By John Leddy, MD, Barry Willer, PhD
Concussion is a subtype of mild traumatic brain injury (TBI) and is the result of sudden deceleration and rotational forces applied to the brain that trigger an acute and subacute pathophysiological metabolic response in the absence of gross structural changes to the brain(1). In the US alone, it is estimated that there are 1.6-3.8 million sport-related concussions (SRC) a year(2). The first summary and agreement statement of the 2001 consensus conference on concussion in sport held in Vienna recommended that SRC be treated by strict rest followed by a graduated return to play(3). Despite the fact that prescribed rest has been the treatment of choice for almost twenty years,(4) there has been surprisingly little research to support it(5). In fact, a randomized controlled trial (RCT) on concussed adolescents from the emergency department(6) showed that participants prescribed five days of strict rest reported more symptoms and had slower symptom resolution when compared with those prescribed usual care (one or two days of rest followed by a stepwise return to activity).
Research on sex differences in concussion recovery has produced conflicting results, with some studies finding females take longer to recover(7) while others do not(8.) It should be noted that none of these studies on sex differences compared outcomes from specific treatments. In a recent RCT of sub-symptom threshold aerobic exercise versus a placebo-like progressive stretching program prescribed within one week of SRC, we demonstrated that aerobic exercise safely reduced recovery time for both male and female adolescent athletes alike(9). Our study, however, did not have a comparison group prescribed rest after concussion.
In a quasi-experimental trial published in the Archives of Physical Medicine and Rehabilitation in 2019, we added a relative rest comparison group to the two treatment arms of our RCT to compare recovery times across the three treatment interventions(10). The secondary purpose of this study was to compare the recovery trajectory of females with males. Adolescent athletes (aged 13-18 years) presenting within 10 days of SRC (mean 5 days after injury) received a recommendation for rest (Rest Group, n=48). Their outcomes were compared with matched samples of adolescents assigned to aerobic exercise (Exercise Group, n=52) or placebo-like stretching (Placebo Group, n=51).
The rest group recovered in a mean of 16 days, which was significantly delayed (p=0.020) when compared with the exercise group (13 days). The placebo group recovered in 17 days. Four percent of the exercise group, 14% of the placebo group and 13% of the rest group had delayed recovery (defined as symptoms persisting more than 30 days). This study showed that relative rest and a placebo-like stretching program were very similar in days to recovery and symptom improvement pattern after SRC. Both conditions were less effective, however, than early sub-symptom threshold aerobic exercise. Furthermore, the incidence of delayed recovery was lower for the exercise group (4%) yet almost identical for the rest and placebo groups (13% and 14%, respectively). A study with a much larger sample size of adolescents from the emergency room(11) found that 30% of 2413 children with concussion had delayed recovery beyond 30 days from injury, making our 4% with the exercise group look very good.
With respect to females in our study, while they reported slightly higher symptoms at the initial visit than males in each group, these differences were not statistically significant. Importantly, males and females in each group did not differ in recovery time or incidence of delayed recovery. Interestingly, there was a sharp rise in symptom scores the day after the initial visit in females who had been prescribed relative rest. Conversely, there was a sharp decline of symptoms in females who were prescribed aerobic exercise or placebo stretching, which was not observed in the males.
The mechanism for this observation is not clear but it is possible that females advised to rest after SRC may have ruminated, which increased their symptoms. Studies12,13 have shown that females tend to ruminate about medical conditions more than males, with one report( 14) linking increased rumination and depressive symptoms after mild TBI in females to brain-derived neurotrophic factor (BDNF, which repairs neurons after injury) gene polymorphisms. It may therefore be particularly important for medical providers to avoid recommendations for strict rest and to recommend active treatment for females early after SRC to avoid early exacerbation of symptoms. Unfortunately, this study did not obtain any information about the menstrual cycle or hormonal levels, something which will be essential to future studies that examine clinical outcomes of females following SRC.
Why might sub-threshold aerobic exercise help females recover from concussion? Among the many physiological differences between males and females is cerebral blood flow (CBF) regulation. Females have greater CBF both at rest(15) and during exercise(16) versus males. A small controlled study published by our group in 2016 evaluated the control of CBF during exercise in females with persistent post-concussive symptoms (PPCS) before and after a sub-symptom threshold aerobic exercise treatment program(16). CBF was measured by transcranial Doppler during the Buffalo Concussion Treadmill Test (BCTT). The concussed female athletes had significantly greater CBF versus a healthy matched control group at similar treadmill workloads in association with appearance of
symptoms and premature exercise cessation. Sub-threshold aerobic exercise normalized CBF during exercise in the concussed females in association with symptom resolution and restoration of normal exercise tolerance. This study also found evidence of normalization of autonomic nervous system (ANS) dysfunction after exercise. The ANS is responsible for maintaining physiological homeostasis in the face of physiological stressors experienced by the body (for example, after injury or during changes in activity or emotion). ANS dysfunction17 after concussion appears to limit or blunt the appropriate response to physiological stressors, as revealed by measures of cerebrovascular vasoreactivity18, blood pressure regulation (19,) heart rate variability(20,) and CO2 sensitivity(16). Exercise is one type of stressor that elicits symptoms when the stress level exceeds a tolerable level. Thus, sub-symptom threshold aerobic exercise training may stress physiological systems within the body’s auto-regulatory capabilities after concussion to incrementally restore ANS control to normal(21). Females demonstrate altered ANS function in the first week after SRC12, which may help to explain why aerobic exercise, which improves ANS function, may be particularly effective for concussed females.
Females are different than males physiologically; thus, it is not surprising that they respond to a physiological injury such as concussion differently than males. Our work has shown that concussed females appear to be susceptible to symptom exacerbation when prescribed strict rest, which may have been particularly harmful to them during the decades we were recommending that they abstain from all physical activity until symptom resolution after concussion. The good news is that females appear to respond equally to males when advised to resume activities while staying below their individual symptom-exacerbation thresholds and even when prescribed early sub-threshold aerobic exercise treatment after SRC. Further research into sex differences in concussion recovery is needed, and it is recommended that such differences be examined within the context of the female hormonal milieu as well as current treatment recommendations.
- Barth JT, Freeman JR, et al., Acceleration-Deceleration Sport-Related Concussion: The Gravity of It All. J Athl Train. 2001;36(3):253-256.
- Langlois JA, Rutland-Brown W, et al. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21(5): 375-378.
- Aubry M, Cantu R, Dvorek J, et al. Summary and agreement statement of the First International Conference on Concussion in Sport, Vienna 2001. Recommendations for the improvement of safety and health of athletes who may suffer concussive injuries. Br J Sports Med. 2002 Feb;36(1):6-10.
- Moser RS, Schatz P, et al. Examining prescribed rest as treatment for adolescents who are slow to recover from concussion. Brain Inj. 2015;29(1):58-63. doi:10.3109/02699052.2014.964771
- 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(4):250-259.
- Thomas DG, Apps JN, et al. Benefits of Strict Rest After Acute Concussion: A Randomized Controlled Trial. Pediatrics. 2015; 135(2):213-223. doi:10.1542/peds.2014-0966
- Henry LC, Elbin RJ, et al. Examining Recovery Trajectories After Sport-Related Concussion With a
Multimodal Clinical Assessment Approach. Neurosurgery. 2016 doi:10.1227/NEU.0000000000001041
- Frommer LJ, Gurka KK, et al. Sex differences in concussion symptoms of high school athletes. J Athl Train.
2011; 46(1): 76-84.
- Leddy JJ, Haider MN, et. al. Early subthreshold aerobic exercise for sport-related concussion: a randomized
clinical trial. JAMA Pediatrics, Epub ahead of print. 2019. doi:doi:10.1001/jamapediatrics.2018.4397
- Willer BS, Haider MN, et al. Comparison of Rest to Aerobic Exercise and Placebo-like Treatment of Acute
Sport-Related Concussion in Male and Female Adolescents. Arch Phys Med Rehabil. 2019; 100(12):2267-
- Grool AM, Aglipay M, et al. Asociation between early participation in physical activity following acute
concussion and persistent postconcussive symptoms in children and adolescents. JAMA. 2016; 316(23):2504-
- Johnson BD, O’Leary MC, et. al. Face cooling exposes cardiac parasympathetic and sympathetic dysfunction in recently concussed college athletes. Physiol Rep. 2016; 6(9):, e13694. doi:10.14814/phy2.13694
- Lohaus A, Vierhaus M, et al. Rumination and symptom reports in children and adolescents: Results of a cross-sectional and experimental study. Psychology & health. 2013;28(9):1032-1045.
- Gabrys RL, Dixon K, et. al. Self-Reported Mild Traumatic Brain Injuries in Relation to Rumination and Depressive Symptoms: Moderating Role of Sex Differences and a Brain-Derived Neurotrophic Factor Gene Polymorphism. Clinical journal of sport medicine: official journal of the Canadian Academy of Sport Medicine. 2019 Nov;29(6):494-499. doi: 10.1097/JSM.0000000000000550.
- Satterthwaite TDm Shinohara RT, et al. Impact of puberty on the evolution of cerebral perfusion during adolescence. Proc Natl Acad Sci U S A. 2014;111(23):8643-8648. doi:10.1073/pnas.1400178111
- Clausen M, Pendergast DR, et al. Cerebral Blood Flow During Treadmill Exercise Is a Marker of Physiological Postconcussion Syndrome in Female Athletes. J Head Trauma Rehabil. 2016; 31(3): 215-224. doi:10.1097/HTR.0000000000000145
- Esterov D, Greenwald B. Autonomic dysfunction after mild traumatic brain injury. Brain sciences. 2017; 7(8): 100.
- Serador J, Tosto J, et al. Cerebrovascular Regulation is Impaired Immediately Post Concussion and Associated with Increased Estimated ICP. The FASEB Journal. 2015;29(1 Supplement): 800.811.
- Bishop S, Dech R, et al, Acute stages of concussion: Suppression of blood pressure during postural hemodynamic drives. Journal of Cerebral Blood Flow and Metabolism. 2016;36, 292. doi:10.1177/0271678X16639008
- Blake TA, McKay CD, et al. The impact of concussion on cardiac autonomic function: A systematic review. Brain Inj. 2016; 30(2), 132-145: doi:10.3109/02699052.2015.1093659
- Leddy JJ, Kozlowski K. Regulatory and autoregulatory physiological dysfunction as a primary characteristic of post concussion syndrome: implications for treatment. NeuroRehabilitation. 2007;22(3):199-205.
John J. Leddy, MD, is Professor of Clinical Orthopedics and Rehabilitation Sciences at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, a Fellow of the American College of Sports Medicine and of the American College of Physicians. He is the Medical Director of the University at Buffalo
Concussion Management Clinic, a Member of the Expert Panel for the Berlin Fifth International Consensus Conference on Concussion in Sport, and a consultant to the NIH on sport concussion research. In conjunction with Dr. Barry Willer, he developed the Buffalo Concussion Treadmill Test.
Barry Willer, MD, is Professor, Department of Psychiatry at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences and a member of the Board of Directors the North American Brain Injury Society. He is the Director of Research for the University at Buffalo Center for Research on Concussion.
He has a long history of research on acquired brain injury, including director of the first Center of Research on Community Integration, which developed the original data center for the TBI model systems program. He also authored the Community Integration Questionnaire and the Whatever It Takes model for TBI