vol. 4 no.

SPORTS HEALTH

[ Orthopaedic Surgery ]

Rehabilitation of Concussion and

Post-concussion Syndrome
John J. Leddy, MD,* Harkeet Sandhu, MD, Vikram Sodhi, MD,
John G. Baker, PhD, and Barry Willer, PhD
Context: Prolonged symptoms after concussion are called post-concussion syndrome (PCS), which is a controversial disorder with a wide differential diagnosis.
Evidence Acquisition: MEDLINE and PubMed searches were conducted for the years 1966 to 2011 using the search terms
brain concussion/complications OR brain concussion/diagnosis OR brain concussion/therapy AND sports OR athletic injuries. Secondary search terms included post-concussion syndrome, trauma, symptoms, metabolic, sports medicine, cognitive behavioral therapy, treatment and rehabilitation. Additional articles were identified from the bibliographies of recent
reviews.
Results: Of 564 studies that fulfilled preliminary search criteria, 119 focused on the diagnosis, pathophysiology, and
treatment/rehabilitation of concussion and PCS and formed the basis of this review. Rest is the primary treatment for the
acute symptoms of concussion. Ongoing symptoms are either a prolonged version of the concussion pathophysiology or a
manifestation of other processes, such as cervical injury, migraine headaches, depression, chronic pain, vestibular dysfunction,
visual dysfunction, or some combination of conditions. The pathophysiology of ongoing symptoms from the original
concussion injury may reflect multiple causes: anatomic, neurometabolic, and physiologic.
Conclusions: Treatment approaches depend on the clinicians ability to differentiate among the various conditions associated with PCS. Early education, cognitive behavioral therapy, and aerobic exercise therapy have shown efficacy in certain
patients but have limitations of study design. An algorithm is presented to aid clinicians in the evaluation and treatment of
concussion and PCS and in the return-to-activity decision.
Keywords: concussion; post-concussion syndrome; physiology; rehabilitation; cognitive behavioral therapy

oncussion, a form of mild traumatic brain injury (TBI),

is a leading public health problem, with an estimated
1.6 to 3.8 million sport-related concussions each year in
the United States.63 The majority of patients with sport-related
concussion recover within a 7- to 10-day period, although children
and adolescents require more time to recover than do collegiate
or professional athletes.8,75 Persistence of symptoms beyond the
generally accepted time frame for recovery may represent a
prolonged concussion or may herald the development of
post-concussion syndrome (PCS).117 The accepted time frame
for recovery is not scientifically established and is influenced by
factors such as age, sex, and history of prior concussions.43,54,74
Approximately 10% of athletes have persistent signs and symptoms
of concussion beyond 2 weeks.117 In non-sportrelated concussion,
most individuals recover completely within the first 3 months68;
however, up to 33%12,95 may exhibit symptoms beyond that.

There is some uncertainty about the definition of PCS, in

part because it is diagnosed according to clinical criteria. PCS
is defined by the fourth edition of the Diagnostic and Statistics
Manual as (1) cognitive deficits in attention or memory and
(2) at least 3 or more of the following symptoms: fatigue, sleep
disturbance, headache, dizziness, irritability, affective disturbance,
apathy, or personality change.13 However, these criteria are
conservative. The broader definition of PCS is represented by
clinical criteria of the World Health Organizations International
Classification of Diseases, or ICD-10namely, 3 or more of the
following symptoms: headache, dizziness, fatigue, irritability,
insomnia, concentration difficulty, or memory difficulty. Use of
these criteria is 6 times more sensitive for identifying patients
with PCS.13 After 3 weeks, patients (especially athletes) begin
to worry about when they will recover, and by 6 weeks, if
symptoms persist, PCS can alter their lives.117

From the Department of Orthopaedics and the Sports Medicine Institute, Buffalo, New York, and the Department of Psychiatry, State University of New York at Buffalo
School of Medicine and Biomedical Sciences, Buffalo, New York
*Address correspondence to John J. Leddy, MD, FACSM, FACP, University Sports Medicine, 160 Farber HallSUNY, Buffalo, NY 14214 (e-mail: [email protected]).
DOI: 10.1177/1941738111433673
2012 The Author(s)
147

Leddy et al

There is considerable controversy regarding PCS because

of the nonspecificity of symptoms and the fact that most
cognitive deficits resolve within 1 to 3 months after mild TBI in
the majority of patients.2,16 The differential diagnosis includes
depression, somatization, chronic fatigue and pain, cervical
injury, vestibular dysfunction, visual dysfunction, or some
combination of these conditions.2 Patients often present with
considerable insecurity about PCS symptoms: headache, fatigue,
sleep disturbance, vertigo, irritability, anxiety, depression,
apathy, and difficulty with concentration and exercise.117 The
clinical challenge is to determine whether prolonged symptoms
reflect a version of the concussion pathophysiology versus
a manifestation of a secondary process, such as premorbid
clinical depression or migraine headaches.21,62 If symptoms that
were experienced early after the injury are exacerbated with
exertion, but improved with rest, then the original concussion
pathophysiology is likely persisting.62 If ongoing symptoms are
exacerbated by even minimal activity and no longer respond
to rest, this may represent psychologic symptoms related to
prolonged inactivity and frustration with inability to return
to usual activities.62 Data suggest that at least some patients
with PCS have measurable pathophysiology. For example,
concussed athletes with prolonged depressive symptoms
showed reduced functional magnetic resonance imaging
activation in the dorsolateral prefrontal cortex and striatum
and attenuated deactivation in medial frontal and temporal
regions accompanied by gray matter loss in these areas.18
Some PCS patients have persistent abnormalities of brain
blood flow on single-photon emission computed tomography
scan,1 neurochemical imbalances (eg, serum S100B),102 and
electrophysiologic indices of impairment.4,27 Postural instability
is much more likely when other signs and symptoms are the
result of organic-based PCS.40

Theory of Prolonged Symptoms

Animal research suggests that the concussed brain is in
a vulnerable state that places it at increased risk of more
debilitating injury should more trauma occur before metabolic
homeostasis is restored.32,70 This vulnerable state can be
inferred in humans from data that concussion risk increases
after having had 1 or more concussions43 and from the second
impact syndrome (SIS).15 SIS is based on rare and disputed
cases in children and adolescents in which a second mild head
injury is thought to occur before resolution of a concussion,
with resulting malignant brain edema. McCrory76 argues that
rather than SIS being a complication of recurrent concussion,
it represents diffuse cerebral swelling, which is a wellrecognized complication of TBI in children. Additionally,
a recent review of death caused by blunt trauma found
subdural hematoma to be the cause of all 17 cases of SIS.
It is unclear whether concussion may have increased the
risk of bleeding or whether the initial injuries were occult
subdural injuries diagnosed as concussions.107 There is also
accumulating evidence of potential long-term sequelae in
humans from studies showing that previous concussions may
148

Mar Apr 2012

be associated with slower recovery of neurologic function43

and that repeated concussions can result in permanent
neurocognitive impairment41,43,53 and perhaps an increased
incidence of depression.42 Predictors of PCS are not known
with certainty, but some clinical variables appear to increase
the risk. These include a history of prior concussions,42,43,90
female sex,90,93 younger age,71,90 history of cognitive
dysfunction,106 and affective disorders, such as anxiety and
depression.17,72,74 Predictors related to injury severity, such as
length of posttraumatic amnesia and cognitive difficulties, are
clearly associated with symptoms at 1 month but less so at 6
months after injury.7 Interestingly, no study has identified injury
severity as a factor contributing to the development of PCS.
Anatomic/Mechanical
The acceleration-deceleration forces applied to the moving
brain cause shearing of neural and vascular elements55 with
sudden neuronal depolarization followed by a period of
nerve cell transmission failure101,115 that can result in loss
of consciousness.84 Animal studies of concussion show
neuropathologic changes in the hippocampus and diffuse
axonal injury along with disruption of the blood-brain barrier
and eventual neuronal loss.5,48,85,118 Diffusion tensor imaging of
the corpus callosum within 6 days of concussion in adolescents
showed white matter edema that correlated with symptom
severity.116 Quantitative electroencephalography and singlephoton emission computed tomography showed focal cortical
dysfunction in conjunction with persistent blood-brain barrier
disruption and reduced global and regional cerebral blood flow
in patients with PCS for more than a month post-injury.60
Neurometabolic
The neurometabolic basis for concussion and post-concussive
symptoms has been described in animal models.51
Experimental brain injury induces a cascade of neurochemical,
ionic, and metabolic changes that change cerebral glucose
metabolism and blood flow and alter mitochondrial
respiration.50,57,58,78 There is an initial phase of hyperglycolysis,
followed by a prolonged phase of metabolic depression that
can last 7 to 10 days in adult rats.51 This basic pathologic
response has been reported after human brain injury in
positron emission tomography studies showing a similar
pattern of early hyperglycolysis, followed by glucose metabolic
depression (Figure 1).9,10 In magnetic resonance spectroscopy
studies of human concussion, athletes who reported being
symptom free at 3 to 15 days did not demonstrate complete
metabolic recovery until a mean of 30 days post-injury.111
Mitochondrial metabolism took significantly longer (an
additional 15 days) to recover in athletes with a second
concussion.112
Physiologic
Concussion-induced mechanical changes coupled with the
neurometabolic alterations can affect functional cerebral

vol. 4 no. 2

SPORTS HEALTH

injury resulting from a twisting mechanism or direct trauma

to the upper cervical/posterior skull region may damage this
center. Thus, brain injury may alter central ANS regulation,
disrupting cardiorespiratory control of ventilation and leading
to the symptom exacerbation seen with physical exertion after
concussion.67

Assessment and Differential

Diagnosis

Figure 1. Neurometabolic cascade following concussion.

K+, potassium; CMRglucose, cerebral metabolic rate of glucose
utilization; Ca2+, calcium; CBF, cerebral blood flow. With
permission (adapted from Hovda et al50).

circulation.5,104,105 Concussion is also associated with metabolic

and physiologic changes in organ systems outside the brain.67
Concussed patients have higher heart rates at rest59 and after
cognitive45 and physiological stress.30 Autonomic nervous
system (ANS) function may be disturbed after concussion.88
Severe TBI,59 cerebral infarction,113 and concussion in athletes29
are associated with greater sympathetic nervous activity and
lower parasympathetic activity when compared with controls.
Autonomic dysregulation is proportional to TBI severity and
improves during TBI recovery.35 Increased sympathetic nervous
activity may be due to an altered endocrine99 or neuropeptide36
milieu after TBI. Autoregulation, the maintenance of cerebral
blood flow at appropriate levels during changes in systemic
blood pressure, and cerebral blood flow are also disturbed
after concussion,56,103 which may explain why symptoms often
reappear or worsen with physical and/or mental exertion.
Impairment of the cerebral vasculature after TBI sensitizes the
brain to secondary insults, such as hypotension, intracranial
hypertension, and dehydration.33
Cerebral artery regulation is very sensitive to the arterial
carbon dioxide tension (PaCO2) and responds with
vasoconstriction when PaCO2 is low and vasodilation when
it increases.69 The major determinant of the blood PaCO2 is
pulmonary ventilation. This physiologic process is diminished
in severely brain-injured humans24 and is altered early after
experimental concussive injury in animals.34 If concussed
patients have an altered ANS balance, pulmonary ventilation
may be altered as well, especially during exertion.
It is not known how physiologic dysfunction develops and
persists after TBI. The primary ANS control center is located
in the brainstem.98 Recent functional magnetic resonance
imaging evidence82 suggests that the ANS is more diffusely
distributed in the human brain beyond the brainstem to
include higher cortical (eg, dorsolateral prefrontal, posterior
insular, and middle temporal cortices) and limbic-related
regions (eg, amygdala, hippocampus, and thalamus). A head

Patient history should include a description of the mechanism

and force of the head trauma; the number and severity of
symptoms, including retrograde and anterograde amnesia;
and a history of any prior concussions, including mechanism,
symptom type, and duration.79 The nature, burden, and duration
of symptoms appear to be the primary determinant of injury
severity in concussion.79 A history of multiple concussions
appears to increase the risk for PCS.43,90 The older teenage or
adult patient may be experiencing PCS if symptoms persist
beyond 3 to 4 weeks, especially in athletes.117 A history of
migraine headaches, depression, anxiety, attention-deficit/
hyperactivity disorder, or learning disability is also crucial since
TBI can exacerbate these conditions.62 Depression is an important
differential diagnoses for PCS, in part because of overlapping
symptoms. A study of physician-diagnosed depressive disorder
found that 9 out of 10 patients met liberal criteria for PCS,
whereas 5 out of 10 met more conservative criteria.52
A detailed headache history is helpful because those with
migraines may be at increased risk of concussion with severe
and prolonged postconcussion symptoms.62,64 Upper cervical
spine injury can also mimic the symptoms of concussion and
PCS.23,109
The physical examination should include an assessment of
concentration (eg, drills such as stating the months of the year
in reverse, a series of digits backward tests), memory (recall of
3 words at 5 minutes), and examination of the cranial nerves,79
particularly extraocular motion, since PCS patients can have
persistent abnormalities of smooth pursuit saccadic eye
movements.46 The Romberg test,20 tandem gait, and vestibular
testing should also be performed.87 After the neurologic
examination, the cervical spine should be carefully assessed
for tenderness, spasm, and range of motion. Precipitation
of headaches, dizziness, or vertigo should direct therapy to
address a cervical injury.109
The physical examination should include an assessment of
concentration (eg, drills such as stating the months of the year
in reverse, a series of digits backward tests), memory (recall of
3 words at 5 minutes), and examination of the cranial nerves,79
particularly extraocular motion, since PCS patients can have
persistent abnormalities of smooth pursuit saccadic eye
movements.46 The Romberg test,20 tandem gait, and vestibular
testing should also be performed.87 After the neurologic
examination, the cervical spine should be carefully assessed
for tenderness, spasm, and range of motion. Precipitation
of headaches, dizziness, or vertigo should direct therapy to
address a cervical injury.109
149

Leddy et al

Diagnostic Testing
A standardized treadmill test employing a Balke protocol66 to
determine physiologic recovery has very good interrater and
sufficient retest reliability for identifying patients with symptom
exacerbation from concussion.65 Concussion symptoms are
typically exacerbated by exercise,77 while exercise may rapidly
improve depression.22 If patients can exercise to exhaustion
without reproduction or exacerbation of headache or other
concussion symptoms, then the symptoms may be due to
another problem.65,66 Computerized neuropsychological testing
is widely employed in sport even though there are concerns
with retest reliability and no data are available to suggest
improved outcomes.14,94,100

Rehabilitation of Concussion
and Pcs
Current guidelines recommend a period of cognitive and
physical rest in the early postinjury period because symptoms
can increase with cognitive and physical exertion.73,77
Prolonged rest, especially in athletes, can lead to physical
deconditioning,117 metabolic disturbances,44 and secondary
symptoms such as fatigue and reactive depression.11 There is
no scientific evidence that prolonged rest for more than several
weeks in concussed patients is beneficial.
Reassurance, discussions of expected recovery time, and
compensatory strategies can improve symptoms of PCS.80,114
An information booklet92 and psychological intervention81 can
reduce PCS symptoms at 3 to 6 months after injury.
A recent systematic review of psychological interventions
for PCS concluded that there was limited evidence of benefit.2
Cognitive behavioral therapy is a form of psychological
intervention that focuses on identifying and changing patterns
of maladaptive thinking and behavior that can exacerbateor,
in some cases, even causeaffective symptoms often associated
with persistent effects of direct brain injury, including depression
and anxiety. Three randomized controlled trials and 7 other
studies of cognitive behavioral therapy all found some benefit,
although there were limitations in study design.2
In children, most post-concussion symptoms resolve within
a month.89 The exceptions are children who have a history of
previous head injury, learning difficulties, or family stressors.89
An information booklet on strategies for dealing with
posttraumatic symptoms resulted in fewer symptoms and less
behavioral changes in children 3 months after injury.91
Interventions to improve cognition have improved
performance on selected neuropsychological test scores and
cognitive function following neurocognitive rehabilitation in
patients with mild or mild-to-moderate TBI.19,47,49 Neurocognitive
rehabilitation uses cognitive tasks to improve cognitive
processes, or it may involve developing compensatory strategies
to address difficulties with aspects of cognition, such as
attention, memory, and executive functioning. Empirical support
varies for neurocognitive rehabilitation of different cognitive
processes. Neurocognitive rehabilitation of attention processes
150

Mar Apr 2012

has received the most empirical support after TBI.19,47,86,96 A small

randomized controlled trial of an 11-week program of combined
neurocognitive rehabilitation and cognitive behavioral therapy
in mild-to-moderate TBI improved divided auditory attention,
anxiety, and depression in participants who were symptomatic
for 5 years.108
There is no scientific evidence that medication speeds
recovery from concussion in humans. The most common
medications prescribed for PCS are antidepressants.80 Selective
serotonin reuptake inhibitors have become the primary
treatment for head injuryassociated depression25,117 and can
improve depression and the cognitive deficits associated
with concussion.25,31,117 Tricyclic antidepressants such as lowdose amitriptyline110 are often used clinically to aid sleep and
headaches in patients with PCS, but there are no controlled
trials of their efficacy in restoring normal function.
The excitatory amino acids glutamate and aspartate may
be important mediators of brain injury. NMDA and AMPA
antagonists have been proposed for brain injury recovery.83
The deficits in attention and memory seen after TBI
mimic those in Alzheimer disease. There is some evidence
that cholinergic agents (physostigmine and donepezil
acetylcholinesterase inhibitors that temporarily increase brain
acetylcholine levels) and lecithin and CDP-choline (precursors
of brain acetylcholine) alleviate some of the cognitive deficits
suffered by brain injured patients.39,97
Vestibular dysfunction is commonly associated with TBI.3
Vestibular suppressants may delay recovery and have been
replaced by vestibular rehabilitation for posttraumatic vertigo.26
Vestibular rehabilitation may reduce dizziness and improve gait
and balance in children and adults.3
The upper cervical spine is particularly vulnerable to trauma
because it is the most mobile part of the vertebral column,
with a complex proprioceptive system that has connections to
the vestibular and visual systems.61 Cervical vertigo or dizziness
after whiplash injury can mimic the symptoms of PCS. It may
be due to mechanoreceptor dysfunction109 or posttraumatic
vertebrobasilar circulatory insufficiency.23
Physiologic disequilibrium may be a significant modulating
factor in concussion and PCS.67 Uncontrolled human activity too
soon after concussion is detrimental to recovery.43,73 Experimental
animal data show that premature voluntary exercise within
the first week after concussion impairs recovery while aerobic
exercise performed 14 to 21 days after concussion improves
cognitive performance.37,38 Neurotrophins (brain-derived
neurotrophic factor) promote neuronal recovery.6 Premature
voluntary exercise within the first week after concussion interferes
with the postconcussion rise of brain-derived neurotrophic
factor and is associated with impaired cognitive memory task
performance.37,38 Conversely, aerobic exercise performed 14 to 21
days after TBI upregulated brain-derived neurotrophic factor in
association with improved cognitive performance.37,38
The most recent consensus statement on concussion in sport
advises that when asymptomatic at rest, concussed patients
should progress stepwise from light aerobic activity, such as

vol. 4 no. 2

SPORTS HEALTH

Figure 2. Return-to-activity algorithm for concussion and postconcussion syndrome.*Time for symptom resolution will vary
depending on clinical circumstances. Most athletes recover within 1 to 3 weeks. **Treadmill testing in patients with persistent
symptoms should not be performed before 3 weeks after injury. Neuropsychological testing is not indicated, because the patient
is still symptomatic. If neuropsychological testing has been used, assume that there is a baseline preinjury test or valid normative
data for the particular patient. Exercise to exhaustion without exacerbation of symptoms. Exercise stopped at a submaximal effort
level because of symptom exacerbation. Repeat testing interval will vary depending on clinical circumstances; it may be several
days to several weeks. If athlete is not recovering, consider aerobic exercise rehabilitation. If computerized neuropsychological
testing has been used and remains abnormal, continue exercise treatment and consider consultation with a neuropsychologist to
evaluate for a specific cognitive deficit. RTA, return to activity; PCS: postconcussion syndrome; NP, neuropsychological.

walking or stationary cycling, up to sport- or work-specific

activities.79 The guideline recognizes the important physiologic
component of testing and recovery after concussion.
Controlled aerobic exercise rehabilitation after establishing
symptom-free exercise capacity via treadmill testing has helped
athlete and nonathlete PCS patients recover.66 Exercise testing
and rehabilitation should be employed only if patients have
persistent symptoms for 3 to 6 weeks or more.38,65,66 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.28
Figure 2 presents a suggested progression for making the
return-to-activity decision in patients who have recovered from
the acute effects of concussion and in those whose symptoms
persist beyond 3 weeks.65,66

Conclusions
Rest is the primary treatment for the acute symptoms of
concussion.79 Ongoing symptoms reflect either a prolonged
version of the concussion or a manifestation of other
processes, such as cervical injury, migraine headaches,
depression, chronic pain, vestibular dysfunction, visual
dysfunction, or a combination of conditions.62 The
pathophysiology of ongoing symptoms from the original
concussion injury may reflect multiple causes: anatomic,
neurometabolic, and physiologic.51,67,116 Treatment
approaches depend on the clinicians ability to differentiate
among the various conditions associated with PCS. Early
education,80,114 cognitive behavioral therapy,2 and aerobic
exercise therapy66 have been shown to be effective in
certain patients.

151

Leddy et al

Mar Apr 2012

Sort Recommendations
SORT: Strength of Recommendation Taxonomy
A: consistent, good-quality patient-oriented evidence
B: inconsistent or limited-quality patient-oriented evidence
C: consensus, disease-oriented evidence, usual practice, expert opinion, or case series
SORT Evidence
Rating

Clinical Recommendation
Early education,80,114 cognitive behavioral therapy,2 and aerobic exercise therapy66 have shown efcacy in certain patients

referenceS
1.

2.

3.

4.

5.

6.
7.
8.

9.

10.

11.

12.

13.

14.

15.
16.

17.

152

Agrawal D, Gowda NK, Bal CS, Pant M, Mahapatra AK. Is medial temporal
injury responsible for pediatric postconcussion syndrome? A prospective
controlled study with single-photon emission computerized tomography. J
Neurosurg. 2005;102(2)(suppl):167-171.
Al Sayegh A, Sandford D, Carson AJ. Psychological approaches to treatment
of postconcussion syndrome: a systematic review. J Neurol Neurosurg
Psychiatry. 2010;81(10):1128-1134.
Alsalaheen BA, Mucha A, Morris LO, et al. Vestibular rehabilitation for
dizziness and balance disorders after concussion. J Neurol Phys Ther.
2010;34(2):87-93.
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(1):177-203.
Baldwin SA, Fugaccia I, Brown DR, Brown LV, Scheff SW. Blood-brain
barrier breach following cortical contusion in the rat. J Neurosurg.
1996;85(3):476-481.
Barde YA. Trophic factors and neuronal survival. Neuron.
1989;2(6):1525-1534.
Bazarian JJ, Atabaki S. Predicting postconcussion syndrome after minor
traumatic brain injury. Acad Emerg Med. 2001;8(8):788-795.
Belanger HG, Vanderploeg RD. The neuropsychological impact of
sports-related concussion: a meta-analysis. J Int Neuropsychol Soc.
2005;11(4):345-357.
Bergsneider M, Hovda DA, Lee SM, et al. Dissociation of cerebral glucose
metabolism and level of consciousness during the period of metabolic
depression following human traumatic brain injury. J Neurotrauma.
2000;17(5):389-401.
Bergsneider M, Hovda DA, Shalmon E, et al. Cerebral hyperglycolysis
following severe traumatic brain injury in humans: a positron emission
tomography study. J Neurosurg. 1997;86(2):241-251.
Berlin AA, Kop WJ, Deuster PA. Depressive mood symptoms and fatigue
after exercise withdrawal: the potential role of decreased fitness. Psychosom
Med. 2006;68(2):224-230.
Binder LM, Rohling ML, Larrabee GJ. A review of mild head trauma: part I.
Meta-analytic review of neuropsychological studies. J Clin Exp Neuropsychol.
1997;19(3):421-431.
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(3):350-356.
Broglio SP, Ferrara MS, Macciocchi SN, Baumgartner TA, Elliott R. Test-retest
reliability of computerized concussion assessment programs. J Athl Train.
2007;42(4):509-514.
Cantu RC. Second-impact syndrome. Clin Sports Med. 1998;17(1):37-44.
Carroll LJ, Cassidy JD, Peloso PM, et al. Prognosis for mild traumatic
brain injury: results of the WHO Collaborating Centre Task Force on Mild
Traumatic Brain Injury. J Rehabil Med. 2004;43(suppl):84-105.
Chamelian L, Feinstein A. The effect of major depression on subjective and
objective cognitive deficits in mild to moderate traumatic brain injury. J
Neuropsychiatry Clin Neurosci. 2006;18(1):33-38.

18.

19.
20.

21.
22.

23.
24.

25.

26.
27.
28.

29.
30.
31.
32.
33.

34.

35.

36.

37.

38.

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(1):81-89.
Cicerone KD. Remediation of working attention in mild traumatic brain
injury. Brain Inj. 2002;16(3):185-195.
Del Percio C, Babiloni C, Marzano N, et al. Neural efficiency of athletes
brain for upright standing: a high-resolution EEG study. Brain Res Bull.
2009;79(3-4):193-200.
Dimberg EL, Burns TM. Management of common neurologic conditions in
sports. Clin Sports Med. 2005;24(3):637-662.
Dimeo F, Bauer M, Varahram I, Proest G, Halter U. Benefits from aerobic
exercise in patients with major depression: a pilot study. Br J Sports Med.
2001;35(2):114-117.
Endo K, Ichimaru K, Komagata M, Yamamoto K. Cervical vertigo and
dizziness after whiplash injury. Eur Spine J. 2006;15(6):886-890.
Enevoldsen EM, Jensen FT. Autoregulation and CO2 responses of cerebral
blood flow in patients with acute severe head injury. J Neurosurg.
1978;48(5):689-703.
Fann JR, Uomoto JM, Katon WJ. Sertraline in the treatment of major
depression following mild traumatic brain injury. J Neuropsychiatry Clin
Neurosci. 2000;12(2):226-232.
Friedman JM. Post-traumatic vertigo. Med Health R I. 2004;87(10):296-300.
Gaetz M, Weinberg H. Electrophysiological indices of persistent postconcussion symptoms. Brain Inj. 2000;14(9):815-832.
Gagnon I, Galli C, Friedman D, Grilli L, Iverson GL. Active rehabilitation for
children who are slow to recover following sport-related concussion. Brain
Inj. 2009;23(12):956-964.
Gall B, Parkhouse W, Goodman D. Heart rate variability of recently concussed
athletes at rest and exercise. Med Sci Sports Exerc. 2004;36(8):1269-1274.
Gall B, Parkhouse WS, Goodman D. Exercise following a sport induced
concussion. Br J Sports Med. 2004;38(6):773-777.
Gebke KB. Mild traumatic brain injury. Curr Sports Med Rep. 2002;1(1):23-27.
Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl
Train. 2001;36(3):228-235.
Golding EM, Robertson CS, Bryan RM Jr. The consequences of traumatic
brain injury on cerebral blood flow and autoregulation: a review. Clin Exp
Hypertens. 1999;21(4):299-332.
Golding EM, Steenberg ML, Contant CF Jr, Krishnappa I, Robertson CS,
Bryan RM Jr. Cerebrovascular reactivity to CO(2) and hypotension after mild
cortical impact injury. Am J Physiol. 1999;277(4)(pt 2):H1457-H1466.
Goldstein B, Toweill D, Lai S, Sonnenthal K, Kimberly B. Uncoupling of the
autonomic and cardiovascular systems in acute brain injury. Am J Physiol.
1998;275(4)(pt 2):R1287-R1292.
Gray TS. Autonomic neuropeptide connections of the amygdala. In: Tahe
Y, Morley JE, Brown MR, eds. Neuropeptides and Stress. Berlin, Germany:
Springer-Verlag; 1989:92-105.
Griesbach GS, Gomez-Pinilla F, Hovda DA. The upregulation of plasticityrelated proteins following TBI is disrupted with acute voluntary exercise.
Brain Res. 2004;1016(2):154-162.
Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla F. Voluntary
exercise following traumatic brain injury: brain-derived neurotrophic

vol. 4 no. 2

39.

40.
41.

42.

43.

44.

45.

46.

47.

48.

49.
50.

51.

52.
53.
54.
55.

56.
57.

58.

59.
60.

61.

62.
63.

factor upregulation and recovery of function. Neuroscience.

2004;125(1):129-139.
Griffin SL, van Reekum R, Masanic C. A review of cholinergic agents in
the treatment of neurobehavioral deficits following traumatic brain injury. J
Neuropsychiatry Clin Neurosci. 2003;15(1):17-26.
Guskiewicz KM. Assessment of postural stability following sport-related
concussion. Curr Sports Med Rep. 2003;2(1):24-30.
Guskiewicz KM, Marshall SW, Bailes J, et al. Association between recurrent
concussion and late-life cognitive impairment in retired professional football
players. Neurosurgery. 2005;57(4):719-726.
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(6):903-909.
Guskiewicz KM, McCrea M, Marshall SW, et al. Cumulative effects associated
with recurrent concussion in collegiate football players: the NCAA
Concussion Study. JAMA. 2003;290(19):2549-2555.
Hamilton MT, Hamilton DG, Zderic TW. Exercise physiology versus
inactivity physiology: an essential concept for understanding lipoprotein
lipase regulation. Exerc Sport Sci Rev. 2004;32(4):161-166.
Hanna-Pladdy B, Berry ZM, Bennett T, Phillips HL, Gouvier WD. Stress
as a diagnostic challenge for postconcussive symptoms: sequelae of mild
traumatic brain injury or physiological stress response. Clin Neuropsychol.
2001;15(3):289-304.
Heitger MH, Jones RD, Macleod AD, Snell DL, Frampton CM, Anderson TJ.
Impaired eye movements in post-concussion syndrome indicate suboptimal
brain function beyond the influence of depression, malingering or
intellectual ability. Brain. 2009;132(pt 10):2850-2870.
Helmick K. Cognitive rehabilitation for military personnel with mild
traumatic brain injury and chronic post-concussional disorder: results of
April 2009 consensus conference. NeuroRehabilitation. 2010;26(3):239-255.
Hicks RR, Smith DH, Lowenstein DH, Saint Marie R, McIntosh TK. Mild
experimental brain injury in the rat induces cognitive deficits associated
with regional neuronal loss in the hippocampus. J Neurotrauma.
1993;10(4):405-414.
Ho MR, Bennett TL. Efficacy of neuropsychological rehabilitation for mildmoderate traumatic brain injury. Arch Clin Neuropsychol. 1997;12(1):1-11.
Hovda DA, Lee SM, Smith ML, et al. The neurochemical and metabolic
cascade following brain injury: moving from animal models to man. J
Neurotrauma. 1995;12(5):903-906.
Hovda DA, Yoshino A, Kawamata T, Katayama Y, Becker DP. Diffuse
prolonged depression of cerebral oxidative metabolism following concussive
brain injury in the rat: a cytochrome oxidase histochemistry study. Brain
Res. 1991;567(1):1-10.
Iverson GL. Misdiagnosis of the persistent postconcussion syndrome in
patients with depression. Arch Clin Neuropsychol. 2006;21(4):303-310.
Iverson GL, Gaetz M, Lovell MR, Collins MW. Cumulative effects of
concussion in amateur athletes. Brain Inj. 2004;18(4):1.
Iverson GL, Gaetz M, Lovell MR, Collins MW. Cumulative effects of
concussion in amateur athletes. Brain Inj. 2004;18(5):433-443.
Johnston KM, McCrory P, Mohtadi NG, Meeuwisse W. Evidence-based
review of sport-related concussion: clinical science. Clin J Sport Med.
2001;11(3):150-159.
Junger EC, Newell DW, Grant GA, et al. Cerebral autoregulation following
minor head injury. J Neurosurg. 1997;86(3):425-432.
Katayama Y, Becker DP, Tamura T, Hovda DA. Massive increases in
extracellular potassium and the indiscriminate release of glutamate following
concussive brain injury. J Neurosurg. 1990;73(6):889-900.
Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP. Administration
of excitatory amino acid antagonists via microdialysis attenuates the increase
in glucose utilization seen following concussive brain injury. J Cereb Blood
Flow Metab. 1992;12(1):12-24.
King ML, Lichtman SW, Seliger G, Ehert FA, Steinberg JS. Heart-rate
variability in chronic traumatic brain injury. Brain Inj. 1997;11(6):445-453.
Korn A, Golan H, Melamed I, Pascual-Marqui R, Friedman A. Focal
cortical dysfunction and blood-brain barrier disruption in patients with
postconcussion syndrome. J Clin Neurophysiol. 2005;22(1):1-9.
Kristjansson E, Treleaven J. Sensorimotor function and dizziness in neck
pain: implications for assessment and management. J Orthop Sports Phys
Ther. 2009;39(5):364-377.
Kutcher JS, Eckner JT. At-risk populations in sports-related concussion. Curr
Sports Med Rep. 2010;9(1):16-20.
Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact
of traumatic brain injury: a brief overview. J Head Trauma Rehabil.
2006;21(5):375-378.

SPORTS HEALTH

64.

65.

66.

67.

68.
69.
70.

71.
72.

73.

74.

75.

76.
77.

78.
79.

80.

81.

82.

83.

84.

85.
86.

87.

88.

89.

Lau B, Lovell MR, Collins MW, Pardini J. Neurocognitive and symptom

predictors of recovery in high school athletes. Clin J Sport Med.
2009;19(3):216-221.
Leddy JJ, Baker JG, Kozlowski K, Bisson L, Willer B. Reliability of a graded
exercise test for assessing recovery from concussion. Clin J Sport Med.
2011;21(2):89-94.
Leddy JJ, Kozlowski K, Donnelly JP, Pendergast DR, Epstein LH, Willer B. A
preliminary study of subsymptom threshold exercise training for refractory
post-concussion syndrome. Clin J Sport Med. 2010;20(1):21-27.
Leddy JJ, Kozlowski K, Fung M, Pendergast DR, Willer B. Regulatory and
autoregulatory physiological dysfunction as a primary characteristic of post
concussion syndrome: Implications for treatment. Neurorehabilitation.
2007;22(3):199-205.
Levin HS, Mattis S, Ruff RM, et al. Neurobehavioral outcome following minor
head injury: a three-center study. J Neurosurg. 1987;66(2):234-243.
Levy M, Koeppen B, Stanton B. Berne and Levy Principles of Physiology.
Philadelphia, PA: Elsevier Mosby; 2006.
Longhi L, Saatman KE, Fujimoto S, et al. Temporal window of vulnerability
to repetitive experimental concussive brain injury. Neurosurgery.
2005;56(2):364-374.
Lovell MR, Collins MW, Iverson GL, et al. Recovery from mild concussion in
high school athletes. J Neurosurgery. 2003;98(2):296-301.
Luis CA, Vanderploeg RD, Curtiss G. Predictors of postconcussion symptom
complex in community dwelling male veterans. J Int Neuropsychol Soc.
2003;9(7):1001-1015.
Majerske CW, Mihalik JP, Ren D, et al. Concussion in sports: postconcussive
activity levels, symptoms, and neurocognitive performance. J Athl Train.
2008;43(3):265-274.
McCauley SR, Boake C, Levin HS, Contant CF, Song JX. Postconcussional
disorder following mild to moderate traumatic brain injury: anxiety,
depression, and social support as risk factors and comorbidities. J Clin Exp
Neuropsychol. 2001;23(6):792-808.
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(19):2556-2563.
McCrory P. Does second impact syndrome exist? Clin J Sport Med.
2001;11(3):144-149.
McCrory P, Johnston K, Meeuwisse W, et al. Summary and agreement
statement of the 2nd International Conference on Concussion in Sport,
Prague 2004. Clin J Sport Med. 2005;15(2):48-55.
McCrory P, Johnston KM, Mohtadi NG, Meeuwisse W. Evidence-based review of
sport-related concussion: basic science. Clin J Sport Med. 2001;11(3):160-165.
McCrory P, Meeuwisse W, Johnston K, et al. Consensus statement on
concussion in sport: 3rd International Conference on Concussion in Sport
held in Zurich, November 2008. Clin J Sport Med. 2009;19(3):185-200.
Mittenberg W, Canyock EM, Condit D, Patton C. Treatment of postconcussion syndrome following mild head injury. J Clin Exp Neuropsychol.
2001;23(6):829-836.
Mittenberg W, Tremont G, Zielinski RE, Fichera S, Rayls KR. Cognitivebehavioral prevention of postconcussion syndrome. Arch Clin Neuropsychol.
1996;11(2):139-145.
Napadow V, Dhond R, Conti G, Makris N, Brown EN, Barbieri R. Brain
correlates of autonomic modulation: combining heart rate variability with
fMRI. Neuroimage. 2008;42(1):169-177.
Nilsson P, Hillered L, Ponten U, Ungerstedt U. Changes in cortical
extracellular levels of energy-related metabolites and amino acids following
concussive brain injury in rats. J Cereb Blood Flow Metab. 1990;10(5):631-637.
Ommaya AK, Gennarelli TA. Cerebral concussion and traumatic
unconsciousness: correlation of experimental and clinical observations of
blunt head injuries. Brain. 1974;97(4):633-654.
Oppenheimer DR. Microscopic lesions in the brain following head injury. J
Neurol Neurosurg Psychiatry. 1968;31(4):299-306.
Palmese CA, Raskin SA. The rehabilitation of attention in individuals
with mild traumatic brain injury, using the APT-II programme. Brain Inj.
2000;14(6):535-548.
Peterson CL, Ferrara MS, Mrazik M, Piland S, Elliott R. Evaluation of
neuropsychological domain scores and postural stability following cerebral
concussion in sports. Clin J Sport Med. 2003;13(4):230-237.
Pomeranz B, Macaulay RJ, Caudill MA, et al. Assessment of autonomic
function in humans by heart rate spectral analysis. Am J Physiol. 1985;248(1)
(pt 2):H151-H153.
Ponsford J, Willmott C, Rothwell A, et al. Cognitive and behavioral outcome
following mild traumatic head injury in children. J Head Trauma Rehabil.
1999;14(4):360-372.
153

Leddy et al

90.

Ponsford J, Willmott C, Rothwell A, et al. Factors influencing outcome

following mild traumatic brain injury in adults. J Int Neuropsychol Soc.
2000;6(5):568-579.
91. Ponsford J, Willmott C, Rothwell A, et al. Impact of early intervention
on outcome after mild traumatic brain injury in children. Pediatrics.
2001;108(6):1297-1303.
92. Ponsford J, Willmott C, Rothwell A, et al. Impact of early intervention on
outcome following mild head injury in adults. J Neurol Neurosurg Psychiatry.
2002;73(3):330-332.
93. Preiss-Farzanegan SJ, Chapman B, Wong TM, Wu J, Bazarian JJ. The
relationship between gender and postconcussion symptoms after sportrelated mild traumatic brain injury. PM R. 2009;1(3):245-253.
94. Randolph C, McCrea M, Barr WB. Is neuropsychological testing useful in the
management of sport-related concussion? J Athl Train. 2005;40(3):139-152.
95. Rimel RW, Giordani B, Barth JT, Boll TJ, Jane JA. Disability caused by minor
head injury. Neurosurgery. 1981;9(3):221-228.
96. Rohling ML, Faust ME, Beverly B, Demakis G. Effectiveness of
cognitive rehabilitation following acquired brain injury: a meta-analytic
re-examination of Cicerone et als (2000, 2005) systematic reviews.
Neuropsychology. 2009;23(1):20-39.
97. Saija A, Hayes RL, Lyeth BG, Dixon CE, Yamamoto T, Robinson SE. The
effect of concussive head injury on central cholinergic neurons. Brain Res.
1988;452(1-2):303-311.
98. Sano K, Yoshioka M, Ogashiwa M, et al. Autonomic, somatomotor and
electroencephalographic responses upon stimulation of the hypothalamus
and the rostral brain stem in man. Confin Neurol. 1967;29(2):257-261.
99. Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha
A. Hypothalamopituitary dysfunction following traumatic brain injury
and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA.
2007;298(12):1429-1438.
100. Segalowitz SJ, Mahaney P, Santesso DL, MacGregor L, Dywan J, Willer B.
Retest reliability in adolescents of a computerized neuropsychological
battery used to assess recovery from concussion. NeuroRehabilitation.
2007;22(3):243-251.
101. Shetter AG, Demakas JJ. The pathophysiology of concussion: a review. Adv
Neurol. 1979;22:5-14.
102. 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(5):300-305.

Month Month XXXX

103. Strebel S, Lam AM, Matta BF, Newell DW. Impaired cerebral autoregulation
after mild brain injury. Surg Neurol. 1997;47(2):128-131.
104. Taylor AR. Post-concussional sequelae. Br Med J. 1967;3(5557):67-71.
105. Taylor AR, Bell TK. Slowing of cerebral circulation after concussional head
injury: a controlled trial. Lancet. 1966;2(7456):178-180.
106. Teasdale TW, Engberg A. Duration of cognitive dysfunction after concussion,
and cognitive dysfunction as a risk factor: a population study of young men.
BMJ. 1997;315(7108):569-572.
107. Thomas M, Haas TS, Doerer JJ, et al. Epidemiology of sudden death in
young, competitive athletes due to blunt trauma. Pediatrics. 2011;128(1):
e1-e8.
108. Tiersky LA, Anselmi V, Johnston MV, et al. A trial of neuropsychologic
rehabilitation in mild-spectrum traumatic brain injury. Arch Phys Med
Rehabil. 2005;86(8):1565-1574.
109. Treleaven J, Jull G, Sterling M. Dizziness and unsteadiness following
whiplash injury: characteristic features and relationship with cervical joint
position error. J Rehabil Med. 2003;35(1):36-43.
110. Tyler GS, McNeely HE, Dick ML. Treatment of post-traumatic headache with
amitriptyline. Headache. 1980;20(4):213-216.
111. Vagnozzi R, Signoretti S, Cristofori L, et al. Assessment of metabolic brain
damage and recovery following mild traumatic brain injury: a multicentre,
proton magnetic resonance spectroscopic study in concussed patients.
Brain. 2010;133(11):3232-3242.
112. 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(6):1286-1295.
113. van Ravenswaaij-Arts CM, Kollee LA, Hopman JC, Stoelinga GB, van Geijn
HP. Heart rate variability. Ann Intern Med. 1993;118(6):436-447.
114. Wade DT, King NS, Wenden FJ, Crawford S, Caldwell FE. Routine follow up
after head injury: a second randomised controlled trial. J Neurol Neurosurg
Psychiatry. 1998;65(2):177-183.
115. Ward AA Jr. The physiology of concussion. Clin Neurosurg. 1964;12:95-111.
116. Wilde EA, McCauley SR, Hunter JV, et al. Diffusion tensor imaging of acute
mild traumatic brain injury in adolescents. Neurology. 2008;70(12):948-955.
117. Willer B, Leddy JJ. Management of concussion and post-concussion
syndrome. Curr Treat Options Neurol. 2006;8(5):415-426.
118. Yamaki T, Murakami N, Iwamoto Y, et al. Cognitive dysfunction and
histological findings in rats with chronic-stage contusion and diffuse axonal
injury. Brain Res Brain Res Protoc. 1998;3(1):100-106.

For reprints and permission queries, please visit SAGEs Web site at http://www.sagepub.com/journalsPermissions.nav.

154