Concussions: A Growing Psychiatric Epidemic

A Primer on Traumatic Brian Injury and Concussions
A Primer on Traumatic Brian Injury and Concussions
Until more effort is put into preventing injury in the first place, psychiatrists will likely continue to be key players in the game.

Also known as “concussion,” chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease believed to be the result of multiple mild traumatic brain injuries (mTBIs).

CTE was first described by Martland in 1928 as being “punch drunk,” a syndrome of confusion and ataxia in boxers having suffering repeated blows to the head.1 In 1937, Millspaugh described “dementia pugilistica,” symptoms of cognitive and motor dysfunction, once again mainly observed in boxers.2

The term “chronic traumatic encephalopathy” was first coined by Miller in 1966 to encompass the mood, cognitive, and motor dysfunctions of dementia pugilistica.3 In 1973, Corsellis introduced a pattern separating CTE from other neurodegenerative diseases.4

The modern definition of CTE was brought to the national spotlight by the case studies of Omalu et al. that highlighted neuropsychiatric and neuropathologic changes in National Football League (NFL) players,5 inspiring the movie “Concussion.” This article focuses on CTE in American football and why it is of importance to psychiatrists and mental health professionals.

Epidemiology and Risk Factors

The most common risk factor across case studies of CTE is a history of at least one mTBI. Onset generally occurs in mid-life, usually after retirement from professional play.6 Timing is variable, given the heterogeneity of career length among NFL players; many begin their careers in junior high school, but some start at the tender age of 6.7 

Of 1.2 million interscholastic football players in any given year, up to 5.6% sustain an mTBI. The majority (53%) of cases, however, remain unreported to medical personnel.8

Although the literature supports a correlation between repeated mTBIs and CTE, definitive causation has not been determined.9 Still, 63% to 71% of players with repetitive mTBIs eventually develop CTE.10

Among NFL players, the reported prevalence of CTE ranges from 3.7%6 to 90%.10 This disparity is largely due to disagreement among clinicians regarding what constitutes an mTBI, and the consequences faced by NFL players, their coaches, equipment managers, and team clinicians reporting them.11

Players who are running-backs, begin play before age 12, and have a history of previous mTBI are at a high risk of re-injury.12 A relationship between number of years played, development of CTE, and the stage of phosphorylated Tau (pTau) pathology has also been suggested.10,12

Retired NFL players who have had 3 or more mTBIs have a 5-fold increased risk for mild cognitive impairment, and 3-fold higher risk for depression.13,14 The APOE ε4 genotype increases the risk for cognitive impairment in CTE.12

 

Pathophysiologic Features

Evidence suggests that repetitive disturbance of axons along with altered neurotransmission is linked to widespread glutamate release, ionic fluxes, and metabolic uncoupling.15 These changes may generate a chain of events leading to CTE.15

Animal models have shown decreased serum and cerebrospinal fluid (CSF) levels and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that dephosphorylates the p-Tau protein essential for microtubule assembly.  Accumulation of p-Tau eventually causes neuronal death.16

A recent consensus conference defined the irregular pattern of p-Tau immunoreactivity deposition surrounding microvasculature in the depths of cortical sulci as pathognomonic for CTE, a distinction from other tauopathies.

Supportive features include abnormal p-Tau neurofibrillary tangles (NFTs) distributed in layers I-II of the cortex; p-Tau thorn-like astrocytes in the subpial and periventricular regions of the cortex; pretangles, extracellular tangles, or NFTs; and dendritic swellings in the hippocampus.

Also supportive of CTE are dot-like structures and TDP-43 immunoreactive neuronal inclusions in the antromedial temporal cortex, amygdala, and the hippocampus, as well as septal abnormalities, atrophy of mammillary bodies, and third ventricle dilation.17 Staging for CTE pathology has been proposed.10

There are some similarities between Alzheimer’s disease (AD) and CTE, suggesting a separate classification of CTE-AD; the presence of Aβ plaques correlates with more severe p-Tau pathology and advanced stages and clinical presentations.18

Plaques in CTE-AD are more likely to be found within the sulci, contrasting with the gyral depositions observed in AD. Death tends to occur 10 years earlier, suggesting that repetitive mTBI may accelerate and change the deposition and accumulation of Aβ; presence of Aβ plaques may correlate with CTE progression and may speed up the aging process of the brain. The presence of Aβ plaques is believed to increase the odds of developing cognitive dysfunction in CTE by 4.5 times in individuals with Aβ pathology.18

Although CTE cannot currently be diagnosed via imaging, there are a few PET ligands for p-Tau that show some promise. [F-18]FDDNP consistently identifies p-Tau deposits in brains with clinically-suspected CTE in the same distribution of p-Tau NFTs on autopsy, and the ligand [11C]DPA-713  has detected TBI-related neuronal inflammation in 9 former NFL players with clinically-suspected CTE. The PiB amyloid ligand is also being investigated for utility in PET neuroimaging.19

Image 1 depicts the different stages of CTE.

Neuropsychiatric Symptoms

The average age of symptom onset is between 30 and 64 years of age. Within the first 48 hours to 2 weeks after an mTBI, cognitive deficits are common.20 Four stages of neuropsychiatric symptoms were proposed in 201310, and are similar to the posthumous progression described in 2011 by Omalu et al.5

Stage I symptoms include memory loss, executive dysfunction, difficulty concentrating, inattention, aggression, depression, explosivity, and suicidality. Headache is fairly common. At this stage, very few individuals will see a psychiatrist.

 

In stage II, symptoms begin to progress — cognitive features worsen, and language dysfunction appears. Behavioral symptoms progress to include impulsivity; mood symptoms become more prominent, and lability appears.

By stage III, approximately 75% of individuals show cognitive decline with the development of visuospatial difficulties; difficulty concentrating and inattention become more severe. Behavioral symptoms continue to worsen and become more extreme. Mood symptoms worsen as well.

By Stage IV, up to 100% of individuals are symptomatic. Cognitive impairment is severe; many individuals are described as having “severe memory loss with dementia,” “profound” inattention and loss of concentration, and dysarthria. Paranoia may develop. Mood symptoms can be severe, with approximately 31% of individuals studied having contemplated suicide. Of those diagnosed with pure stage III or IV CTE, 26% had suicidal tendencies, and 14% completed suicide.10

Additional observations made by Omalu included decreased information processing speed, increase in religiosity, lack of insight, poor judgment, involvement in obviously illegal activities, substance abuse, indiscretion, sexual inappropriateness, verbal and physical abuse, problems with interpersonal relationships, isolation, restlessness, hyperactivity, and somatic complaints. He also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.5

Through interviewing next-of-kin, it was suggested that some individuals diagnosed with CTE had exhibited mood and behavioral changes before developing cognitive impairment, and the rest exhibited cognitive impairment first.

The group with behavior and mood changes first tended to be more violent, explosive, depressed, out of control, and showed symptoms at a significantly younger age than the cognitive impairment group.  The group that developed cognitive impairment first was more likely to progress to dementia.21

See Table 1 for staging of both neuropathologic and neuropsychiatric sequelae of CTE.

Prevention and Treatment

Prevention and management of mTBI includes pre-participation counseling: education of coaches, trainers, players, and families about the risk of mTBI during play and the need for close monitoring when an mTBI is suspected.12 

Promising technologies include the Head Impact Telemetry System; and the Integrated Concussion Examination, a cloud-based system that captures players’ baseline pre-season neurocognitive functioning, history of concussions, balance, and coordinate performance data for comparison after an mTBI.8

Assessment for mTBI involves standardized sideline assessment tools, with the caveat of being adjunctive to proper evaluation of suspected TBI. Management of mTBI involves immediate removal of the player from play, restriction from training/practice/gameplay to avoid further injury.12

Because head impacts are a major concern in football, there has been a race among manufacturers to provide the most advanced and protective helmet technology. However, early evidence suggests that helmets may only be providing players with a false sense of security.

 

In one study, half of a collegiate football team was instructed in helmetless practice, while the other half practiced with helmets. The helmetless group experienced 28% fewer head impacts after just 1 season, suggesting that practicing without helmets in tackle football may be more safe, however the study was limited by small size.22

Players should be advised to follow a brain-healthy lifestyle. Recommendations include cessation of smoking and drug abuse, exercise, proper nutrition, weight loss, stress reduction/mindfulness training, sufficient sleep, and management of cerebrovascular risk factors such as hypertension, hyperlipidemia and diabetes.

In one recent study,  fish oil (containing EPA and DHA), high-potency multivitamins, and supplements containing ginkgo, vinpocetine, acetyl-1-carnitine, phosphatidylserine, n-acetyl-cysteine, and huperizine A seemed to increase cerebral perfusion and improve performance on neuropsychiatric testing after approximately 6 months in players with multiple mTBIs or CTE.23 More research is needed to identify supplements that may be beneficial during rehabilitation from mTBI and CTE.

Future Research

There is abundant evidence suggesting that repeated mTBIs are related to CTE, but to date, there is insufficient data to confirm a causal link. There is demand for epidemiological, longitudinal, cross-sectional, retrospective and prospective studies to determine the incidence and prevalence of mTBI and CTE — not only in the NFL, but also across the general public and in other contact sports such as soccer, where children as young as 4-5 years of age are already doing “headers”. Every header represents a potential mTBI to the vulnerable young brain.

Continued research should also analyze the relationship between clinical symptoms and pathological features, which would further our understanding of the brain as a whole. Serum and CSF biomarkers, as well as PET neuroimaging using p-Tau radioligands, could be used to achieve an earlier diagnosis of CTE in live patients. Genetic data may identify at-risk individuals, guiding return-to-play counseling.

The relationship between suicidality and multiple mTBIs in former athletes should also be explored, as well as the idea of a “threshold” number of mTBIs for CTE development. Such data would add to the list of known risk factors for suicide, potentially saving hundreds to thousands of lives.

Finally, more research should be geared toward prevention. The early results of helmetless practice are promising, but larger studies need to be conducted to confirm validity.

Conclusion

Chronic traumatic encephalopathy is becoming a ‘hot-button’ issue. American football is a multi-billion dollar industry — the Super Bowl alone has become such a giant event that advertisement revenue is likely to hit record highs this Sunday.

Football scholarships allow many young men to pursue an education they may otherwise not be able to afford, and in states where there are no professional teams, collegiate football is king.

Studies have consistently shown that retired NFL players are at a higher risk of developing CTE.  It is highly unlikely that the current innovations in helmet safety, or instructions on how to properly tackle, are going to reduce that risk enough to make the game safer overall — on the field is where prevention must start.

Until more effort is put into preventing injury in the first place, psychiatrists will likely continue to be key players in the game.

Emily C. Olson, DO, is a psychiatry resident at the Saint Louis University School of Medicine who received her medical degree from Des Moines University College of Osteopathic Medicine. George T. Grossberg, MD, is Director of Geriatric Psychiatry at the SLU School of Medicine and a member of the Psychiatry Advisor editorial board. He is also a past president of both the American Association of Geriatric Psychiatry and the International Geriatric Association

TABLE 1

CTE Stage
(McKee et al.)10
Pathological FeaturesNeuropsychiatric Features
I

Macroscopic:
Grossly Normal

Microscopic:
Perivascular p-Tau NFTs in focal epicenters restricted to the sulcal depths of the superior, superior lateral, or inferior frontal cortex

Cognitive:

  • Memory loss (mild)
  • Executive dysfunction (mild)
  • Inattention (mild-moderate)
  • Difficulty concentrating (mild-moderate)

Behavioral:

  • Aggression
  • Explosivity

Mood:

  • Depression
  • Suicidality

Neurologic:

  • Headache
II

Macroscopic:
Mild enlargement of frontal horn and lateral and third ventricles.

Microscopic:
Spread of p-Tau NFTs to the superficial cortical layers next to the focal epicenters as well as the nucleus basalis of Meynert and locus coeruleus

Cognitive:

  • Memory loss (mild-moderate)
  • Executive dysfunction (mild-moderate)
  • Inattention (moderate)
  • Difficulty concentrating (moderate)
  • Language dysfunction

Behavioral:

  • Aggression
  • Explosivity
  • Impulsivity

Mood:

  • Depression
  • Suicidality
  • Mood lability
  • Apathy

Neurologic:

  • Headache
  • Motor Neuron Disease symptoms
III

Macroscopic:
Mild cerebral atrophy, dilation of the ventricles, a sharp concavity of the third ventricle, and loss of pigmentation in the substantia nigra and locus coeruleus

Microscopic:
Dense p-Tau pathology in the medial temporal lobe structures and widespread regions of the septal , frontal, temporal, insular, and parietal cortices, diencephalon, brainstem, and spinal cord

Cognitive:

  • Memory loss (moderate)
  • Executive dysfunction (moderate)
  • Inattention (severe)
  • Difficulty concentrating
  • Language dysfunction

Behavioral:

  • Aggression
  • Explosivity
  • Impulsivity
  • Paranoia

Mood:

  • Depression
  • Suicidality
  • Mood lability
  • Apathy

Neurologic:

  • Headache
  • Motor Neuron Disease symptoms
IV

Macroscopic:
Cerebral, medial temporal lobe, thalamic, hypothalamic, and mammillary body atrophy

Microscopic:
Widespread p-Tau pathology involving regions of the neuraxis (including white matter), extensive neuronal loss and gliosis in the cerebral cortex and sclerosis of the hippocampus

Cognitive:

  • Memory loss (severe)
  • Executive dysfunction (severe)
  • Inattention (profound)
  • Difficulty concentrating (profound)
  • Language dysfunction

Behavioral:

  • Aggression
  • Explosivity
  • Impulsivity
  • Paranoia

Mood:

  • Apathy
  • Suicidality
  • Depression
  • Mood lability

Neurologic:

  • Headache
  • Motor Neuron Disease symptoms
  • Dysarthria
  • Parkinsonian symptoms
  • Gait ataxia
Image 1: According to McKee et al: “The four stages of CTE. In stage I CTE, p-tau pathology is restricted to discrete foci in the cerebral cortex, most commonly in the superior, dorsolateral or lateral frontal cortices, and typically around small vessels at the depths of sulci (black circles). In stage II CTE, there are multiple epicentres at the depths of the cerebral sulci and localized spread of neurofibrillary pathology from these epicentres to the superficial layers of adjacent cortex. The medial temporal lobe is spared neurofibrillary p-tau pathology in stage II CTE. In stage III, p-tau pathology is widespread; the frontal, insular, temporal and parietal cortices show neurofibrillary degeneration with greatest severity in the frontal and temporal lobe, concentrated at the depths of the sulci. Also in stage III CTE, the amygdala, hippocampus and entorhinal cortex show neurofibrillary pathology. In stage IV CTE, there is severe p-tau pathology affecting most regions of the cerebral cortex and the medial temporal lobe, sparing calcarine cortex in all but the most severe cases. All images, CP-13 immunostained 50-µm tissue sections.” 10

References

1.           Martland H. Punch Drunk. J Am Med Assoc. 1924;91(15):1103-1107.

2.           Millspaugh JA. Dementia Pugilistica. U S Nav Med Bull. 1937;35:297-361.

3.           Miller H. Mental after-effects of head injury. Proc R Soc Med. 1966;59(3):257-261.

4.           Corsellis JA, Bruton CJ, Freeman-Browne D. The aftermath of boxing. Psychol Med. 1973;3(3):270-303.

5.           Omalu B, Bailes J, Hamilton RL, et al. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in american athletes. Neurosurgery. 2011;69(1):173-183.

6.           Gavett BE, Stern RA, McKee AC, et al. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin Sport Med Med. 2011;30(1):179-188.

7.           Mez J, Todd S, Deneshvar D, Stein T, McKee A. Pathologically Confirmed Chronic Traumatic Encephalopathy in a 25-Year-Old Former College Football Player. JAMA Neurology.

8.           Broglio SP, Sosnoff JJ, Shin S, et al. Head Impacts During High School Football: A Biomechanical Assessment. J Athl Train (National Athl Trainers’ Assoc. 2009;44(4):342-349.

9.           Azad TD, Li A, Pendharkar A V, Veeravagu A, Grant GA. Junior Seau – An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury. World Neurosurg. 2015.

10.         McKee AC, Stein TD, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy.

11.         McNamee M, Partridge B, Anderson L. Concussion Ethics and Sports Medicine. Clin Sports Med. 2015.

12.         Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(24):2250-2257.

13.         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.

14.         Guskiewicz KM, Marshall SW, Bailes J, et al. Recurrent Concussion and Risk of Depression in Retired Professional Football Players. Med Sci Sport Exerc. 2007;39(6):903-909.

15.         Giza CC, Hovda DA. The New Neurometabolic Cascade of Concussion. Neurosurgery. 2014;75:S24-S33.

16.         Arun P, Oguntayo S, VanAlbert S, et al. Acute decrease in alkaline phosphatase after brain injury: a potential mechanism for tauopathy. Neurosci Lett. 2015;609:152-158.

17.         McKee AC, Cairns NJ, Dickson DW, et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 2016;131(1):75-86.

18.         Stein TD, Montenigro PH, Alvarez VE, et al. Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol. 2015;130(1):21-34.

19.         Eisenmenger LB, Huo EJ, Hoffman JM, et al. Advances in PET Imaging of Degenerative, Cerebrovascular, and Traumatic Causes of Dementia. Semin Nucl Med. 2016;46(1):57-87.

20.         Wortzel HS, Granacher RP. Mild Traumatic Brain Injury Update : Forensic Neuropsychiatric Implications. J Am Acad Psychiatry Law. 2015;43(4).

21.         Stern R a, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81:1122-1129.

22.         Swartz EE, Broglio SP, Cook SB, et al. Early Results of a Helmetless-Tackling Intervention to Decrease Head Impacts in Football Players. J Athl Train. 2015;51(1):6-8.

23.         Amen DG, Wu JC, Taylor D, Willeumier K. Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. J Psychoactive Drugs. 2011;43(1):1-5.