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Led by: Sam DeLong

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Premorbid anxiety and depression and baseline neurocognitive, ocular-motor and vestibular performance

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Led by: Dr. Jane McDevitt

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Caccese et al 2020
Led by: Dr. McDevitt

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2021 Concussion Conference available until June 30, 2022

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Giza & Kutcher, 2014

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Abstract

Purpose of Review:

Concussions are a major public health issue, and particularly so in the setting of sports. Millions of athletes of all ages may face the risks of concussion and repeat concussion. This article introduces the terminology, epidemiology, and underlying pathophysiology associated with concussion, focused on sports-related injuries.

Recent Findings:

Concussion is a clinical syndrome of symptoms and signs occurring after biomechanical force is imparted to the brain. Because of the subjective nature of symptom reporting, definitions of concussion differ slightly in different guidelines. Concussion nomenclature also includes mild traumatic brain injury, postconcussion symptoms, postconcussion syndrome, chronic neurocognitive impairment, subconcussive injury, and chronic traumatic encephalopathy. Between 1.6 and 3.8 million sports-related concussions are estimated in the United States annually, particularly in youth athletes. Rates of concussion are higher in sports such as football, rugby, ice hockey, and wrestling in males, and soccer and basketball in females. The underlying pathophysiology of concussion centers on membrane leakage, ionic flux, indiscriminate glutamate release, and energy crisis. These initial events then trigger ongoing metabolic impairment, vulnerability to second injury, altered neural activation, and axonal dysfunction. While the linkage between acute neurobiology and chronic deficits remains to be elucidated, activation of cell death pathways, ongoing inflammation, persistent metabolic problems, and accumulation of abnormal or toxic proteins have all been implicated.

Summary:

Concussion is a biomechanically induced syndrome of neural dysfunction. Millions of concussions occur annually, many of them related to sports. Biologically, a complex sequence of events occurs from initial ionic flux, glutamate release, and axonal damage, resulting in vulnerability to second injury and possibly to longer-term neurodegeneration.

INTRODUCTION

Concussions have moved to the forefront of public awareness, particularly in the world of sport. In the past few years, multiple national and international organizations have made considerable efforts to publish sports concussion reviews, guidelines, position statements, and best practice recommendations. 1-6 (Refer to Appendix A for a summary of the American Academy of Neurology's evidence-based guideline for clinicians.) The lay press has covered concussion injuries in high-profile and youth athletes who participate in sports from football to soccer to snow sports. While concern for premature return-to-contact risk has traditionally been the focus for sports-related concussion, a growing worry exists of the potential for long-term cumulative impairments resulting from multiple concussions over an athlete's career. It is clear that the medical issues related to sports concussion are complex, and therefore a multidisciplinary approach is optimal for the evaluation and management of these injuries.

DEFINITIONS

The term concussion originates from the Latin concussio or concutere, which means "to strike together" or "to shake violently." Concussion has generally been used to refer to the mild end of the traumatic brain injury (TBI) spectrum, where biomechanical forces transmitted to the brain induce physiologic dysfunction and neurologic impairments, generally in the absence of detectable macrostructural damage. While some have used the terms concussion and mild TBI synonymously, there can be distinctions.

Traditionally, the severity of TBI has been measured by the Glasgow Coma Scale (GCS), a clinical rating with a maximum of 15 points given for eye opening, speech, and motor response. This scale has been validated across the injury spectrum to be predictive of long-term outcomes, but is not well suited to distinguish variations in recovery at the mild end. Mild TBI generally refers to a GCS of 13 to 15, regardless of mechanism or demonstrable structural injury using CT or x-ray. Therefore, it is possible for someone with a mild TBI by GCS to have a skull fracture or intracranial hemorrhage, as long as their clinical rating on the GCS is within 13 to 15.

Concussion may be most widely thought of as a clinical syndrome of neurocognitive or behavioral dysfunction resulting from a biomechanically induced alteration of brain physiology. This generally occurs in the absence of intracranial pathology, although advanced neuroimaging suggests that microstructural changes can be detected. Common acute symptoms include headache, dizziness, nausea, confusion, memory impairment, imbalance, and behavioral changes. Underlying cerebral dysfunction is manifest primarily through clinical symptoms or measurable neurologic impairments in cognition, reaction time, balance, or behavior, and, for most, is recoverable over time. No definitive biomechanical threshold has been identified to induce the concussion syndrome in all individuals.

In practice, the terms concussion and mild TBI are often used interchangeably. However, beyond the historical and clinical distinctions mentioned above, the perception of what these terms mean is often different in the patient and in the medical care provider. Recent studies suggest that the term mild TBI was associated with a greater severity and seriousness of injury, while concussion was less alarming. 7

More recently, the concept of subconcussive injury has been increasingly used in both the lay press and the medical literature. While no universally accepted definition exists for subconcussive injury, the theoretical construct is that a biomechanically induced physiologic/microstructural injury is imparted but the affected individual does not manifest symptoms. The predominant concern for subconcussive injury has been in the sports and military arenas, because of the possibility/probability of sustaining multiple biomechanical injuries in rapid succession with inadequate time for full physiologic recovery in between injuries. Experimental evidence exists to suggest that such a scenario can result in increased acute/subacute vulnerability and possibly also a greater risk for longer-term impairment or even neurodegeneration.

Postconcussion symptoms are simply the subjective report of neurobehavioral impairments after concussion. The most common acute symptoms include headache, nausea, dizziness, confusion, memory impairment, incoordination, attention problems, and behavioral changes. Postconcussion syndrome has been described as persistent symptoms (headache, dizziness, memory impairment, irritability, attention/concentration problems, depression, anxiety) lasting a variable duration (more than 3 months up to 12 months or longer) following a concussion. 8-12 Some of the definitions 8-10 include implications that some loss of consciousness occurred and that the etiology of the symptoms was predominantly psychological dysfunction. More recently, chronic postconcussion syndrome has been used to refer to chronic persistent symptoms seen in a small subset of individuals after a concussion. 12

In addition to the chronic symptoms after concussion discussed above, the terminology chronic neurocognitive impairment has been proposed by the American Medical Society for Sports Medicine. 3 This refers to demonstrable neurologic, cognitive, or behavioral impairment, generally measured using validated tests or neuropsychological tools. Chronic neurocognitive impairment is detected during a patient's lifetime, and multiple studies support the presence of this sequela, particularly in professional athletes with longer exposure to contact sports. 1 These impairments are not necessarily progressive, as longitudinal data are still lacking. Lastly, the diagnosis of chronic traumatic encephalopathy refers to a pathologically proven accumulation of tau in the brain, reported in multiple cases of retired athletes and military personnel. 13 In retrospect, these individuals had neurobehavioral impairments during life; however, the causal linkage to earlier concussions and a progressive neurodegenerative course are implied but unproven. Some have classified chronic traumatic encephalopathy as essentially synonymous with dementia pugilistica, 13,14 while others have included it as only one type of chronic TBI. 12

EPIDEMIOLOGY

The vast majority of sports-related TBIs are concussions. It is estimated that 1.6 to 3.8 million sports-related concussions occur annually in the United States alone. 15 It is likely that this is an underestimate, as many concussions do not come to medical attention. Over the past decade, the number of diagnosed concussions (in and out of sports settings) has increased, most likely because of increased public awareness and concern about these ubiquitous injuries. TBI in general, including concussions, has the highest rates in the pediatric age ranges. 16

While the total number of sports concussions is on the rise, equally important in assessing concussion risk are the rates of concussion. In sports, this is usually quantified as the number of diagnosed concussions per "athlete exposure" (one event, game, or practice in which the athlete participates and is at risk). While imperfect-this metric does not take into account the actual duration of the contact-risk exposure-concussion rates offer a reasonable comparator to estimate risk between different sports.

Evidence-based reviews and primary studies have investigated the risk of concussion by sport. 1 Some sports, such as boxing and mixed martial arts, do not have good published data upon which to determine concussion rates but are almost certainly among the highest risk. For sports with published data, in males, the highest-risk sports are football, rugby, ice hockey, and wrestling. In females, the highest-risk sports are soccer and basketball. 17

While males sustain more concussions than females, in sports with comparable rules played by both genders (soccer, basketball, softball/baseball), females have about twice the rate of concussion as males. 18 The reasons for these gender differences are uncertain, but most research has focused on differences in neck strength. 19 Other possibilities include hormonal differences 20 or differences in symptom reporting. 21

One distinct component of sports-related concussion is the propensity for repeated injuries. Rates of repeat TBI vary widely, from 5.6% to 36% of the TBI population at large, and likely higher in contact/collision sports settings. 22 It is this characteristic that makes the evaluation and management of sports concussions unique. Sports concussions are a mild form of TBI, and, when sustained, an expectation of recovery and eventual return-to-contact-risk activity exists. This likelihood for returning to risk and the chance for repeat concussions is one of the driving points behind the need for improved recognition and diagnostics, as well as for more objective programs for return to play.

PATHOPHYSIOLOGY

The underlying pathobiology of concussive injury has been well summarized. 23,24 These insights originated from animal data and were subsequently confirmed using invasive monitors in cases of severe human TBI. More recently, the use of advanced neuroimaging has allowed demonstration, with noninvasive methods, of many components of the neurometabolic cascade after concussion. 25

Biomechanical forces distort cellular membranes. In neurons, this results in transient membrane defects (mechanoporation) and ionic flux. An indiscriminate release of potassium and influx of sodium and calcium occurs, generating a physiologic state resembling the spreading depression described in migraine. At the same time, these depolarized neurons trigger a widespread release of glutamate. The membrane ionic pumps deplete intracellular energy stores, which results in a relative energy crisis. Simultaneously, an initial decrease in cerebral blood flow occurs. This mismatch, termed uncoupling, worsens the metabolic dysfunction. It is likely that this window of metabolic dysfunction determines the time period of increased biological vulnerability to a second concussion, as shown by experimental work. 26 However, determining this window in human patients is more challenging. A study using magnetic resonance spectroscopy reported a reduction of the metabolite N-acetylaspartate for up to 30 days after a concussion in adult athletes. 27 Interestingly, a subset of these athletes sustained a second concussion before full recovery and the levels of N-acetylaspartate took longer to recover. 27,28 While not ready for routine clinical use, these studies in animals and humans support the concept of biological vulnerability after concussion and underlie the recommendation "when in doubt, sit it out."

Stretching of axons also results in impaired transport and connectivity in the concussed brain. Beading and undulations in axons have been reported in experimental studies of concussion. 29 Human studies using diffusion tensor imaging as a surrogate measure for axonal integrity have reported alterations in fractional anisotropy (directional diffusion of water) in the white matter of concussed children, 30 adolescents, 31 athletes, 32 and military personnel. 33 In multiple studies, there has been loose correlation between diffusion tensor imaging measures and clinical cognitive testing. No gold standard normative database exists yet for routine clinical use of diffusion tensor imaging, but again, the noninvasive imaging provides translational support for the neurobiological changes originally discovered in animal models.

The linkage between acute pathophysiology and chronic changes after concussion is an area of high priority for study, but no direct causal pathways have yet been proven. Some ongoing hypotheses include the development of chronic excitotoxicity due to delayed glutamate release, persistent metabolic impairment that creates vulnerability to repeated injury or even to excessive neural activation, or initiation of chronic inflammatory states and abnormal protein degradation that may result in toxic accumulations of amyloid or tau. Each of these has been proposed as a possible physiologic link between concussion and later neurodegeneration. Current evidence suggests for the most part that an isolated concussion is recoverable, but the likelihood of developing persistent symptomatology and chronic dysfunction may be related to multiple concussions with inadequate time for recovery.

CONCLUSION

Concussion is a clinical syndrome of mild TBI that is initiated by biomechanical force and results in a predominantly functional, physiologic injury. Common acute symptoms include headache, dizziness, nausea, confusion, memory impairment, imbalance, and behavioral changes.

Concussions are a major public health issue, with millions occurring annually, many in the context of sports. The rates for concussion and TBI are highest in the pediatric and adolescent age ranges. The highest-risk sports for males of all ages include football, rugby, ice hockey, and wrestling, and for females, soccer and basketball. In comparable sports (soccer, basketball, and softball/baseball), females have about twice the rate of concussion as males.

The clinical manifestations and physiologic perturbations associated with concussion are largely recoverable with time, but repeated concussions, particularly within a window of vulnerability, may open the door for more chronic postconcussive syndrome or even neurodegeneration. A basic understanding of concussion definitions and pathophysiology is essential for the practicing clinician.

USEFUL RESOURCES

The American Academy of Neurology (AAN) has a number of current resources on sports concussions for physicians, coaches and athletic trainers, and patients and their families.

Sports Concussion Toolkit
www.aan.com/concussion
Resources on sports concussion for physicians, coaches, parents, and athletes. For a complete list of resources included in the Sports Concussion Toolkit, see Appendix B.

Neurology Now Traumatic Brain Injury Collection for iPad

A special iPad app issue, published in July 2014, of collected articles on traumatic brain injury and concussion published in Neurology Now, the AAN's magazine for neurologic patients and their caregivers. The Neurology Now app and access to all content is free and available from the Apple App Store.

KEY POINTS

Medical issues related to sports concussion are complex, and therefore a multidisciplinary approach is optimal for the evaluation and management of these injuries.

The term concussion has generally been used to refer to the mild end of the traumatic brain injury spectrum, where biomechanical forces transmitted to the brain induce physiologic dysfunction and neurologic impairments, generally in the absence of detectable macrostructural damage.

In sports, the rate of concussion is usually quantified as the number of diagnosed concussions per "athlete exposure" (one event, game, or practice in which the athlete participates and is at risk).

For sports with published data, in males, the highest-risk sports for concussion are football, rugby, ice hockey, and wrestling. In females, the highest-risk sports are soccer and basketball. Females have a higher rate of concussions than males in comparable sports.

One distinct component of sports-related concussion is the propensity for repeated injuries.

Recently, the use of advanced neuroimaging has allowed demonstration, with noninvasive methods, of many components of the neurometabolic cascade after concussion.

Current evidence suggests for the most part that an isolated concussion is recoverable, but the likelihood of developing persistent symptomatology and chronic dysfunction may be related to multiple concussions with inadequatetime for recovery.

Concussions are a major public health issue, with millions occurring annually,many in the context of sports.

REFERENCES

8. Centers for Disease Control and Prevention. International classification of diseases, ninth revision, clinical modification (ICD-9-CM). www.cdc.gov/nchs/icd/icd9cm.htm. Updated June 18, 2013. Accessed October 3, 2014.

9. Centers for Disease Control and Prevention. International classification of diseases, tenth revision, clinical modification (ICD-10-CM). www.cdc.gov/nchs/icd/icd10cm.htm. Updated August 22, 2013. Accessed October 3, 2014.

10. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV. 4th ed Washington, DC: American Psychiatric Association; 1994. [ Google Scholar]

20. Wunderle K, Hoeger KM, Wasserman E, Bazarian JJ. Menstrual phase as predictor of outcome after mild traumatic brain injury in women [published online ahead of print November 20, 2013]. J Head Trauma Rehabil 2013. 10.1097/HTR.0000000000000006. [[ PubMed] PMC free article] [ Google Scholar]

Articles from Continuum : Lifelong Learning in Neurology are provided here courtesy of American Academy of Neurology

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Concussions are a major public health issue, and particularly so in the setting of sports. Millions of athletes of all ages may face the risks of concussion and repeat concussion. This article introduces the terminology, epidemiology, and underlying pathophysiology ...

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Giza & Hovda, 2014

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Ionic flux and glutamate release

Early studies demonstrated that biomechanical injury results in ionic flux and hyperacute indiscriminate glutamate release . Potassium efflux, and sodium and calcium influx, occur due to mechanoporation of lipid membranes (creation of sublethal defects via traumatic insult) at the cellular level. Initial ionic flux and depolarization can then trigger voltage- or ligand-gated ion channels, creating a diffuse 'spreading depression-like' state that may be the biological substrate for very acute post-concussive impairments.

Energy crisis

In an effort to restore ionic and cellular homeostasis, ATP-requiring membrane ionic pumps shift into overdrive, causing hyperglycoloysis, relative depletion of intracellular energy reserves and increase in ADP . In very early phases, this increased demand for energy occurs in a setting of normal or reduced cerebral blood flow, resulting in an uncoupling, or mismatch, between energy supply and demand.

Intracellular calcium flux, which occurs early and may persist longer than other ionic disturbances, is accommodated by sequestration of calcium into mitochondria. However, this short-term solution can then result in mitochondrial dysfunction, exacerbate problems with oxidative metabolism and worsen the cellular energy crisis.

In addition to the acute energy perturbations, intracellular redox state is altered. This puts additional stress on the system by generative damaging free radicals and shifting metabolic pathways that can trigger longer-lasting impairments and set the stage for vulnerability to repeated injury, which is particularly relevant for the clinical setting of sports-related concussion.

After an initial period of hyperglycolysis and metabolic uncoupling, glucose metabolic rates go into a state of impaired metabolism that can last up to 7-10 days in adult animals, and is associated with behavioral impairments in spatial learning . The duration of this hypometabolic period appears to vary with age, with younger animals showing shorter periods (3 days) of impairment . Post-traumatic changes in metabolism may be mediated by altered gene expression and enzyme/transporter regulation .

Cytoskeletal damage

Biomechanical forces imparted onto neurons and glia can damage the delicate and complex microstructural components including dendritic arbors, axons and astrocytic processes. Following intra-axonal calcium flux, neurofilament side-arms can be phosphorylated and collapse, resulting in loss of structural integrity in axons . Microtubule disruption due to axonal stretch can interfere with bi-directional axonal transport, potentially isolating the synapse, diminishing normal neurotransmission and in severe cases, result in axonal disconnection. Intra-axonal calcium flux results in proteolytic damage to subaxolemmal spectrin and other cytoskeletal components . More recent studies have indicated that cytoskeletal anchor points in the cell membrane, mediated through proteins such as integrins, may represent a primary molecular target of traumatic injury in both neurons and vascular cells .

Axonal dysfunction

Axons prove to be particularly vulnerable to biomechanical stretch. Early studies showed increased axolemmal permeability after experimental TBI . As mentioned above, damage to the neurofilaments and microtubules leads to axonal dysfunction and potential for disconnection. While axonal disconnection was once thought to invariably lead to demise of the neuronal cell body, in vivo animal studies have shown that perisomatic axotomy can occur with atrophy and shrinkage of the neuron, without cell death . It is assumed that this type of severely damaged neuron is not capable of normal function. Some studies have suggested that dietary supplementation of particular fatty acids may mitigate, or at least alter the timeline of, axonal damage after experimental TBI . In vitro stretch injury models demonstrate post-stretch axonal undulations and beading - in some cases these would recover, but in others the axonal damage was lasting .

In addition, recent studies using fluid percussion injury centered over the white matter tracts of the corpus callosum indicate that unmyelinated axons are more vulnerable to injury (and show greater resultant impairment of electrophysiological function) than myelinated fibers . This finding, although not replicated in a comparative study of immature animals, has developmental implications, as it is known that myelination of axonal tracts is one of the ongoing maturational changes that occur in the young brain.

Altered neurotransmission

Changes in ligand-gated excitatory and inhibitory neurotransmission have been reported after in vivo experimental TBI. Alterations in glutamate (N-methyl-D-aspartate NMDA) receptor subunit composition and function have been reported following TBI in both the immature and mature brain . Functional consequences of NMDAR subunit change in developing rat pups have been described as interfering with normal developmental plasticity, electrophysiology and memory . In adult rats, NMDAR changes have also been associated with functional alterations including differential patterns of calcium flux , immediate early gene activation and phosphorylation/activation of downstream signal transduction molecules such as CaMKII (calcium/calmodulin-dependent protein kinase II), ERK (extracellular signal-related kinase), CREB (cAMP response element binding protein) and BDNF (brain derived neurotrophic factor) .

Post-injury excitatory-inhibitory balance can also be upset by changes in inhibitory neurotransmission involving GABA and its receptors. Studies have consistently shown dropout of hilar GABAergic interneurons following lateral fluid percussion injury (FPI) in adult rats . In a recent study of post-TBI augmentation of fear-based learning, a putative model for post-TBI vulnerability to develop anxiety disorders and/or PTSD, decreased levels of GAD67, the biosynthetic enzyme for GABA, have been reported in the amygdala . The amygdala is a critical structure implicated in the development of aberrant fear-based learning in animal models but also in some human studies .

Inflammation

More recent studies suggest that inflammatory changes are also triggered by mild TBI. In both adults and immature rats, microarray studies report extensive upregulation of cytokine and inflammatory genes after TBI . Microglial activation after adult FPI, with or without exposure to the pesticide paraquat, has been associated with damage to the substantia nigra and implicated in the increased risk for parkinsonism after TBI . Similar neuroinflammatory changes have also been reported subacutely in the absence of behavioral deficits in a different study . A theory relating glutamate release and activation of immune receptors to oxidative stress and potentially later cellular injury has been proposed and termed "immunoexcitotoxicity" .

Cell death

Models of mild TBI have generally shown little cell death, even in settings where measurable cognitive impairments are described . However, the consequences of repeated mild TBI are less well described - functional impairments appear to be greater than single TBI in most models , raising the possibility that there may be longer term structural changes, although studies looking at chronic axonal injury and/or atrophy are lacking.

It is unclear whether chronic structural changes may evolve over longer time courses after even a single mild injury. However, following a single moderate/severe FPI in adult rats, ongoing cerebral and hippocampal atrophy have been described , as have chronic losses in dopaminergic neurons in the substantia nigra . Chronic evolution of injury has also been described after a single controlled cortical impact (CCI) injury in adult animals . Immature (P7) mice show late appearance of cognitive deficits and tissue loss after a single CCI , but other studies using a single FPI in developing rats (P19) showed no significant hippocampal or cortical neuronal loss .

Pathophysiology Meets Symptoms ()

Table 1

Post-TBI pathophysiology

Acute symptom / clinical correlate

Ionic flux

Migraine headache, photophobia, phonophobia

Energy crisis

Vulnerability to second injury

Axonal injury

Impaired cognition, slowed processing, slowed reaction time

Impaired neurotransmission

Impaired cognition, slowed processing, slowed reaction time

Protease activation, altered cytoskeletal proteins, cell death

Chronic atrophy, development of persistent impairments

While studies proving associations between the following pathophysiological changes after concussion/mild TBI remain to be conducted, it is tempting to speculate on how acute neurobiological change results in the clinical symptoms associated with concussion. Several reasonable connections can be made, and are presented in .

Ionic flux and migraine

The widespread ionic flux described after FPI has often been described as 'spreading depression-like', and the original description of the spreading depression of Leao was in the context of migraine . In fact, DC potential shifts have been described in both experimental TBI and with direct electrocorticography after more severe human TBI .

An additional intriguing connection that suggests a relationship between ionic compensatory mechanisms and cerebral responses to concussion is the description of significant mental status change and evidence for cerebral edema after mild TBI in the pedigree of a family with an ion channelopathy normally associated with familial hemiplegic migraine . In this description, the CACNA1A mutation was associated with several clinical phenotypes, including an exaggerated response to mild TBI in some family members. There are an increasing number of ion channelopathies being identified, and it is interesting to speculate whether genetic factors such as these may underlie the 'glass jaw' phenomenon whereby some athletes are more readily symptomatic after mTBI, or whether this type of genetic vulnerability underlies the malignant cerebral edema seen in cases of 'second impact syndrome'.

Finally, there is considerable overlap of typical post-concussion symptoms with those commonly described in migraine, particularly headache, nausea, vomiting, photophobia, phonophobia and dizziness. In fact, some studies indicate the reporting of headache symptoms or a prior history of migraine as potential risk factors for prolonged recovery or more severe symptoms after concussion .

Energy crisis and vulnerability

Clinically it is known that a history of prior concussion/mTBI is a strong risk factor for subsequent concussion, and that in prospective studies, this risk appears greatest in the first 10 days post-injury . There are many factors that may play into this increased clinical risk, but biological vulnerability due to ongoing energy crisis is one that can be addressed by the current practice of delaying return to contact risk. The challenge here is identifying the duration of this period of metabolic vulnerability, as it likely varies between concussed individuals.

Human studies using magnetic resonance spectroscopy (MRS) have shown reductions in the metabolite N-acetylaspartate (NAA) in frontal white matter of concussed adults compared to normal controls . Over 30 days, NAA levels returned to normal, except in individuals who sustained a second concussion, in whom NAA did not recover fully until 45 days after the initial injury . Such findings support the concept of metabolic vulnerability after concussion. However, in these studies, the depressed NAA levels did not correlate well with reported symptoms, and thus the clinical significance of post-concussion NAA remains uncertain.

Animal studies have shed some light on this. In a weight drop model in adult rats, the greatest perturbations of neurochemical markers of metabolic stress occurred when injuries were separated by 3 days . Repeated concussive injuries in adult mice showed worsening of neurocognitive function and traumatic axonal injury when injuries were spaced out by 3 or 5 days, but not when injuries were separated by 7 days .

In a closed head impact model in juvenile rats, the period of reduced glucose metabolism post-injury was associated with impairments in working memory and generally lasted about 3 days. When a second injury occurred within this period of impaired glucose metabolism (post-injury day 1), the severity of both hypometabolism and memory impairment was greater. If the second injury occurred after full metabolic recovery from the first injury (post-injury day 5), the two injuries acted like single, separate injuries .

Overall, these investigations indicate that the timing of repeated injuries may have significant consequences on the severity of post-concussion pathophysiology and subsequent cognitive disturbances. They also indirectly support the current clinical management protocols of removing concussed athletes from contact risk immediately to allow time for biological recovery. Further work is needed to identify what biomarker can be used to determine the time of recovery for individual patients - symptoms, cognition, balance, reaction time and neuroimaging have all been proposed. It is likely that the duration of time for recovery in humans will be longer than that described in the animal models.

Axonal dysfunction and slowed cognition

For mild TBI and concussion in humans, there is little pathological data , but advanced MRI using diffusion tensor imaging (DTI) has been used to measure changes in directionality of water diffusion that may be indicative of white matter disruption. Fractional anisotropy (FA) one such measure, with higher FA values indicating more water diffusion in a particular direction and lower FA values indicating less directionality. Increased FA values have been reported in corpus callosum early after mild TBI (6 days) in adolescents, and these values were correlated with a validated symptom scale W. Early increases in FA were also reported in a cohort of adolescents after concussion but no correlation was found between the DTI changes and cognitive function . Recent studies have reported changes in DTI measures and cognitive testing after a period contact/collision sports participation in individuals with no diagnosed concussion .

For more severe TBI, damage to the white matter strongly correlates to burden of neurocognitive impairment. FA generally is decreased in major fiber tracts (corpus callosum being most studied), and white matter disruption is associated with burden of neuropsychological deficits using standard testing .

Overall, data from DTI studies of mild TBI has been more variable, with some acute studies showing increased FA and some showing decreased FA . It is likely that multiple parameters can affect the results of DTI studies, including timing after injury, age of subjects, severity of injury, region of brain analyzed as well as the specifics of the methods used . Thus, while DTI appears to be a very sensitive imaging modality to study concussion/mTBI noninvasively, its use for routine clinical management of individual patients is still premature.

Again, animal studies provide some additional perspective. Using a mouse model of more severe TBI - controlled cortical impact - correlations between DTI measures and histopathology were elegantly described across a time range from hours up to one month post TBI . These studies show that DTI is more sensitive than conventional MRI at detecting white matter injury after TBI. They also shed some light into the changing nature of DTI signal as the TBI evolves over time. Early changes (<24 hrs) included maximal staining of axonal varicosities with amyloid precursor protein (APP) and neurofilament light chain markers, while later time points (4 days to 1 month) showed maximal staining for gliosis (GFAP - glial fibrillary acidic protein).

Rodent models of mild repeated TBI have shown impairments in spatial learning and memory in the absence of overt histological damage or cell death . Increased APP was most prominent in animals with repeat closed head injury separated by 3 days, and these animals also showed the greatest impairment in motor function and spatial learning, when compared to single injury animals or those with repeat TBI separated by 1 week . Graded deficits in working memory after mild and repeat closed head injury (24 hours apart) have been reported along with increases in APP staining in corpus callosum and subcortical white matter .

Taken together, these studies show that cognitive deficits occur after mild TBI in the absence of overt cell death. Graded degrees of axonal injury/dysfunction occur after mTBI and repeat mTBI, and can be associated with graded levels of neurobehavioral impairment. However, in mild TBI, the linkage between imaging measures of axonal damage and clinically measurable cognitive problems is still in evolution.

Altered neurotransmission, slowed cognition and reaction time

Neurotransmitter and synaptic alterations are other mechanisms of neural dysfunction that occur in the absence of overt cell death and may contribute to acute and transient neurobehavioral impairments after concussion. Clinical studies show early post-concussion problems in attention and memory that generally recover over time; these have been measured using simple sideline questions , the Standardized Assessment of Concussion (SAC) , paper and pencil neuropsychological testing and computerized cognitive testing . Slowed reaction time has been measured in conjunction with computerized tests as well as with a simple 'stick-drop' device .

Human studies of fMRI activation following concussion have often used cognitive measures of working memory. Abnormal patterns of increased BOLD activation have been reported days and weeks after concussion/mTBI in adults and older teens (average age 16.6y) . These changes may serve as a biomarker of ongoing neural dysfunction or in one study, as a marker for prolonged recovery . A more recent study of slightly younger teens (average age 14.5y) after concussion showed worse working memory associated with significantly reduced task-related BOLD activity .

As mentioned above, animal studies have demonstrated TBI-induced deficits in excitatory neurotransmission, often involving the NMDAR . Interestingly, in the immature brain, these impairments are associated with a loss of experience-dependent plasticity that results in lasting learning and memory deficits . Even if a period of 'recovery' is allowed before stimulating experience-dependent plasticity, restoration of memory functions is only partial . Ongoing studies are aimed at developing mechanism-based interventions to help restore these impairments.

It is difficult to entirely tease out the contributions of axonal injury vs impaired neurotransmission to post-concussion cognitive and behavioral deficits. Quite likely both are involved, and determining the predominant mechanism in a given individual may depend on continued study into biomarkers to help identify those at risk for persistent impairments, and to determine interventions most likely to be effective.

Interestingly, as mentioned above, while post-traumatic metabolic changes in the immature brain appear to be shorter lasting than in adults , axonal vulnerability and impairments in plasticity may be more prominent in the young brain. Additional work is necessary to determine on balance whether the young brain is more or less vulnerable to mild TBI, although some clinical evidence suggests, at least for concussion, recovery takes longer in high school athletes compared to collegiate or adult professional athletes.

How much is too much? Acute-to-Chronic Pathobiology ()

Evidence for the chronic sequelae of repeated mild TBI/concussion has long been associated with pathological studies of boxers . More recently, case studies of contact sport athletes have shown both gross and microscopic pathology that has been attributed to repeated exposure to concussive blows . In these more recent cases, deposition of aggregated tau protein has been reported as the pathological hallmark of the condition now termed chronic traumatic encephalopathy (CTE). However, the waters surrounding our current understanding of CTE have been muddied by selection bias inherent to any case report study, an uncertain dose relationship between mTBI and pathology, concomitant associations between repeat concussion and other neurodegenerative conditions and the lack of a unifying biological mechanism to translate the acute (but generally recoverable) pathophysiology of concussion into a chronically progressive disorder.

Energy crisis, protease activation and cell death

Acute impairments of cellular metabolism have described problems in both glycolytic and oxidative pathways (minutes to days, see above). Excess calcium flux is sequestered in mitochondria but then results in diminution of oxidative capacity that can spill over into the subacute period (days-weeks). Contact/collision sports and military duty, among other professions, are distinct from most accidental mTBI because of the inherent goal of returning to contact risk activity. The occurrence of repeated mTBI prior to full recovery from a first mTBI may set in play more lasting metabolic perturbations that may then trigger activation of intracellular proteases and the cascade that leads to apoptotic cell death.

Animal studies support the concept that more severe TBI can result in chronic evolution of injury that results in ongoing cell death and atrophy out to 1 year . Even in a pediatric model of moderate-to-severe experimental TBI, progressive cell death and volume loss, associated with emergence of additional cognitive decline, has been reported over 1-3 months post-TBI . Longitudinal studies of brain atrophy after experimental repeat mild TBI/concussive injury remain to be done.

Altered protein degradation and toxic accumulation

In addition to the effects of chronic energy impairment as a trigger to protease activation and apoptotic cell death, it is well known that normal cellular protein homeostasis depends upon a functioning system of protein degradation. This system requires energy, ubiquitin and a protein complex called the proteasome . There are many examples in neurodegenerative disease of cellular oxidative stress leading to oxidatively damaged proteins that can affect metabolic enzymes and/or the ubiquitin-proteasome system. This could then result in the accumulation of abnormal/toxic proteins . These mechanisms have been implicated in Alzheimer disease, tauopathies, synucleinopathies (Parkinson disease) and ALS, to name a few, and it is not surprising that these links are now being made in TBI. Early and prolonged proteasomal activation has been proposed based upon immunohistochemical findings after severe human TBI .

Accumulation of abnormal proteins has also been reported in animal models of TBI under multiple circumstances. Wild-type rodents show accumulation of oligomeric and phosphorylated tau after parasagittal fluid percussion injury and blast neurotrauma . Interestingly, deposition of amyloid or tau was not seen at chronic time points in a study of repetitive mild TBI, even though the animals showed cognitive impairments and astrogliosis . Transgenic animals (3xTG-ApoE4) have also been reported to show increased accumulation of abnormal proteins after TBI .

Aggregation and progression of toxic molecules has recently gained traction in a series of articles suggesting that damaged tau oligomers, not neurofibrillary tangles, are the triggering molecules for spread of tau pathology in Alzheimer disease (for review see ). Elevated levels of extracellular tau have been reported after severe human TBI, and may hypothetically initiate the process of progressive tauopathy .

Based upon these data, the mechanism of impaired protein homeostasis and degradation after TBI is plausible. Confirmatory studies remain to be conducted. Such a mechanism may likely involve oxidative damage to metabolic or proteasome molecules. There is evidence that proteins such as amyloid and tau, which accumulate in known neurodegenerative disorders, also show perturbations after both clinical and experimental TBI.

Chronic axonal dysfunction

As discussed above, axonal dysfunction can result in impaired cognitive functioning and slowed reaction times, either through slowed conduction, damage to cerebral networks or deficits in neurotransmission. These mechanisms may be detected early after mTBI using DTI and fMRI .

DTI has also been used to detect white matter abnormalities subacutely and chronically after mTBI. One recent study used DTI to examine military personnel evacuated from Afghanistan and Iraq for TBI, and found persistent changes in multiple regions . Even in a civilian youth cohort with concussions, changes in DTI were detected early after injury while the subjects were symptomatic, but then showed similar changes at 4 months post-injury, a time when most were asymptomatic. The clinical significance of these DTI signal changes in a subacute/chronic setting is only beginning to be understood, but these white matter alterations have been associated with post-traumatic stress disorder and depression in different cohorts. Perhaps equally concerning are recent reports of abnormal DTI measures in athletes subjected to repeated mild head blows (heading in soccer) even without a diagnosis of concussion .

While axonal disconnection after severe TBI can certainly result in cognitive impairment, it is uncertain how much post-concussion white matter pathology is due to disconnection vs alterations in axonal physiology . Furthermore, the idea that axotomy results in the inevitable death of the neuron has been challenged by evidence showing some neurons survive axonal disconnection but may be rendered dysfunctional . What also remains uncertain is the ability of the damage axon to recover, or the time frame of events that dictates recovery vs disconnection. Recent evidence has focused on the possibility for persistent axonal degeneration following TBI, perhaps even a single TBI . As mentioned earlier, myelination also appears to protect axons from trauma, with unmyelinated axons more vulnerable . These mechanisms of chronic axonal damage may then be particularly problematic in settings of repeat mTBI without adequate time for recovery between injuries, immature myelination or individuals with genetic vulnerabilities.

# data[].attributes.attachment_link.title
The New Neurometabolic Cascade of Concussion

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Early studies demonstrated that biomechanical injury results in ionic flux and hyperacute indiscriminate glutamate release . Potassium efflux, and sodium and calcium influx, occur due to mechanoporation of lipid membranes (creation of sublethal defects via traumatic insult) at the cellular level.

# data[].attributes.body
Broglio et al., 2014

# data[].attributes.attachment_link.title
National Athletic Trainers’ Association Position Statement: Management of Sport Concussion

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To provide athletic trainers, physicians, and other health care professionals with best-practice guidelines for the management of sport-related concussions.An estimated 3.8 million concussions occur each year in the United States as a result of sport…

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2019 Concussion Summit Dr. Giza Concussion Pathophysiology

# data[].attributes.subject
2019 Concussion Summit Dr. Giza Concussion Pathophysiology

# data[].attributes.attachment_link.authors[].name
University of Michigan Injury Prevention Center

# data[].attributes.attachment_link.title
2019 Concussion Summit Christopher Giza  Concussion Pathophysiology

# data[].attributes.body
Eckner et al., 2017
Led by: Karlee (and Dr. McDevitt)

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Abstract

Case-control observational study.

Keywords: Athlete, Concussion, Headache, Migraine

Introduction

As concussion grading scales have fallen out of favor, a more individualized approach to concussion assessment and management has been advocated.[ 1] Such an approach requires assessment of individual modifying factors that may place an athlete at elevated risk for sustaining concussion, as well as for experiencing a prolonged recovery course, or presenting with a particular constellation of clinical signs and symptoms. Such modifying factors may include age, sex, concussion history, pre-existing learning disabilities, attention deficit hyperactivity disorder, and other comorbidities.[ 2] Management decisions should take these modifying factors into account as each concussion is unique and can result in a variety of clinical outcomes, ranging from rapid symptom resolution to chronic neurological impairment. Therefore, any potential prognostic information obtained before or after the injury should be utilized when managing sport-related concussion.

Migraine headache has also been suggested as a potential modifying factor for concussion. In support of this, Gordon et al. reported a positive association between migraine headache and concussion in a cross-sectional survey of Canadian respondents aged 12-24 years.[ 3] In this study, respondents with history of concussion had 2.36 times greater odds of having been diagnosed with migraine headache than those without. Similarly, a prospective cohort study by Kuczynski et al. reported a personal or family history of migraine in 82% of children aged 0-18 years presenting to the emergency department with mild traumatic brain injury.[ 4] While not specific to migraine, Schneider et al. also reported that male youth ice hockey players with a positive response to the Sport Concussion Assessment Tool headache question at preseason baseline had an incidence rate ratio for being diagnosed with concussion during the season of 1.47 compared to those with a negative response, after adjusting for age and concussion history.[ 5] The complaint of baseline headaches may also be associated with an increased incidence and severity of other symptoms associated with concussion.[ 6] In addition, clinical experience suggests that migraineurs may experience a prolonged recovery course following injury,[ 7] and concussed athletes experiencing migraine-like symptoms in the acute post-injury period have been shown to recover more slowly than those not experiencing migraine-like symptoms.[ 8, 9]

There are pathophysiological alterations in migraine headache that may underlie a physiological susceptibility to concussion and post-concussion symptoms. This is supported by previous research suggesting a common molecular pathophysiological cause of migraine and mild traumatic brain injury (mTBI).[ 10- 12] For example, extracellular potassium and intracellular sodium, calcium, and chloride are all increased with respect to their usual concentrations in the brain after mTBI as well as in migraine.[ 13- 15] Furthermore, both mTBI and migraine are associated with an excess release of excitatory amino acids such as glutamate, in addition to beta-endorphins.[ 10, 14] Mild head trauma may also stimulate trigeminal sensory afferents through cervicogenic mechanisms similar to those seen in migraine.[ 16] Following forced flexion and extension of the cervical spine, upper cervical sensory nerve roots converge on the trigeminal nucleus caudalis, resulting in the sequential activation of second and third order neurons in the nociceptive pathways of the brain stem, hypothalamus, and thalamus. This in turn can lead to cortical spreading depression.[ 16] If damage to cervical structures also occurs during the mTBI, nociceptive input from cervical segments arriving to the trigeminal nucleus may also serve as a source of referred pain, ultimately resulting in mechanical hyperalgesia.[ 16]

To better characterize the relationship between migraine headache and concussion we conducted this case control study in athletes presenting to a combined sport neurology and orthopedic sports medicine clinic. The purpose of this study was to compare the presence of migraine headache between athletes being evaluated for acute concussion and a reference group being evaluated for musculoskeletal injuries.

Methods

Participants

A total of 263 respondents (40.4% female) completed the study questionnaire. Study eligibility criteria included age 12-24 years and participation in an organized sport or athletic activity for at least 30 minutes two or more times per week. Potential participants were given a brief written description of the study and the 1-page study questionnaire upon checking-in to a busy University-associated outpatient sports medicine clinic. Those athletes being seen by a sport neurology provider for concussion were classified as cases, while those athletes being seen by an orthopedic sports medicine provider for any reason other than concussion were classified as controls. The instructions to participants explained that the questionnaire was anonymous and that participation in the study was voluntary. Informed consent was implied by completion and return of the anonymous questionnaire. Participants under the age of 18 were instructed to obtain parent/guardian approval before completing the questionnaire. Participants were instructed to complete the questionnaire only once. The ethics of this study were approved by the institutional research ethics board at the lead author's institution.

Procedures

Participants completed the 1-page study questionnaire before or after their medical appointment and returned it to clinic staff at the time of check-out. The questionnaire inquired about the participant's age, sex, reason for visit (concussion vs. any other injury), self and immediate family history of diagnosed migraine headache, concussion history, and their sport/athletic activity participation. A modified version of the ID Migraine Questionnaire was also included in the questionnaire. The ID Migraine Questionnaire is a valid and reliable 3-item screening instrument that has been shown to be 81% sensitive and 75% specific for migraine headache.[ 17] The modification to the original ID Migraine Questionnaire instructed respondents not to consider any new headaches related to a recent concussion when answering the ID Migraine questions to reduce the possibility of a positive ID Migraine response being due solely to post-concussion symptoms. Participants were considered to have a history of migraine headache either if they reported a prior diagnosis by a health care provider or had a positive response to the modified ID Migraine Questionnaire.

A copy of the questionnaire printed on blue paper was provided to athletes whose appointment was with a sport neurology provider and a copy of the questionnaire printed on white paper was provided to athletes seeing an orthopedic provider. The color of the questionnaire was cross-checked with the participant-reported reason for visit to ensure correct assignment to the case and control groups. A total of 3 respondents seen by a sport neurology provider for any reason other than concussion or seen by an orthopedic provider who reported a visit reason of concussion were excluded from the analysis. In addition, 3 respondents were excluded because their age fell outside of the eligible age range, and 36 were excluded because they did not meet the study's minimum sport or athletic activity participation criteria.

Statistical Analysis

Descriptive statistics and frequencies were calculated for continuous and discrete variables, respectively. T-tests were used to compare continuous outcomes between groups. Chi-square tests were used to compare discrete outcomes between groups, with calculation of associated odds ratios. Comparisons between the concussion and control groups were considered the primary analyses of the study. Additional secondary analyses were performed to compare those participants with a prior history of migraine headaches to those without. Variables found to be significantly related to either concussion/control group status or prior history of migraine headache were then included in multiple logistic regression models, with calculation of adjusted odds ratios.

Results

A total of 221 participants were deemed eligible for study inclusion [115 concussion cases (52%), 106 orthopedic controls (48%)]. The concussion group was younger (16.2 ± 2.4 vs. 17.1 ± 3.0 years; p < 0.001) and contained 8% fewer females (33% vs. 41%; X2 = 1.3, p = 0.25) than the control group. Additional primary comparisons between the concussion and control groups are presented in . The concussed group had 1.80 times greater odds of being previously diagnosed with migraine headache by a medical provider (95% CI: 0.79 - 4.10) and 1.64 times greater odds of a positive response to the modified ID Migraine Questionnaire (95% CI: 0.90 - 3.02) compared to the control group. Twenty-three participants in the concussion group (23.7%) and 16 participants in the control group (16.7%) who had not previously been diagnosed with migraine headache by a medical provider had a positive response to the modified ID Migraine Questionnaire. Based on the study definition of either a prior clinician diagnosis or a positive modified ID Migraine response to indicate a history of migraine headache, those in the concussed group had 1.70 times greater odds of having a history of migraine headache (95% CI: 0.95 - 3.06) compared to controls. A post-hoc power analysis demonstrates that our study sample was underpowered (Power = 0.42) to detect a significant primary relationship of the observed magnitude between migraine headache history and group status, using a two-tailed alpha of 0.05. The odds of having a first degree relative diagnosed with migraine headache in the concussed group were 0.98 times (95% CI: 0.57 - 1.67) those of the control group. Those in the concussion group were significantly more likely to have sustained a previous concussion than controls (OR = 3.21; 95% CI: 1.83 - 5.62).

Table 1

In secondary analyses, females were significantly more likely to have a history of migraine headache than males (39.5% vs. 25.0%; p = 0.024). There was no significant relationship between history of migraine headache and age (16.61 ± 2.20 vs. 16.66 ± 2.93 years in migraineurs vs. those without migraine headache; p = 0.890), family history of migraine headache (47.8% of migraineurs vs. 37.0% of those without migraine headache; p = 0.134), or prior history of concussion (52.2% of migraineurs vs. 39.9% of those without migraine headache; p = 0.089). A total of 14 participants who had previously been diagnosed by a medical provider with migraine headache also had a prior history of concussion. In this subset of participants, 11 (78.6%) sustained their first concussion prior to being diagnosed with migraine headache.

A multiple logistic regression that controlled for between-group differences in age and sex, demonstrated a significant positive association between concussion group status and history of migraine headache (Adjusted OR = 1.90; 95% CI: 1.03 - 3.50. p = 0.039). However, when concussion history was also accounted for in the multiple logistic regression model, the relationship between concussion group status and history of migraine headache failed to reach statistical significance (History of migraine: Adjusted OR = 1.68; 95% CI: 0.89 - 3.16. p = 0.107; History of prior concussion: Adjusted OR = 3.15; 95% CI: 1.76 - 5.65. p < .001). A secondary multiple logistic regression analysis controlling for the effects of age and sex identified a significant positive association between history of migraine headache and prior history of concussion (Adjusted OR = 1.86; 95% CI: 1.02 - 3.37. p = 0.042).

Discussion

These results suggest that migraine headache may be a risk factor for concussion in athletes. However, a true cause-effect relationship cannot be inferred from these data. In this study, prior concussion was a stronger risk factor for being a member of the concussion group than migraine headache in both the bivariate and multivariate models. There was also a significant positive association between prior concussion history and prior history of migraine headache in the secondary multivariate analysis. This raises a "chicken-and-egg" question as to whether presence of migraine headache predisposes athletes to concussion, or concussion predisposes athletes to develop migraine headache. While not a definitive finding, almost 80% of those participants reporting both a history of clinician-diagnosed migraine headache and prior concussion sustained their concussion prior to receiving their migraine headache diagnosis.

The association between sport-related concussion and subsequent migraine headache is consistent with prior research. In a 2015 study of collegiate athletes, 35.9% with a prior history of concussion, and 40.4% of those with a history of more than one concussion, also self-reported a history of migraine.[ 18] In a similar study of high school football players, 40.7% of those indicating a history of concussion also reported a personal history of migraine.[ 19] However, as these studies were retrospective in nature, it is unclear whether a predisposition to headaches existed prior to the documented concussions. Additionally, a 2015 study of retired NFL players with prior history of concussion found a significantly higher incidence and frequency of headache, migraine, and chronic migraine when compared to the general population.[ 20] Furthermore, a report in non-athletes that almost one third of patients experiencing chronic migraine headache precipitated by minor head trauma have a family history of migraine, suggests that there may be an inherent predisposition to refractory post-traumatic migraine headache symptoms in this subset of the population.[ 21]

The reason for a possible elevated risk of migraine following concussion is uncertain. Endogenous opioids, i.e. those that are naturally occurring within the brain such as beta-endorphins, may play a role. Endogenous opioids are known to increase following mTBI.[ 22] In both episodic and chronic migraine, basal plasma beta-endorphin levels are decreased.[ 22, 23] Of note, a similar finding has also been observed in medication overuse headache.[ 24] These observations suggest that unique differences in endogenous pain modulation involving the opioid system in migraineurs could conceivably contribute to the pathophysiology of other pain hypersensitivities. Specifically, it is possible that such biochemical baseline abnormalities decrease the symptom threshold in migraineurs following head trauma, subsequently predisposing to more pronounced and/or more refractory symptoms post-injury.

Individuals with post-traumatic headache have also exhibited nociceptive dysfunction consistent with a generalized impairment of the spinothalamic system.[ 25] Chronic post-traumatic headache seems to result from a combination of injury to both central and peripheral structures, possibly leading to central pain, and chronic sensitization of intra- and extracranial nociceptors.[ 26, 27] This apparently traumatically-induced sensory profile is compatible with the central sensitization seen in migraine sufferers and may further explain an elevated risk of migraine headache following concussion.

There may also be other pathophysiological underpinnings for development of persistent post-traumatic migraine headache, i.e., migraine headache following head trauma, after concussion. An association between chronic pain and dysfunctional pain modulation has been reported for migraine, as well as other types of primary headache disorders.[ 28] Pain "remapping" has been observed in migraineurs following injury to the trigeminal system.[ 29] This response appears to be specific to migraine, suggesting the pathophysiology of migraine is impressionable and responds uniquely to external insults such as concussion. This would suggest that the refractory clinical course noted in some athletes with chronic post-traumatic headache may be more attributable to an inherent susceptibility for dysfunctional pain modulation than a direct result of the injury itself.

The relationship between migraine headache and concussion is further complicated by the fact that head trauma is a known trigger for migraine headaches. Indeed, the diagnosis of "footballer's migraine" has been described in the medical literature for over 40 years.[ 30] Given the significant overlap between symptoms of concussion and those of migraine headache, it is possible that in some cases an athlete experiencing a migraine headache could be mis-diagnosed with concussion. It is possible that the mis-classification of post-traumatic headaches as concussion may spuriously inflate the strength of their association.

There is also a growing body of literature suggesting a potential association between sport-associated head trauma exposure and neuroanatomical,[ 31- 35] neurophysiological,[ 36, 37] and neurocognitive[ 33, 35- 38] changes in athletes not manifesting clinically-evident signs or symptoms of concussion. It is possible that migraineurs may have a lower tolerance than non-migraineurs for such disruptions and that their physiological threshold for developing headaches and related neurological symptoms in response to such changes may therefore be lower. If this is the case, then migraineurs may be predisposed to developing signs and symptoms of concussion in response to lesser degrees of neurological dysfunction that would remain sub-clinical in non-migraineurs. The presence of such a differential threshold for symptom manifestation could also increase the likelihood of migraineurs receiving a concussion diagnosis.

It is important to consider that headache, like most post-concussion symptoms, is not specific to concussion and can also be caused by various other exposures that are relevant to athletes. For example, migraine headache can be triggered by sleep deprivation, physical exertion, changes in environmental conditions, emotional stress, and dehydration. It has been also been demonstrated that dehydration in athletes can mimic other symptoms of a concussion as well.[ 39] Prescription medication use/abuse should also be considered when an athlete presents with concussion-like symptoms in the absence of reported injury. Similarly, excessive use of analgesics following concussion may contribute to persistent post-traumatic headaches in some individuals. A 2014 retrospective chart review of adolescent concussion patients diagnosed with chronic post-traumatic headache found that 70.1% met criteria for probable medication overuse headache.[ 40] Of these, 68.5% had resolution of headaches (or return to pre-concussion headache patterns) after discontinuing analgesics. In attempt to limit the progression to a more prolonged/refractory recovery course, athletes presenting with headache should routinely be screened for the potential of medication overuse headache.

This case-control study has several limitations that merit further discussion. The biggest limitation is the inability of this study design to establish a cause-effect relationship between migraine headache and concussion, as is discussed above. Secondly, participants were surveyed at only one post-concussion time point, the timing of which was not standardized relative to the time of injury. As such, they were not asked to complete a formal post-concussion symptom inventory. Therefore, it is not possible to comment on the potential influence of migraine headache on the severity or duration of post-concussion symptoms based on the results of this study. Thirdly, the anonymous nature of the survey did not permit confirmation that participants being seen in the sport neurology clinic were in fact diagnosed with a concussion, so in some cases an alternative diagnosis may have been assigned. Fourthly, since the relative timing of questionnaire completion and the clinic visit was not strictly controlled for, it is possible that participants who completed the questionnaire after a neurological history was taken during a sport neurology clinic visit may have been more likely to report a history of migraine headache or concussion than those who completed the questionnaire before their visit, or than those who were seen by an orthopedic provider. Finally, this case-control study design does not address the incidence of concussion or migraine headache in the general athlete population.

In conclusion, this study supports the presence of an association between migraine headache and concussion in athletes, but the cause-effect nature of this relationship cannot be determined. Additional prospective research is necessary to further define this relationship, as well as to further assess the potential effects of a migraine headache diagnosis on concussion severity. Until such results are available, clinicians should continue to consider the potential effect of an athlete's migraine headache history on their recovery and risk for re-injury when making return-to-play decisions following concussion.

Acknowledgments

The authors would like to thank the support staff at the University of Michigan NeuroSport and MedSport clinics for their assistance distributing and collecting study questionnaires.

Sources of Funding: Dr. Eckner received partial effort support during this project from the Rehabilitation Medicine Scientist Training Program and the National Institutes of Health (1 K23 HD078502). His active research funding includes the National Institutes of Health (1 K23 HD078502), the National Collegiate Athletics Association, the United States Department of Defense (14132004), the University of Michigan Injury Center, and the Foundation for Physical Medicine and Rehabilitation. Dr. Seifert is a member of the Kentucky State Boxing Commission and has served as a consultant for the United States Department of Defense. He has received personal compensation as a speaker for the National Headache Foundation and the American Headache Society. Dr. Kutcher is a consultant for the National Basketball Association and ElmindA, Ltd.

Footnotes

Conflicts of Interest: Dr. Pescovitz and Mr. Zeiger have nothing to disclose.

References

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Is Migraine Headache Associated with Concussion in Athletes? A Case-Control Study

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Kerr et al., 2019
Led by: Dr. Jane McDevitt

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The Effects of a Single Bout of Soccer Heading of Single and Dual-Task Tandem Gait in Collegiate Recreationally Active Individuals (Burns, Lohr, McDevitt, 2021)

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The Sympathetic Nervous System and Vascular Health | Drs. Jody Greaney & Anna Stanhewicz

Jody Greaney, Ph.D., FACSM, and Anna Stanhewicz, Ph.D., are scientists at Pennsylvania State University. They have been studying the process through which the sympathetic nervous system communicates with the vascular system during total body heating and cooling, particularly in aging adults.

As humans age, this communication process becomes less efficient and can cause an increase in cardiovascular risk. Drs. Greaney and Stanhewicz are studying this process in attempt to determine intervention strategies that may mitigate the cardiovascular risk.

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ACSM | The American College of Sports Medicine

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Jody Greaney, Ph.D., FACSM, and Anna Stanhewicz, Ph.D., are scientists at Pennsylvania State University. They have been studying the process through which the sympathetic nervous system communicates with the vascular system during total body heating and cooling, particularly in aging adults. As humans age, this communication process becomes less efficient and can cause an increase in cardiovascular risk.

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Boston 6-9, 2023
Boston, MA (75th Celebration)

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About the EATA Convention

Each year the Eastern Athletic Trainers' Association holds an annual educational convention where on average, 1500 athletic trainers, athletic training students and other healthcare providers, come together to hear leaders in their field speak on a variety of healthcare topics. Topics range from concussion and illnesses to orthopedic injuries and emergency management. Subject areas fall within the Board of Certification's current Practice Analysis. At the convention banquet, the EATA Executive Board recognizes all award, student scholarship and research grant winners.

Go to EATA 74th Convention Registration Web Site- Registration is Open

2022 January 7-10, Foxwoods Resort & Casino, Mashantucket, CT

2023 January 6-9, Boston, MA (75th Celebration!)

2024 January 5-8, Foxwoods Resort & Casino, Mashantucket, CT

2025 January 9-13, Loews, Philadelphia, PA

2026 January 9-12, Boston, MA

June 28 - July 1, 2022 Philadelphia, PA

# data[].attributes.attachment_link.description
Each year the Eastern Athletic Trainers' Association holds an annual educational convention where on average, 1500 athletic trainers, athletic training students and other healthcare providers, come together to hear leaders in their field speak on a variety of healthcare topics. Topics range from concussion and illnesses to orthopedic injuries and emergency management.

# data[].attributes.headline
Premorbid Primary Headache and Vestibular and Oculomotor Baseline Assessments in Collegiate Athletes (Burns, Langford, Tierney, McDevitt, 2021)

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Premorbid Primary Headache and Vestibular and Oculomotor Baseline Assessments in Collegiate Athletes (Burns, Langford, Tierney, McDevitt, 2021)

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Memory Impairments Associated with Mild Traumatic Brain Injury: A Critically Appraised Topic (Burns, Sanford, Tierney, McDevitt, 2022)

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Memory Impairments Associated with Mild Traumatic Brain Injury: A Critically Appraised Topic (Burns, Sanford, Tierney, McDevitt, 2022)

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Memory impairements and fMRI, Burns IJATT

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June 28th - July 1, 2022 in Philadelphia, PA (Convention Center)

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Enhance your VNATA 2021 experience by networking with peers, speakers, and exhibitors June 22 – September 30! Your virtual experience includes the following opportunities to expand your network and connect with athletic trainers from around the world.

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Previous concussions increase risk of mental health disability in college athletes (Burns, Kerod, McDevitt; 2022, JCTRES)

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Previous concussions increase risk of mental health disability in college athletes (Burns, Kerod, McDevitt; 2022, JCTRES)

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Previous Conx increases mental health JCTRES 2022