4 minutes and then immediately after resting to regaining resting values, you will be asked to breathe as fast and as hard as you can for 4 minutes. You will be seated and at no risk of falling, however, there will always be a member of the research team monitoring you closely 6) Following 5 minutes of resting, you will be ask to perform stand and squats while being spotted for two 5 minute sessions (session 1: a cycle of stand for 10 seconds, squat for 10 seconds; and session 2; a cycle of stand for 5 seconds, squat for 5 seconds) separated by a break. Once you have successfully recovered from the stand and squats, 7) Finally, you will be placed upright on a stationary bicycle to regain resting values before commencing the exercise protocol. On the completion of resting measurements will lead into the start of a continuous 16-minute bout of progressive incremental exercise. In particular, you will cycle for 5 minutes at 30% of your estimated heart rate reserve (HRR) provided you remain symptom free; will attempt to exercise at 70% of you estimated HRR for  another 5 minutes. On the completion of the final Stroop test you will be cool-down by reducing the workload on the bike. There will always be a spotter near the bike in-case of an emergency or if you feel faint.   All tests and data collection will take place in Laboratory Room 108, Health Sciences Centre, at the University of British Columbia ? Okanagan Campus                Anthrometrics Measurements, PRESCREEN QUESTIONNAIRE AND SUBJECT DEMOGRAPHICS, and SCAT2 Administration  CEREBROVASCULAR REACTIVITY- AT REST (15mins)                                                                   4mins of administered 5% CO2 through a breathing circuit extension added to the face mask                                                                                                                                  Break ( take breathing circuit extension off face mask)                                                                                                                                                                                                                                                                                              4mins of hyperventilation (subject breathes as hard and as fast as they can)  BREAK to return Subject to BASELINE VALUES BREAK to return Subject to SEATED position for BASELINE VALUES STAND AND SQUATS (15mins)                                                       Stand for 5sec and Squat for 5sec for 5mins                     Seated until Subject returns to BASELINE VALUES                                                                                 Stand for 10sec and Squat for 10sec for 5mins                                   EXERCISE PROTOCOL on stationary upright bike (16mins)                                                                                 WARMING UP to reach 30% HRR                                                                    30% HRR for 3mins RAMPING UP intensity to reach 70% HRR                                                        70% HRR for 3mins  COOL DOWN SET-UP of Equipment on Subject (15-20mins)  120 Potential risks involved with your participation? : There are some risks that we have to highlight involving your participation in this study. Female participants in this study should not be pregnant. Participation while pregnant may result in potential harm to your fetus.  Exercise: Exercise in concussion patients has been known to result in the exacerbation of concussion symptoms (e.g.; headache, dizziness, nausea, and fatigue).  A sports medicine specialist experienced in treating concussions will be on hand throughout each experimental session.  The protocol will be stopped at the first sign of concussion symptom onset or at the subject?s request.  We will use a specialized bike to ensure your safety while exercising. However, if you feel any discomfort while exercising (i.e.; chest pain, shortness of breath, dizziness or nausea) stop exercising and inform us immediately.  The protocol will be terminated for your safety.  Ultrasound:  Ultrasound of blood flow in your brain is a non-invasive and painless technique in this experiment. It poses no risk. Vascular assessments:  The inflation of a blood pressure cuff around your arm can be painful and may give an unpleasant sensation in the lower arm, similar to pins and needles. This sensation disappears when the cuff is deflated. Additionally exercising during cuff inflation can also heighten sensation to a slight burn, also your hand may feel heavy, but again these sensations are lessened when exercise is stopped and disappear on cuff deflation.  Standing up and squat stand protocol: Upon standing out of bed or during the squat stand protocol, you may experience symptoms associated with fainting (light-headedness, dizziness) or may possible faint. These symptoms should subside however if they progress and you feel you may faint you will be returned to a lying position. We will be continuously monitoring your blood pressure and brain blood flow, from these measurements we will be able to identify if you are at risk of fainting, and prevent this from occurring.   Assessment of cerebral reactivity (an index of the blood flow reserve to the brain): There are no risks associated with the mild changes in carbon dioxide; however you may experience minor headache or dizziness during increases in carbon dioxide.  You will be closely monitored throughout the protocol, however, and in our experience of conducing greater than 2000 of these tests there have been no ill effects reported. A physician will be on-call during all experimental sessions should any complications arise.  In the unlikely event of any complication, such as cardiac arrest, emergency medical response will be immediately alerted. Dr. Brad Monteleone will supervise the stress testing. An investigator certified to perform cardiopulmonary resuscitation and in the use of an automated external defibrillator will be present at every testing session and will follow standard emergency protocols.  However, complications are very unlikely given the rigorous screening you will first undertake prior to admission to the study. What are the benefits for participating? You will not benefit personally from participation in this study. Your participation in this experiment will contribute to the understanding of how concussions affect the brain during exercise and tasks demanding high levels of concentration, with the hope of developing a method to quantifying the safe return of athletes post concussion to sport. What are my responsibilities? Since prior exercise, alcohol and caffeine intake all affect the ability to regulate brain blood flow and blood pressure you will also be asked to refrain from alcohol and caffeine consumption and vigorous exercise 24 hours prior to experimental days. Also, you will be asked to eat a light meal 3 hours prior to the experimental sessions.    121 What happens if I decide to withdraw my consent?  Your participation in this research is entirely voluntary. You may withdraw from this study at any time and you do not have to provide any reasons for your withdrawal, if you do not wish to do so. If you decide to enter the study and to withdraw at any time in the future, there will be no penalty or loss of benefits to which you are otherwise entitled, and your future medical care will not be affected. The study doctor(s)/investigators may decide to discontinue the study at any time, or withdraw you from the study at any time, if they feel that it is in your best interests. If you choose to enter the study and then decide to withdraw at a later time, all data collected about you during your enrolment in the study will be retained for analysis. By law, this data cannot be destroyed.    Confidentiality: Your confidentiality will be respected.  However, research records and health or other source records identifying you may be inspected in the presence of the Investigator or his or her designate, by representatives of Health Canada, and the UBC Research Ethics Board for the purpose of monitoring the research. No information or records that disclose your identity will be published without your consent, nor will any information or records that disclose your identity be removed or released without your consent unless required by law.   You will be assigned a unique study number as a subject in this study.  Only this number will be used on any research-related information collected about you during the course of this study, so that your identity [i.e. your name or any other information that could identify you] as a subject in this study will be kept confidential.   Information that contains your identity will remain only with the Principal Investigator and/or designate.  The list that matches your name to the unique study number that is used on your research-related information will not be removed or released without your consent unless required by law. Your rights to privacy are legally protected by federal and provincial laws that require safeguards to insure that your privacy is respected and also give you the right of access to the information about you that has been provided to the sponsor and, if need be, an opportunity to correct any errors in this information.  Further details about these laws are available on request to your study doctor. Please note that you may ask questions at any time.  We will be glad to discuss your results with you when they have become available and we welcome your comments and suggestions.  If you have any concerns about your rights as a research subject and/or your experiences while participating in this study, contact the Research Subject Information Line in the University of British Columbia Office Research Services' at 604-822-8598.  A trained research assistant will be available on every occasion to explain the procedure and answer any questions.  What happens if something goes wrong during this study?  Signing this consent form in no way limits your legal rights against the sponsor, investigators, or anyone else. Any adverse event that should arise will be logged in an investigators laboratory book, and will be followed through to ensure your safety and well-being. The researchers of this study will be freely available if you would like to discuss any problems or concern that may arise. Following the completion of the project you will be provided with a feedback sheet explaining the outcome and any substantive findings.  Can I be asked to leave the study? In a rare event that a medical emergency occurs during this study period, you will be automatically withdrawn from the study to ensure your safety and well-being.   After this study is completed?  Results of this project may be published and presented at national and internal conferences. Any data presented will not be linked to any specific  122 participant, as your data will be assigned a personal identification number to ensure anonymity in the raw data collected, analysis and documentation of results. You will be provided with a feedback sheet explaining the outcome and any substantive findings.  Contact Information: Please feel free to contact us at any time with questions and concerns you may have about participating in this research study.  Dr. Phil Ainslie                Dr. Bradley Monteleone     Room 118, Health Science Centre     #104, 1634 Harvey Avenue        University of British Columbia                              Kelowna              Email: Philip.ainslie@ubc.ca      Email:bmontele@telus.net                                                                                                                                                                                                                                                                                  Work: 250-807-8980                    Work:250-860-4122                                                                      Dr. Paul van Donkelaar     Kurt Smith                                    Room 360C, ARTS Building     Room 180, ARTS Building University of British Columbia    University of British Columbia Email: paul.vandokelaar@ubc.ca    Email: kurt.smith@ubc.ca Work: 250-807-8858                                                   Cell: 250-863-8528   Katelyn Marsden                                                                                                                                  Room 180, ARTS Building                                                                                                  University of British Columbia                                                                                                    Email: kit_marsden@hotmail.com                                                                                                                                 Cell: 250-928-0273 (24hr Contact) If you wish to contact an independent person regarding any aspect of your participation in this study please contact:  Dr Gordon Binsted Dean, School of Health and Exercise Sciences Faculty of Health and Social Development University of British Columbia 3333 University Way, Kelowna, B.C.  V1V 1V7  Office: 250-807-9642 Nicole Strachan                                                       Room 180, ARTS Building                                                                                                  University of British Columbia      Email: n-strachan@hotmail.com     Cell: 250-575-7151  123 Consent Form for Participants In signing this form you are consenting to participate in this research project. I have received a satisfactory explanation of what the study entails, and I have read and understand the purpose and procedures of this study as described in the participant information sheet, and I voluntarily agree to participate. I understand that at any time during the investigation I will be free to withdraw without jeopardizing any medical management, employment or educational opportunities. I have received all pages of the consent form and understand the contents of these pages, the proposed procedures and possible risks. I have had the opportunity to ask questions and have received satisfactory answers to all inquiries regarding this study. I will receive a signed and dated copy of the consent form. I know that: 1) My participation in the project is entirely voluntary, and I am free to withdraw from this study at any time without any disadvantage                                                                                              .   2) The data on which the results of the project depend upon will be retained in secure storage for 5 years, after which they will be destroyed                                                                                        .  3) I will be required to complete a pre-screen and a familiarization of the lab                                                        . 4) I understand that any personal information collected during the study remain anonymous and confidential.    ________________________          ___________________________         _____________ Signature of Subject                 Printed name            Date  _______________________          ________________________             ___________ Signature of Parent/Guardian     Printed name   Date   _______________________         ________________________               ___________ Principal Investigator or/   Printed name             Date designated representative      124 Appendix D  : Prescreen Questionnaire   PRESCREEN QUESTIONNAIRE AND SUBJECT DEMOGRAPHICS Title of Project: Cerebral Blood Flow Response to Exercise following Concussion Subject Identification Code (i.e. S101): ___________________                                      Age:  ________________ Sex:  M  ?   F  ? Weight: _________________ lbs  ?  kg  ? Height: __________________  Education Level: ________________________       Personal Medical History Assessment (please ? and/or give relevant detail) Have you ever been diagnosed with or experienced any of the following: 1) Mild traumatic brain injury or concussion?       Yes ?   No ? If Yes: How many concussions have you had? _______________ How did the concussion(s) occur (i.e. blow to the head during hockey game)? ___________________________________________________________________ ___________________________________________________________________ Was your concussion classified as Mild, Moderate, or Severe?  __________________ What were the symptoms you exhibited?  __________________________________ How long ago did the concussion(s) occur?   ________________________________ How long have you been asymptomatic (no obvious symptoms)?  _______________ What kind of treatment or care did you receive post-concussion?  ___________________________________________________________________ ___________________________________________________________________  125 ...................................................................................................................... 2) Epilepsy or any other neurological disorder that requires medication (ADD or ADHD)? Yes ?   No ? ...................................................................................................................... 3) Heart Conditions (pacemaker, arrhythmia, angina, coronary heart disease, bradycardia)? Yes ?   No ? ...................................................................................................................... 4) High Blood Cholesterol? Yes ?   No ? ...................................................................................................................... 5) High or Low Blood Pressure? Yes ?   No ? ...................................................................................................................... 6) Any Metabolic Disorders (e.g. diabetes, irritable bowel syndrome, anorexia, gastro intestinal disorder or history of impairments of gag reflex)? Yes ?   No ? ...................................................................................................................... 7) Have you have had a stroke? Yes ?   No ? ...................................................................................................................... 8) Do you ever lose consciousness (fainting or black outs)? Yes ?   No ?  ...................................................................................................................... 9) Do you have any respiratory diseases/problems (e.g. asthma, cold, pulmonary vascular disease, emphysema)? Yes ?   No ? ...................................................................................................................... 10) Do you have and muscular skeletal disease (e.g. osteoporosis, arthritis)? Yes ?   No ? ......................................................................................................................  126 11)  Recent lower body or joint issues that limit your ability to perform exercise (hip,    knee, or ankle) Yes ?   No ? ...................................................................................................................... 12) Do you Smoke? Yes ?   No ? ...................................................................................................................... 13) Do you have any allergies to any medication (e.g. liquids or tables)? Yes ?   No ? ...................................................................................................................... 14) If females, could you be pregnant? Yes ?   No ? ......................................................................................................................  15) Are you currently on any medication (e.g. antihistamines, cold mixtures)? Yes ?   No ? ...................................................................................................................... 16) What sports are you involved in? _____________________________________  ...................................................................................................................... 17) How many days are you physically active (>30mins/session)? ______________  Thank you for your time and co-operation! All information provided on this questionnaire will be kept confidential. Feel free to ask any question regarding this questionnaire or the research project.  Researcher Only:  Manual Blood Pressure Check   Systolic: ______________  Diastolic: ______________    127 Participant has no significant current or past medical history of clinical significance Yes ?   No ?  Participant given signed informed consent (witnessed) Yes ?   No ?                                         128 Appendix E  : Sport Concussion Assessment Tool 2  

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