Current Sports Medicine Reports:
Competitive Sports: Section Articles
Use of Graded Exercise Testing in Concussion and Return-to-Activity Management
Leddy, John J. MD, FACSM FACP1; Willer, Barry PhD2
1Department of Orthopaedics, University at Buffalo, Buffalo, NY; and 2Department of Psychiatry, University at Buffalo, Buffalo, NY
Address for correspondence: John J. Leddy, MD, FACSM FACP, University Sports Medicine, 160 Farber Hall - SUNY, Buffalo, NY 14214; E-mail: firstname.lastname@example.org; email@example.com.
Abstract: Concussion is a physiologic brain injury that produces systemic and cognitive symptoms. The metabolic and physiologic changes of concussion result in altered autonomic function and control of cerebral blood flow. Evaluation and treatment approaches based upon the physiology of concussion may therefore add a new dimension to concussion care. In this article, we discuss the use of a standard treadmill test, the Buffalo Concussion Treadmill Test (BCTT), in acute concussion and in postconcussion syndrome (PCS). The BCTT has been shown to diagnose physiologic dysfunction in concussion safely and reliably, differentiate it from other diagnoses (e.g., cervical injury), and quantify the clinical severity and exercise capacity of concussed patients. It is used in PCS to establish a safe aerobic exercise treatment program to help speed recovery and return to activity. The use of a provocative exercise test is consistent with world expert consensus opinion on establishing physiologic recovery from concussion.
Expert consensus holds that the best treatment during the immediate and early recovery period after concussion is rest from physical and cognitive exertion (41). The concept that rest is best is supported partially by animal and human evidence that excessive activity soon after concussion prolongs recovery (22,36). There is also some evidence of a vulnerable period early after concussion during which the brain is susceptible to repeat injury and/or worsening symptoms with cognitive or physical stress (19). The concept of using rest for recovery from the acute effects of concussion also has been extended generally to apply to those with postconcussion syndrome (PCS), i.e., the persistence of symptoms beyond several weeks or months (25). The efficacy of rest in all phases of concussion recovery recently has been challenged (44). A study by Majerske et al. (36) demonstrated that cognitive recovery is best when the patient is involved in some limited exercise and cognitive activity after concussion but is worse when the activity is either too great or too little.
Concussion has been thought traditionally to represent primarily a disturbance of cognition, and there is a considerable body of research describing and promoting cognitive testing as the optimal approach to establish the degree of functional (read: cognitive) recovery. More recently, concussion is being described as a physiological insult to the brain (32). The metabolic and physiologic changes that accompany concussion result, among other things, in altered autonomic function and control of cerebral blood flow (CBF) (16,26). As such, evaluation and treatment approaches that are based upon the physiology of concussion may add a new dimension to concussion care. The purpose of this article is to review the use of exercise testing to evaluate physiologic recovery from the acute effects of concussion and to review the theory and evidence behind using individualized aerobic exercise treatment in the return-to-activity (RTA) management of those with concussion and PCS.
Definitions of Concussion and PCS
Concussion is a transient disturbance of neurologic function resulting from traumatic forces imparted to the brain (41). While sport concussion may be differentiated from non-sport-related mild traumatic brain injury (TBI) based upon mechanism of injury (41), the symptoms reported are the same. While there continues to be debate about the finer aspects of concussion diagnosis, there appears to be general consensus on the key elements and a host of measures available to assess symptoms (35), cognitive impairments (8), and balance (23). Most patients recover from the acute effects of concussion within days to weeks, but some take longer, up to several months or more (37). Those that take longer to recover are said to have PCS.
The definition of PCS is much less specific than that of acute concussion. The symptom checklists still apply, but in many instances patients believed to have PCS have no more symptoms than those who have never been concussed (37). Neuropsychological testing of those with PCS does not appear to have much value for confirming the diagnosis (9). The timeframe for recovery is influenced by factors such as athlete status (31), age (34), sex (42), and history of prior concussions (24). Research so far, however, has been unsuccessful at identifying factors that consistently predict PCS, largely because PCS is not one syndrome but is a heterogeneous disorder without reliable diagnostic criteria.
The diagnosis of PCS among nonathletes generally includes persistent symptoms for at least 3 months. Athletes (defined as those individuals competing in sport who sustain a concussion during sport) have delayed recovery when symptoms persist for a time frame longer than normally would be expected for that athlete, i.e., from 3 to 6 wk (25). For example, younger adolescent and children athletes may require 4 to 6 wk to recover from the acute effects of concussion (38) whereas collegiate and professional athletes are outside the typical recovery period after 3 wk or more of persistent symptoms (25,48). These time-to-diagnosis differences and other symptom-based criteria are arbitrary, so one of the objectives of this article is to provide a more scientific definition of PCS based on some of the physiologic changes that are precipitated by concussion.
Pathophysiology of Concussion and PCS
It is intellectually useful (although perhaps not necessarily accurate) to try to differentiate the pathophysiology and clinical presentation of the acute effects of concussion from those of PCS. Linear, rotational, and blast-delivered forces to the brain induce rapid dynamic changes in neurotransmitters, intracellular and extracellular ions, glucose metabolism, and CBF (19). Recent evidence from studies using diffusion tensor imaging shows that this traumatic metabolic cascade also may be accompanied by microstructural injury to neurons, especially in the white matter of the brain (7). The acute pathophysiology of concussion produces a constellation of evolving signs and symptoms that reflect cognitive, emotional, and somatic dysfunction. Animal and human data suggest that this typically resolves, assuming no recurrent insult, within days to weeks after the injury (19,40). The etiology of the persistent symptoms in PCS patients is, however, controversial because until recently, the lack of findings on standard neuroimaging has led some to conclude that PCS, rather than being a direct consequence of brain injury, represents either an unmasking of a subclinical psychological illness, a reactive depression, a form of post traumatic stress disorder, a consequence of pain, or a form of malingering (25).
Recent physiological and advanced neuroimaging studies reveal, however, that some PCS patients have objective evidence of brain dysfunction that may explain their symptoms and limitations. For example, concussed athletes with prolonged depressive symptoms showed reduced functional magnetic resonance imaging (fMRI) activation in the dorsolateral prefrontal cortex and striatum and attenuated activation in medial frontal and temporal regions accompanied by gray matter loss in these areas (11). Some PCS patients have persistent abnormalities of brain blood flow on single-photon emission computerized tomography scan (1), neurochemical imbalances (e.g., serum S100B) (45), and electrophysiological indices of impairment (5). Postural instability is much more likely to be present when the other signs and symptoms are the result of organic-based PCS (23). In magnetic resonance spectroscopy studies, athletes who reported being symptom free at 3 to 15 d did not demonstrate complete metabolic recovery until a mean of 30 d postinjury, and mitochondrial metabolism took an additional 15 d to recover if a second concussion occurred before full metabolic recovery after a first concussion (47). There is fMRI evidence of abnormal CBF volume and distribution in humans both acutely after concussion (39) and in those with PCS (10) that may explain why concussed patients become fatigued easily with cognitive activity.
Concussion-induced mechanical changes coupled with the neurometabolic alterations described above can affect functional cerebral circulation (19). This, in conjunction with post-TBI autonomic dysfunction, has been proposed as a possible etiology for prolonged symptoms of PCS (32). Cerebral autoregulation — the capacity to maintain CBF at appropriate levels during changes in systemic blood pressure (BP) — and CBF itself are disturbed after concussion (26), which may explain why symptoms reappear or worsen with excessive physical exertion or other stressors. This appears to be a particularly important issue in adolescents, where abnormal CBF has been reported up to 4 wk after injury despite reported resolution of resting symptoms (38). Abnormal regulation of CBF may be due to altered autonomic nervous system (ANS) function and/or altered carbon dioxide (CO2) regulation after concussion. CO2 tension in the blood is the primary regulator of CBF (32). Concussed athletes have altered ANS balance (16), which is reflected by higher heart rates (HR) during steady-state exercise versus controls (17). The primary ANS control center, located in the brainstem, may be damaged in concussion, particularly if there is a rotational force applied to the upper cervical spine (18). Altered autonomic regulation after TBI is believed to be due to changes in the autonomic centers in the brain and/or an uncoupling of the connections between the central ANS, the arterial baroreceptors, and the heart. It is proportional to TBI severity and improves during TBI recovery (20).
Concussion and Exercise
Emerging data suggest that exercise improves brain function via favorable effects on brain neuroplasticity (2) as early as after 6 to 8 wk of exercise (46). The rapidity of the effect of exercise on the brain suggests that the mechanism may not involve exercise influence on cerebrovascular disease risk but rather improved neuronal function. Aerobic exercise has been shown to improve significantly fMRI cortical connectivity and activation (12). Moderate aerobic exercise (60% of maximum HR performed for 150 min·wk−1) is cognitively protective (28) and is associated with greater levels of brain-derived neurotrophic factor (BDNF), which is involved in neuron repair after injury, as well as greater hippocampal volume and improved spatial memory (14). Another salutary effect of regular exercise is improved regulation of CBF (3).
It is reasonable to infer that, if introduced at the right time, exercise might improve neuronal function after TBI. Experimental animal data show that premature voluntary exercise within the first week after concussion delays recovery and is associated with impaired cognitive memory task performance by interfering with the postconcussion rise of neuroplasticity molecules including BDNF (21). Aerobic exercise performed 14 to 21 d after concussion, however, upregulates BDNF in association with improved cognitive performance (22). Nonexperimental human data support that too much activity too soon after concussion is detrimental to recovery, but that too little activity is also detrimental (36). Individuals with TBI who exercise are less depressed and report better health status when compared with those who do not exercise (49). Thus exercise treatment after concussion may be beneficial if administered at the appropriate time and as long as the exercise is of appropriate type (i.e., aerobic), intensity, and duration.
Physical deconditioning of the cardiovascular system due to prolonged rest is common in TBI (48). Deconditioning has been associated with reduced CBF (50) whereas exercise training has beneficial effects on CBF control (3), which may relate to restoration of autonomic balance and/or sensitization of the autoregulatory system to gradual increases in systemic BP with controlled exercise (32). With respect to acute concussion, there is no evidence that complete rest beyond 3 d in adults is beneficial, whereas gradual reintroduction of activity appears to be (44). We have shown recently that it is safe for adult PCS patients to exercise up to 74% of maximum predicted capacity (27), which provides an evidence base for stage 2 (light aerobic exercise) of the Zurich Conference Guidelines’ graduated return to play (RTP) protocol (41). We have shown also that aerobic exercise treatment improves symptoms and outcome in PCS subjects in association with improved fitness and autonomic function (i.e., better HR and BP control) during exercise (31). The precise mechanisms for the effect, however, have yet to be elucidated.
The Buffalo Concussion Treadmill Test
We have developed a standard treadmill test, the Buffalo Concussion Treadmill Test (BCTT), that is the only functional test thus far shown to diagnose safely (31) and reliably (29) physiologic dysfunction in concussion, differentiate it from other diagnoses (e.g., cervical injury, depression, migraines) (6), and quantify the clinical severity and exercise capacity of concussed patients (31). The BCTT is based upon the Balke cardiac treadmill test, which requires a very gradual increase in workload that has been shown to be safe in patients with cardiac and orthopedic problems. The HR and BP recorded at the threshold of symptom exacerbation become the basis for the individualized exercise prescription for patients with PCS. The contraindications to performing the BCTT are those that typically would contraindicate the performance of a cardiac stress test. The absolute and relative contraindications to performing the BCTT are presented in Table 1.
BCTT protocol (31)
The test is a modification of the cardiac Balke protocol. The starting speed is 3.6 mph at 0% incline but can be altered if needed (increase speed a little to comfort for taller or athletic persons and reduce the speed for shorter or sedentary persons). During the first minute, the patient walks at 0% incline. The incline is increased by 1% at minute 2 and by 1% each minute thereafter while maintaining the same speed until the maximum incline is reached or the patient cannot continue. Rating of perceived exertion (RPE, Borg scale) and symptoms are assessed every minute. HR (by HR monitor) and BP (by automated cuff if available; if not, HR alone is sufficient) are measured every 2 min, and the test is stopped at a significant exacerbation of symptoms (defined as ≥3 points from that day’s pretreadmill test resting overall symptom score on a 1- to 10-point visual analog scale (VAS), Fig. 1) or at exhaustion (RPE of 19 to 20). If the patient reaches maximum incline and can still continue (not yet at RPE of 19 to 20 or exacerbation of symptoms), the speed is increased by 0.4 mph for each subsequent minute until stopping criteria are fulfilled. The test is deferred in those with significant pretest resting symptoms (i.e., ≥7 on the pretest VAS).
It is more accurate to classify patients experiencing prolonged symptoms after concussion as having one of several “postconcussion disorders” (PCD) rather than a single “PCS” because there is more than one cause of prolonged symptoms after concussion (6). The patient’s performance and symptom pattern during the BCTT, combined with a pretest physical examination, can help with the differential diagnosis of PCD (Table 2). Concussion symptoms, for example, typically are exacerbated by exercise, whereas exercise usually rapidly improves symptoms of depression (13). If patients can exercise to exhaustion without reproduction or exacerbation of headache or other concussion symptoms, and they demonstrate a normal physiological response to exercise, then we conclude that the symptoms are not due to the physiologic concussion but to another problem, most commonly, a cervical injury, vestibular/ocular dysfunction, or a posttraumatic headache syndrome such as migraine (6). A careful physical examination of the cervical spine and a neurologic examination focusing on the vestibular system and oculomotor responses (Table 2) can help identify sources other than concussion that produce similar symptoms such as dizziness, headache, trouble concentrating, and blurred vision (33). In general, an isolated posttraumatic vestibular injury presents with symptoms of true positional vertigo (i.e., a sensation of motion and nausea precipitated by head motion) with a positive Dix-Hallpike maneuver (sustained nystagmus and vertigo with sudden head rotation) but typically without other associated postconcussion symptoms. Vestibular symptoms caused primarily by concussion/PCS, while they may be exacerbated temporarily by head position changes, are typically not as position dependent, do not demonstrate nystagmus with the Dix-Hallpike maneuver, are almost always present at rest (with or without head motion), and are associated usually with multiple other PCS complaints such as lightheadedness and cognitive problems. Furthermore it must be recognized that exercise itself can produce symptoms such as fatigue, headache, and dizziness as the patient approaches voluntary exhaustion. Exercise symptoms, however, can be differentiated from those of physiologic concussion since they typically occur at peak exertion near exhaustion or immediately following intense exercise, whereas concussed patients develop symptoms earlier on in exercise that prevents them from continuing (31). The other common response observed during exercise is a cervical headache, which often improves as the muscles warm up only to return at the end of the test when patients may be straining to finish. The key differentiating point is that those with a cervicogenic headache or dizziness are able to exercise to exhaustion, despite some symptoms, whereas patients who have not recovered from the physiologic disturbance of concussion stop at a submaximal level because of significant symptom exacerbation. It is important to realize that many patients with prolonged symptoms after concussion no longer have concussion as the source of their symptoms; rather, they have symptoms from other sources, most commonly a cervical injury, a vestibular injury, or a posttraumatic migraine (6), which can benefit from therapy specifically tailored to these etiologies (4).Thus the BCTT combined with a careful physical examination can help the practitioner narrow the differential diagnosis of persistent postconcussion symptoms and so direct therapy to the specific cause, enhancing the RTA process.
BCTT versus Computerized Neurocognitive Testing in RTP
Since the BCTT has good reliability for identifying patients with symptom exacerbation from concussion, it can help to establish physiologic recovery from concussion and readiness for RTA (29). In a sample of 117 high school athletes, the BCTT, when used in combination with the Zurich Guidelines’ recommendations for graduated RTP, was 100% successful for returning concussed athletes to sport (Darling et al., accepted for publication). All athletes exercised to exhaustion without exacerbation of concussion symptoms on the BCTT, and all returned to sport without recurrent symptoms. Meanwhile almost half (48%) of the athletes had one or more computerized neuropsychological (cNP) subtest or composite scores (on ANAM or ImPACT) “below average” on the same day that they successfully completed the BCTT. Thus the ability of concussed athletes to exercise to exhaustion on the BCTT without symptom exacerbation better predicted readiness to begin the RTP process than did same-day cNP test performance. cNP test performance did not relate to RTP and was not associated statistically with symptoms reported upon return to school. These data support expert consensus opinion that the ability of concussed athletes to perform provocative exercise without symptom exacerbation establishes readiness to RTP (41).
Exercise Treatment of Concussion and PCS
The primary forms of concussion and PCS treatment traditionally have included rest, education, coping techniques, support and reassurance, neurocognitive rehabilitation, and antidepressants (48). There is some evidence that education, coping techniques, and neurocognitive rehabilitation have modest benefit in PCS patients (33). With respect to acute concussion, while it is accepted generally that children and adolescents require more cognitive and physical rest in the beginning to avoid delaying recovery, there is no evidence that complete rest beyond 3 d in adults is beneficial, whereas gradual reintroduction of activity appears to be most effective (44). Prolonged rest, especially in athletes, can lead to physical deconditioning and secondary symptoms such as fatigue and reactive depression (48).
The Zurich Consensus Statement recognizes the important physiologic component of testing and recovery after concussion. It advises that when asymptomatic at rest, concussed patients should progress stepwise from light aerobic activity such as walking or stationary cycling up to sport or work-specific activities (41). Recurrence of symptoms mandates return to the previously tolerated level of activity before advancing again. We have applied this principle to those with persistent symptoms. Our non-randomized pilot study showed that individualized aerobic exercise treatment improved symptoms in PCS subjects in association with improved fitness and autonomic function (i.e., better HR and BP control) during exercise (31) and, when compared with a period of no intervention, safely sped rate of recovery and restored function (sport and work) (31). A similar rehabilitation program has been established for children with PCS after sport-related concussion that combines gradual, closely monitored physical conditioning, general coordination exercises, visualization, education, and motivation activities (15). The efficacy of exercise treatment in patients with persistent concussion symptoms awaits confirmation in larger randomized trials, and the mechanisms for the effect of exercise on concussion have yet to be elucidated, but in a recent small controlled study in PCS we showed that exercise treatment restored normal local CBF regulation, as indicated by fMRI activation, versus a placebo stretching intervention in association with improved aerobic capacity and resolution of symptoms (30). Some concussion symptoms may therefore be related to abnormal local CBF regulation that is amenable to individualized aerobic exercise treatment.
RTP and RTA
Symptom reports and, despite its widespread use, cNP testing may not be the most reliable indicators of concussion recovery (43). The following is an illustration of how the BCTT can be used to gauge recovery after the symptoms seen acutely after concussion are reported to have resolved at rest. Using the BCTT, the athlete is able to exercise to exhaustion without symptom exacerbation. You conclude that s/he is recovered physiologically and can begin the graduated RTP process safely. Conversely if the athlete developed symptoms that stopped the test before peak exertion, you have objective information that s/he is not physiologically ready and will need more recovery time. The most commonly reported symptoms indicating that the concussion is not resolved are worsening headache, dizziness (i.e., lightheadedness), and/or a sensation that the head feels “full.” A comparison of the HR at the point of symptom exacerbation to the athlete’s theoretical maximum HR gives you a good indication of how close the athlete is to full physiologic recovery. If close to full recovery, the test can be repeated in a few days to a week. The test can be performed in a physician’s office, an athletic training or physical therapy facility, hospital clinic, or a health club, provided that the staff has been trained in treadmill test administration and that there is medical supervision in proximity.
With respect to RTA in patients with physiologic PCD, the BCTT can be performed safely in those who remain symptomatic for more than 3 wk (Fig. 2). If a submaximal symptom exacerbation threshold is identified, patients are given a prescription to perform aerobic exercise (on a stationary cycle, treadmill or elliptical) for 20 min per day at a subthreshold intensity, i.e., at 80% of the threshold HR achieved on the BCTT, once per day for 5 to 6 d·wk−1 using an HR monitor. They are required to have someone present during exercise for safety monitoring and should terminate exercise at the first sign of symptom exacerbation or after 20 min, whichever comes first. The BCTT can be repeated every 2 to 3 wk to establish a new symptom-limited threshold HR until symptoms are no longer exacerbated on the treadmill (Fig. 2). A more reasonable and cost-effective approach that avoids repeated testing, however, is to establish the threshold HR on the initial test and increase the exercise HR target by 5 to 10 bpm every 2 wk (via phone call or email), provided the patient is responding favorably (6). More fit patients and athletes generally respond faster (31) and can increase by 10 bpm every 2 wk, whereas nonathletes typically respond better to 5 bpm increments every 2 to 3 wk. Rate of exercise intensity progression varies, and some patients may have to stay at a particular HR for more than 2 wk, which is fine as the idea is to give patients specific goals to achieve without focusing on how fast it takes to realize full physiologic recovery. Physiologic resolution of PCD is defined as the ability to exercise to voluntary exhaustion at 85% to 90% of age-predicted maximum HR for 20 min without exacerbation of symptoms (31). Patients can then begin the Zurich graduated RTP program. Exercise testing should be considered only for patients without orthopedic or vestibular problems that increase the risk of falling off the treadmill and only in those patients who are at low risk for cardiac disease (31). In those patients who have a nonphysiologic cause of persistent symptoms (e.g., cervicogenic PCD or vestibular PCD), or a combination of disorders (patients with physiologic PCD also can have a neck injury), we have found that including regular aerobic exercise at a subthreshold level (80% of the maximum HR achieved on the BCTT) along with specific treatment for the nonphysiologic disorder is not only not detrimental but in fact appears to enhance recovery (6).
Growing literature suggests that concussion is a physiologic brain injury that produces systemic symptoms and cognitive dysfunction. Most patients who rest acutely recover from concussion within days to weeks but an important minority does not. Treadmill testing as a method to establish physiologic recovery from concussion makes sense since it better replicates what athletes and active persons (such as soldiers) do. For those with PCD, rest beyond 3 wk appears to be detrimental to recovery whereas regular aerobic exercise appears to have beneficial effects on symptoms and cognition, perhaps because aerobic exercise promotes neuroplasticity and improves control of CBF. Treadmill testing in those with PCD can help with the differential diagnosis of persistent symptoms to guide appropriate therapy. Treadmill test performance can establish the degree of physiologic recovery and give patients information on their prognosis. The symptom threshold HR can be used to prescribe an individualized subthreshold progressive aerobic exercise program that can improve symptoms safely, speed RTA, and restore function in many patients with PCD. Individualized exercise is a nonpharmaceutical intervention that challenges the current paradigm of prolonged rest, has minimal adverse effects, can be implemented with standard equipment, and could be used at many physician offices and health facilities, including military facilities and in the field, with relative ease. Further study of exercise testing and treatment in concussion and PCD should include randomized trials to evaluate its potential for safely and more rapidly returning acutely concussed patients and those with PCD to activity and to elucidate the underlying mechanisms of the beneficial effects of exercise evaluation and treatment in those experiencing concussion and PCD.
The authors thank the following organizations for financial support of the projects described in this article: The Robert Rich Family Foundation, The Buffalo Sabres Foundation, Program for Understanding Childhood Concussion and Stroke, The Ralph C. Wilson Foundation, and the National Football League Charities.
The authors declare no conflicts of interest.
1. Agrawal D, Gowda NK, Bal CS, et al. Is medial temporal injury responsible for pediatric postconcussion syndrome? A prospective controlled study with single-photon emission computerized tomography. J. Neurosurg.
2005; 102: 167–71.
2. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin. Proc.
2011; 86: 876–84.
3. Alderman BL, Arent SM, Landers DM, Rogers TJ. Aerobic exercise intensity and time of stressor administration influence cardiovascular responses to psychological stress. Psychophysiology
2007; 44: 759–66.
4. Alsalaheen BA, Mucha A, Morris LO, et al. Vestibular rehabilitation for dizziness and balance disorders after concussion. J. Neurol. Phys. Ther.
2010; 34: 87–93.
5. Arciniegas DB, Topkoff JL. Applications of the P50 evoked response to the evaluation of cognitive impairments after traumatic brain injury. Phys. Med. Rehabil. Clin. N. Am.
2004; 15: 177–203, viii.
6. Baker JG, Freitas MS, Leddy JJ, et al. Return to full functioning after graded exercise assessment and progressive exercise treatment of postconcussion syndrome. Rehabil. Res. Pract.
2012; 2012: 705309.
7. Bazarian JJ. Diagnosing mild traumatic brain injury after a concussion. J. Head Trauma Rehabil.
2010; 25: 225–7.
8. Bleiberg J, Cernich AN, Cameron K, et al. Duration of cognitive impairment after sports concussion. Neurosurgery
2004; 54: 1073–8; discussion 8–80.
9. Boake C, McCauley SR, Levin HS, et al. Diagnostic criteria for postconcussional syndrome after mild to moderate traumatic brain injury. J. Neuropsychiatry Clin. Neurosci.
2005; 17: 350–6.
10. Chen JK, Johnston KM, Frey S, et al. Functional abnormalities in symptomatic concussed athletes: an fMRI study. Neuroimage
2004; 22: 68–82.
11. Chen JK, Johnston KM, Petrides M, Ptito A. Neural substrates of symptoms of depression following concussion in male athletes with persisting postconcussion symptoms. Arch. Gen. Psychiatry
2008; 65: 81–9.
12. Colcombe SJ, Kramer AF, Erickson KI, et al. Cardiovascular fitness, cortical plasticity, and aging. Proc. Natl. Acad. Sci. U. S. A.
2004; 101: 3316–21.
13. Dimeo F, Bauer M, Varahram I, et al. Benefits from aerobic exercise in patients with major depression: a pilot study. Br. J. Sports Med.
2001; 35: 114–7.
14. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U. S. A.
2011; 108: 3017–22.
15. Gagnon I, Galli C, Friedman D, et al. Active rehabilitation for children who are slow to recover following sport-related concussion. Brain Inj.
2009; 23: 956–64.
16. Gall B, Parkhouse W, Goodman D. Heart rate variability of recently concussed athletes at rest and exercise. Med. Sci. Sports Exerc.
2004; 36: 1269–74.
17. Gall B, Parkhouse WS, Goodman D. Exercise following a sport induced concussion. Br. J. Sports Med.
2004; 38: 773–7.
18. Geets W, de Zegher F. EEG and brainstem abnormalities after cerebral concussion. Short term observations. Acta Neurol. Belg.
1985; 85: 277–83.
19. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J. Athl. Train.
2001; 36: 228–35.
20. Goldstein B, Toweill D, Lai S, et al. Uncoupling of the autonomic and cardiovascular systems in acute brain injury. Am. J. Physiol.
1998; 275 (4 Pt 2): R1287–92.
21. Griesbach GS, Gomez-Pinilla F, Hovda DA. The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise. Brain Res.
2004; 1016: 154–62.
22. Griesbach GS, Hovda DA, Molteni R, et al. Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience.
2004; 125: 129–39.
23. Guskiewicz KM. Assessment of postural stability following sport-related concussion. Curr. Sports Med. Rep.
2003; 2: 24–30.
24. Guskiewicz KM, Marshall SW, Bailes J, et al. Recurrent concussion and risk of depression in retired professional football players. Med. Sci. Sports Exerc.
2007; 39: 903–9.
25. Jotwani V, Harmon KG. Postconcussion syndrome in athletes. Curr. Sports Med. Rep.
2010; 9: 21–6.
26. Junger EC, Newell DW, Grant GA, et al. Cerebral autoregulation following minor head injury. J. Neurosurg.
1997; 86: 425–32.
27. Kozlowski KF, Graham J, Leddy JJ, et al. Exercise intolerance in individuals with postconcussion syndrome. J. Athl. Train.
2013; 48: 627–35.
28. Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA
2008; 300: 1027–37.
29. Leddy JJ, Baker JG, Kozlowski K, et al. Reliability of a graded exercise test for assessing recovery from concussion. Clin. J. Sport Med.
2011; 21: 89–94.
30. Leddy JJ, Cox JL, Baker JG, et al. Exercise treatment for postconcussion syndrome: a pilot study of changes in functional magnetic resonance imaging activation, physiology, and symptoms. J. Head Trauma Rehabil.
2013; 28: 241–9.
31. Leddy JJ, Kozlowski K, Donnelly JP, et al. A preliminary study of subsymptom threshold exercise training for refractory post-concussion syndrome. Clin. J. Sport Med.
2010; 20: 21–7.
32. Leddy JJ, Kozlowski K, Fung M, et al. Regulatory and autoregulatory physiological dysfunction as a primary characteristic of post concussion syndrome: implications for treatment. NeuroRehabilitation
2007; 22: 199–205.
33. Leddy JJ, Sandhu H, Sodhi V, et al. Rehabilitation of concussion and post-concussion syndrome. Sports Health
2012; 4: 147–54.
34. Lovell MR, Collins MW, Iverson GL, et al. Recovery from mild concussion in high school athletes. J. Neurosurg.
2003; 98: 296–301.
35. Lovell MR, Iverson GL, Collins MW, et al. Measurement of symptoms following sports-related concussion: reliability and normative data for the post-concussion scale. Appl. Neuropsychol.
2006; 13: 166–74.
36. Majerske CW, Mihalik JP, Ren D, et al. Concussion in sports: postconcussive activity levels, symptoms, and neurocognitive performance. J. Athl. Train.
2008; 43: 265–74.
37. Makdissi M, Cantu RC, Johnston KM, et al. The difficult concussion patient: what is the best approach to investigation and management of persistent (>10 days) postconcussive symptoms? Br. J. Sports Med.
2013; 47: 308–13.
38. Maugans TA, Farley C, Altaye M, et al. Pediatric sports-related concussion produces cerebral blood flow alterations. Pediatrics
2012; 129: 28–37.
39. McAllister TW, Sparling MB, Flashman LA, et al. Differential working memory load effects after mild traumatic brain injury. Neuroimage
2001; 14: 1004–12.
40. McCrea M, Guskiewicz KM, Marshall SW, et al. Acute effects and recovery time following concussion in collegiate football players: the NCAA Concussion Study. JAMA
2003; 290: 2556–63.
41. McCrory P, Meeuwisse W, Aubry M, et al. Consensus statement on concussion in sport — the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Clin. J. Sport Med.
2013; 23: 89–117.
42. Preiss-Farzanegan SJ, Chapman B, Wong TM, et al. The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury. PM R.
2009; 1: 245–53.
43. Randolph C, McCrea M, Barr WB. Is neuropsychological testing useful in the management of sport-related concussion? J. Athl. Train.
2005; 40: 139–52.
44. Silverberg ND, Iverson GL. Is rest after concussion “the best medicine?”: recommendations for activity resumption following concussion in athletes, civilians, and military service members. J. Head Trauma Rehabil.
2013; 28: 250–9.
45. Stalnacke BM, Bjornstig U, Karlsson K, Sojka P. One-year follow-up of mild traumatic brain injury: post-concussion symptoms, disabilities and life satisfaction in relation to serum levels of S-100B and neurone-specific enolase in acute phase. J. Rehabil. Med.
2005; 37: 300–5.
46. Stroth S, Hille K, Spitzer M, Reinhardt R. Aerobic endurance exercise benefits memory and affect in young adults. Neuropsychol. Rehabil.
2009; 19: 223–43.
47. Vagnozzi R, Signoretti S, Tavazzi B, et al. Temporal window of metabolic brain vulnerability to concussion: a pilot 1H-magnetic resonance spectroscopic study in concussed athletes — part III. Neurosurgery
2008; 62: 1286–95; discussion 95–6.
48. Willer B, Leddy JJ. Management of concussion and post-concussion syndrome. Curr. Treat. Options Neurol.
2006; 8: 415–26.
49. Wise EK, Hoffman JM, Powell JM, et al. Benefits of exercise maintenance after traumatic brain injury. Arch. Phys. Med. Rehabil.
2012; 93: 1319–23.
50. Zhang R, Zuckerman JH, Pawelczyk JA, Levine BD. Effects of head-down-tilt bed rest on cerebral hemodynamics during orthostatic stress. J. Appl. Physiol.
1997; 83: 2139–45.
Copyright © 2013 by the American College of Sports Medicine.