Accepted Manuscript

The multi-factorial origins of Chronic Traumatic Encephalopathy (CTE) symp-tomology in post-career athletes: The athlete post-career adjustment (AP-CA)model

Michael Gaetz

PII: S0306-9877(16)30786-1DOI: http://dx.doi.org/10.1016/j.mehy.2017.03.023Reference: YMEHY 8513

To appear in: Medical Hypotheses

Received Date: 26 October 2016Accepted Date: 21 March 2017

Please cite this article as: M. Gaetz, The multi-factorial origins of Chronic Traumatic Encephalopathy (CTE)symptomology in post-career athletes: The athlete post-career adjustment (AP-CA) model, Medical Hypotheses(2017), doi: http://dx.doi.org/10.1016/j.mehy.2017.03.023

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Title: The multi-factorial origins of Chronic Traumatic Encephalopathy (CTE) symptomology in

post-career athletes: The athlete post-career adjustment (AP-CA) model

Author: Michael Gaetz Ph.D.

Faculty of Health Sciences, University of the Fraser Valley, Chilliwack, BC Canada

Corresponding Author:

Michael Gaetz Ph.D.

45190 Caen Road,

Chilliwack, BC

V2R 0N3 Canada

michael.gaetz@ufv.ca

Abstract: 333 words (400 words maximum)

Manuscript: 10,396 words (38 pages total 12 pt font double spaced)

Table: 1

Figure: 1

Key words: chronic traumatic encephalopathy, concussion, athletic identity, career transition

stress, chronic pain, substance abuse, opioid, androgenic anabolic steroid.

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ABSTRACT

CTE has two prominent components: the pathophysiology that is detected in the brain

postmortem and the symptomology that is present in the interval between retirement and end

of life. CTE symptomology has been noted to include memory difficulties, aggression,

depression, explosivity, and executive dysfunction at early stages progressing to problems with

attention, mood swings, visuospatial difficulties, confusion, progressive dementia, and

suicidality [e.g. 6-10]. There are a number of assumptions embedded within the current CTE

literature: The first is the assumption that CTE symptomology reported by athletes and their

families is the product of the pathophysiology change detected post-mortem [e.g. 10]. At

present, there is little scientific evidence to suggest that all CTE symptomology is the product of

CTE pathophysiology. It has been assumed that CTE pathophysiology causes CTE symptomology

[38, 61] but this link has never been scientifically validated. The purpose of the present work is

to provide a multi-factorial theoretical framework to account for the symptomology reported

by some athletes who sustain neurotrauma during their careers that will lead to a more

systematic approach to understanding post-career symptomology. There is significant overlap

between the case reports of athletes with post-mortem diagnoses of CTE, and symptom

profiles of those with a history of substance use, chronic pain, and athlete career transition

stress. The athlete post—career adjustment (AP-CA) is intended to explain some of the

symptoms that athletes experience at the end of their careers or during retirement. The AP-CA

model consists of four elements: neurotrauma, chronic pain, substance use, and career

transition stress. Based on the existing literature, it is clear that any one of the four elements of

the AP-CA model can account for a significant number of CTE symptoms. In addition, depression

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can be a chronic lifelong co-morbid condition that may be present prior to an athletic career, or

may be developed secondary to any of the model elements as shown in Figure 1. Notably,

neurotrauma is a necessary, but not a sufficient condition, for the development of CTE

symptomology.

INTRODUCTION

Chronic Traumatic Encephalopathy (CTE) has recently received considerable attention in the

clinical literature as well as in mainstream and popular media. In fact, it is rare that a movie is

made about a specific area of clinical science while the science is ongoing, but such is the case

with the movie “Concussion”; a focus on the scientific career of Dr. Bennett Omalu and his

study of deceased professional athletes many of whom had donated their brains to study at the

University of Pittsburg and later at the Boston University (now the VA-BU-CLF) Brain Bank. It is

the contention of Omalu and colleagues that CTE is the product of any human activity that

exposes you to a “single traumatic brain injury, episodic traumatic brain injury or repetitive

traumatic brain injury” [1](p. 10). Sports generally considered to generate CTE include combat

sports (e.g. boxing and mixed martial arts), ice hockey, North American football, rugby union

and amateur and professional wrestling [1,2]. Some have stated that it is now known that

“repeated TBI can potentially lead to irreversible and progressive neurodegeneration of CTE”

and can be produced by activities ranging from heading the ball in soccer to being an enforcers

in ice hockey [3] (p.119). CTE has also been detected in deceased military veterans [e.g. 4].

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CTE has two prominent components: the pathophysiology that is detected in the brain

following death and the symptomology that is present in the interval between retirement and

end of life. The pathophysiologic features have generally been defined by CTE researchers [e.g.

5, 6] to include p-tau immunoreactive astrocytic tangles and neurofibrillary tangles (NFT) that

aggregate in specific locations within the brain. CTE symptomology (clinical symptoms) has

been noted to include memory difficulties, aggression, depression, explosivity, and executive

dysfunction at early stages progressing to problems with attention, mood swings, visuospatial

difficulties, confusion, progressive dementia, and suicidality [e.g. 6-10]. CTE has been linked to

the deaths of athletes in the National Football League (NFL) [e.g. 11-13] and the National

Hockey League (NHL) [14]. Related to these negative outcomes are well publicized past and

current legal cases initiated on behalf of retired athletes who claim that professional sports

leagues should have done more to protect and inform them from these negative outcomes

during their sports careers [11]. Some have stated that given the numbers of North Americans

involved in contact sport, “it is clear that the risk of CTE looms as a potential public health

disaster” [15] (p. 4). The concern over CTE has had a direct impact on some athletes who have

decided to retire early in their careers to limit the potential for long-term negative outcomes

[16].

The clinical science and presence of CTE as a mainstream concept have progressed rapidly,

however, some would argue, without the measured and expected degree of scientific rigor. As

a result, there are a number of assumptions embedded within the current CTE literature that

may be clouding a more accurate interpretation of the findings. The first is the assumption that

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CTE symptomology reported by athletes and their families is the product of the

pathophysiology change detected post-mortem [e.g. 10]. Because the vast majority of the CTE

literature is based on case studies, there has been very little information generated that

objectively and intentionally demonstrates this link. The second assumption is that retired

athletes are representative of the general population with the exception that their brains have

sustained at least single or repetitive mild concussive or subconcussive injury. This assumption

is generally incorrect. Athletes who have attained some level of success and notoriety are a

unique sub-population: 1) They often experience significant physical trauma, and in some cases

neural trauma, during their careers. This trauma may lead to persistent neurologic and physical

problems; 2) To achieve their atypical level of success, they must sacrifice other elements of

personal or social engagement and/or development. This can lead to social isolation post-

career and may even lead to problematic personality (identity) development; and 3) Athletes

oftentimes achieve a level of social prominence during their careers. This level of prominence

diminishes or disappears following retirement. These are important factors to consider when

attempting to understand why some athletes have negative outcomes following retirement.

At present, there is little scientific evidence to suggest that all CTE symptomology is the product

of CTE pathophysiology. The purpose of the present work is to provide a multi-factorial

theoretical framework to account for the symptomology reported by some athletes who

sustain neurotrauma during their careers and that will lead to a more systematic approach to

understanding post-career symptomology.

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CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE)

CTE History

Elements of CTE pathophysiology and symptomology were historically described as a

progressive neurodegenerative syndrome that occurred in boxers who had a significant history

in the sport. Martland [17] was the first to describe the syndrome known as ‘‘punch drunk’’ that

characterized some of the symptomatology attributed to the pathophysiology of CTE. While

many of the signs included obvious physical symptoms such as leg dragging, Parkinsonian

symptoms, and speech slowing, some of the symptomology was also consistent with CTE

including cognitive deterioration and confusion. It is also evident that at the time of publication,

the words “concussion” and “traumatic encephalitis” were in use to describe various forms of

neurotrauma in boxers [17]. Parker [18] was among the first to use the term traumatic

encephalopathy to identify a chronic disease of the nervous system observed in former boxers

who sustained repeated injuries to the brain. He described early signs and symptoms such as

ataxia and confusion, postcareer signs such as dysarthria, deafness, ‘‘physical slowing up,’’ and

slow, laboured, grating, nasal speech. Symptomology included deficits in memory, attention,

and concentration. An interesting note in the cases reviewed by Parker was that despite

presence of substantial neurotrauma, evidenced by numerous physical signs, the deterioration

did not seem to worsen over the years of follow-up [18]. These deficits were generally

considered to affect professional boxers only with the “’punch-drunk” syndrome… never

observed in amateur boxers” [19] (p. 363). This early work was built upon by Roberts [20] who

randomly sampled 250 retired boxers and showed severe pathophysiology in 5% and

demonstrable lesions in 17% of cases. The often cited classic study by Corsellis et al. [21]

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described a characteristic pattern of brain injury in boxers, some of whom were amateurs: a

fenestrated or a cavum septum pellucidum, scarring to cerebellar tonsils and other cerebral

areas, neuronal loss in substantia nigra and locus coeruleus, ventricular enlargement, thinning

of the corpus callosum, and neurofibrillary tangles in cerebral cortex and temporal lobe. More

recent attempts to link the current concept of CTE with boxing have been published [22, 23]. In

their review of 36 published articles, Loosemore et al. [22] defined CTE as a demonstrable

change in neurological signs, brain imaging, psychometric testing, electroencephalography, and

other imaging. The authors concluded that a strong association between amateur boxing and

chronic traumatic brain injury did not exist. They added that the neurotrauma sustained in

amateur boxing was lower than other more popular sports (e.g. rugby union and equestrian)

[22]. McCrory et al. [23] had a different perspective stating that both amateur and professional

boxers are potentially at risk of developing CTE. Notably, both of these studies describe

neurologic and cognitive deficits in boxers without the pathophysiologic confirmation of CTE.

The modern era of CTE research

The modern era of CTE study can be credited to Omalu et al.’s [24] description of

neurodegenerative change in a retired NFL football athlete. The description of modern CTE

cases differs from the historical reports in boxers in a number of ways. First, the more recent

cases have been ‘‘autopsy confirmed’’ [e.g. 24]. Second, many of the athletes in current CTE

studies are not boxers (e.g., American football, ice hockey, and professional wrestling) [5, 25].

Third, the modern era of CTE research has been presented by some as pathophysiologically

distinct from the historical precedent described in boxing [1, 6, 8, 25-29].

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A unified definition for modern CTE has been elusive. Some researchers have defined CTE

related to single, episodic, or repetitive blunt force impacts to the head [5]. Others have

defined CTE as developing following repetitive concussive or subconcussive events [8, 30-32].

Some have suggested that CTE can occur with no direct head trauma at all [8, 33]. Recently, an

entirely new category has been proposed for research purposes; Traumatic Encephalopathy

Syndrome (TES) consisting of four variants (TES behavioral/mood variant, TES cognitive variant,

TES mixed variant, and TES dementia) [34].

CTE rates of incidence are unknown based on the research methodologies employed to date.

Prevalence estimates vary from relatively low [3, 29, 35], to moderate [e.g. 36], with some

media reports cresting 90% [12]. This has led some to suggest that CTE is likely more prevalent

than previously considered [37] while other caution that CTE has been over-estimated in some

athlete populations due to sampling bias [32]. As indicated in a recent NIH consensus

document, most agree that a definitive diagnosis of CTE can only be made during

neuropathological examination of the brain at autopsy [38, 39]. Nonetheless, it has also been

argued that a diagnosis of CTE related to sports can be based on a history of repetitive clinical

or subclinical concussions, evidence of disease progression, and a positive neurological exam

[15]. The number of concussive or subconcussive events in these athletes is often unusually

high (e.g. a mean of 20 concussions) [40].

Modern CTE Pathophysiology

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Early descriptions of modern CTE pathophysiology centred on the presence of tau-positive

neuritic threads, sparse intraneuronal NFTs, and cortical amyloid plaques, with little pathology

in the entorhinal cortex or hippocampus [24]. It was noted that NFTs often aggregated in

perivascular regions in cortical layers II and III [10]. Since that time, the identification of CTE has

evolved into classification systems developed by established CTE research groups [29].

However, similar to the varied definitions for CTE, pathophysiologic criteria also vary among

these classification systems.

McKee and colleagues have classified CTE into four stages [41, 42] while Omalu and colleagues

[5] have developed four histomorphologic CTE phenotypes. The inconsistencies between the

staging and phenotype classification schemes have generated criticism [43]. Inconsistencies

between systems include variations in gross morphological atrophy and the presence or

absence of p-tau immunoreactive astrocytic tangles, Aβ plaques, Lewy bodies, and

subependymal accumulation of p-tau. In addition, the issue of sporadic tau depositions in

various populations was not adequately addressed [43]. In an attempt to establish a consistent

pathological diagnosis of CTE, the National Institutes of Health (NIH) convened a Consensus

Conference to define the neuropathological criteria for CTE diagnosis [12]. The “Report from

the First NIH Consensus Conference to Define the Neuropathological Criteria for the Diagnosis

of Chronic Traumatic Encephalopathy”

(http://www.ninds.nih.gov/research/tbi/ReportFirstNIHConsensusConference.htm) clearly

indicated that a diagnosis of CTE can only be made during neuropathological examination of the

brain at autopsy. The group consensus was that “abnormal tau immunoreactivity in neurons

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and glia, in an irregular, focal, perivascular distribution and at the depths of cortical sulci, was

required for the diagnosis of CTE”.

Modern CTE Symptomology

Similar to modern CTE pathophysiology, modern CTE symptomology has evolved since first

described in 2005. The first descriptions were notably simple and straightforward, with the first

case described by Omalu et al. [24] as resembling a dysthymic disorder, with memory and

judgment problems, and Parkinsonian symptoms. Subsequent cases described by Omalu and

co-workers were depicted as having significant increases in psychiatric symptoms. For example,

the second case presented by this group [44] included more detailed neuropsychiatric sequelae

such as becoming agitated in social situations, being reclusive (e.g. often locking himself in the

house for 1 to 2 days), having unpredictable fluctuations in mood and personality,

risky/ambitious/irrational business dealings, and sudden bouts of agitation and irritability with

no rationale. Symptomology in subsequent cases was expanded to include distinct symptoms

such as suicidality, paranoia, hyperreligiosity, and violent behavior including criminality [7, 9,

10]. Some have suggested that CTE symptomology is progressive including worsening memory

impairment, executive dysfunction, management of activities of daily living (enough to impair

social and/or occupational functioning), with dementia in later stages [32]. Others speculate

that there may be several possible long-term outcomes following repetitive neurotrauma

including no neurological signs or symptoms, static deficits, or progressive neurodegeneration

[37]. In addition, some contend that sports-related (CTE) deterioration occurs in three stages 3

stages: Stage 1 - Affective disturbances and psychotic symptoms; Stage 2 - Social instability,

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erratic behavior, memory loss, and initial symptoms and signs of Parkinsonism; and Stage 3 -

General cognitive dysfunction, the progression of dementia, speech, and gait abnormalities, or

full-blown Parkinsonism [15]. CTE symptomology has been described as developing

“insidiously” some years to decades after retirement or exposure to neurotrauma [31].

In relation to the pathophysiologic stages proposed by McKee et al. [6]: Stage I CTE has been

associated with headache and loss of attention and concentration; Stage II CTE includes

depression, mood swings, explosivity, problems with attention and concentration, headache,

and short-term memory loss; Stage III includes cognitive impairment with memory loss,

executive dysfunction, loss of attention and concentration, depression, explosivity and

visuospatial abnormalities; Stage IV includes dementia, short-term memory loss, executive

dysfunction, attention and concentration loss, explosivity and aggression [6]. The proponents of

the Chronic Traumatic Encephalopathy Syndrome [34] have offered a broadened definition that

includes at least one “clinical” feature and at least two “supportive” features. Clinical features

include “Cognitive” (e.g. difficulties in cognition), “Behavioral” (e.g. being emotionally

explosive), and “Mood” (e.g. feeling overly sad, depressed, and/or hopeless). Supportive

features include: 1) Impulsivity, 2) Anxiety, 3) Apathy, 4) Paranoia, 5) Suicidality, 6) Headache,

7) Motor signs 8) Documented decline, 9) Delayed onset [34]. More recently, CTE symptoms

have been categorized into four broad classifications: behavior, cognition, mood, and motor as

per Table 1 [31, 35, 37]. Based on these four classifications, two major clinical variants of CTE

have described, with younger patients exhibiting more pronounced behavioral or mood

disturbances and older patients exhibiting cognitive impairment that overlaps with other age-

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associated cognitive disorders, such as Alzheimer’s disease (AD) [31, 35, 36, 45, 46]. Notable

distinctions between the two major clinical variants were that the behavior/mood group was

considered to be significantly more explosive, out of control, physically and verbally violent, and

depressed. On the other hand, the cognition group were reported to have impaired episodic

memory, and were significantly more likely to progress to dementia (but were also significantly

older at the time of death) [46].

Criticisms of CTE research

The CTE literature has received much criticism. One of the criticisms is that many of the studies

used biased sampling methodologies, specifically, the inherent selection bias associated with

postmortem brain donations from families who may have witnessed disturbing behavioural

changes during life [46]. To their credit, the methodologic limitations of their work, such as

biased sampling, have been acknowledged by some CTE researchers [32, 46, 47]. Nonetheless,

the focus of CTE research has not shifted to improvements in methodology (including case

controlled studies), but has continued with the existing paradigm with efforts for elucidation of

molecular events responsible for the neurodegeneration [28]. As such, criticisms regarding

biases continue. One such criticism involves the availability cascade - the neglect of empirical

data in favor of highly publicized and emotional case findings, with perpetuation of biased

perception, as has been observed in media reports [12, 45]. Further, studies that rely on the

retrospective recall of clinical features by family members and friends of the deceased

individuals with CTE are limited by recall bias [12]. The lack of properly matched non-injured

controls has been noted [45; 48]. Davis et al. [45] correctly state that an adequate control

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group should have a similar demographic profile to cases, similar history of drug exposure, and

similar genetic profile. An adequate control group for CTE studies should also match for

confounding factors, such as underlying depression or anxiety, genetic predisposition to

psychiatric illness, or substance use [49]. The cases to date also suffer from limited case

numbers and differences in methodology between research groups [48].

Further methodologic criticisms have been levied related to the quality of data and the

difficulties establishing CTE incidence or prevalence [50]. Regarding prevalence, Stern and co-

workers correctly stated that not all individuals with exposure to brain trauma develop

neurodegenerative disease [32]. For example, a study on high school students who played

American football from 1946 to 1956 did not have an increased risk of later developing

dementia, Parkinson’s disease, or Amyotrophic Lateral Sclerosis compared to non–football-

playing high school males [51]. In a report on the clinical and pathological case histories for 6

retired Canadian Football League (CFL) athletes who underwent CNS autopsies, repetitive

concussions, positive clinical signs and symptoms of progressive neurodegenerative disease,

were not inevitably associated with CTE (3 of 6 had CTE) [52]. Bieniek et al. [36] screened for

CTE pathology in brains of individuals with exposure to contact sports and matched controls

without such exposure from a brain bank containing neurodegenerative disorders. Of 66

patients with history of exposure to contact sports, 21 (32 %) had tau pathology consistent with

CTE. No CTE pathology was observed in any control case [36]. Finally, a 41-year-old retired NFL

offensive lineman who had likely many head impacts over the course of his career had no CTE

changes at autopsy [28]. As Castellani [28] stated, this raises the issue of the much needed

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prevalence data, as well as the resilience and plasticity of the human brain and its ability to

endure significant concussive and subconcussive injuries impacts.

CTE has been linked with progressive cognitive, motor, and mood decline [38]. Some CTE

researchers have noted that while CTE pathology is progressive, it remains to be determined if

certain individuals are resilient or if the pathology is reversible [6]. However, Davis and

colleagues [45] argued that “no scientific evidence has been presented based on prospective

cohort studies to support (the) contention that CTE is a progressive entity” [45] (p. 644). Ban et

al. [12] added that sampling at a single post-mortem time point is not sufficient proof of

progressive disease. They reasoned that longitudinal studies with multiple time point sampling

at multiple scientific centres are required to make this determination [12]. Issues related to

incidence rates have also been described Iverson and colleagues [43] who stated that

approximately 1 in 4 people identified as having the neuropathological features of CTE did not

have significant clinical symptoms and 1 in 4 cases with clinical symptoms had no demonstrable

neuropathology. Therefore, there seems to be a mismatch between pathology and

symptomology for a significant number of cases.

Criticisms that some of the pathophysiology identified as characteristic of CTE may be part of

the normal aging process or an element of an established neurodegenerative disease process

have also been advanced. It is important to note that many degenerative diseases share the

characteristic of protein tau pathology. Examples include progressive supranuclear palsy,

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Down’s syndrome, dementia pugilistica, amyotrophic lateral sclerosis, postencephalitic

parkinsonism, parkinsonism-dementia complex of Guam, as well as viral and metabolic

disorders; therefore, the presence of tau pathology cannot be considered specific [53; 54]. For

example, numerous researchers have noted that the shared pathological characteristics

between Alzheimer’s disease (AD) [10, 43, 48, 49, 55] and CTE make the diagnosis difficult

especially in cases older than 65 years [5]. The Aβ and NFTs found in CTE are

immunocytochemically identical to those found in AD, suggesting a possible common

pathogenesis [10] that may in some cases be linked to neurotrauma [55]. Further, there had

until recently been only two cases where a biochemical characterization of tau has been

performed and in both cases, the hyperphosphorylated tau of CTE was indistinguishable from

that observed in AD [48]. This has led some to question whether the diagnoses of CTE and AD

and other neurodegenerative disorders are mutually exclusive [49]. This position has been

supported in a recent study that showed that in 268 neurodegenerative disease and control

cases, 32 cases (11.9 %), had histological evidence of CTE. CTE pathophysiology “was highest in

Progressive Supranuclear Palsy (24 %) and Parkinson’s disease (16 %), followed by controls

(12.8 %), AD (10 %), Corticobasal degeneration (7.4 %), Frontotemporal lobe dementias (4.2 %)

and multiple system atrophy (2 %)” [56] (p. 892). Interestingly, all cases identified with CTE had

stage I or II progression and only 2 cases (0.1 %) were reported as having ‘pure’ CTE pathology

[56]. Of note in this study was the number of controls that had evidence of CTE. Results such as

these have prompted some to suggest that a portion of what has been labelled as CTE

pathology may be confused with normal age-related change [5, 45, 50]. Frontotemporal lobe

dementias (FTLD) have also been shown to share many of the pathologic and clinical features of

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CTE [45]. The combined data on normal aging and FTLD have led some to conclude that CTE

stages I and II may represent tau deposition seen in normal aging brains, while stages III and IV

may represent forms of FTLD [45]. Finally, a recent study has demonstrated that the

pathological presence and expression patterns of tau protein are not unique to CTE and exist in

patients with a history of the temporal lobe epilepsy. The authors of this study caution that the

overall pattern of phosphorylated tau detected in these tissues did not lend credence to the

hypothesis that CTE has a unique protein tau signature [57].

In addition to concerns related to the pathologic features of CTE, CTE symptomology has also

been criticized. The inclusion of the clinical feature “suicidality” has spawned much debate and

commentary. Suicidality is a prominent feature in the well-publicized deaths of prominent

athletes [11] and may account for much of the amplified media focus on CTE [58]. There have

been many graphic and dramatic descriptions of suicide attempts, suicide, and “parasuicide” in

the CTE literature [5, 7-10, 11, 44]. Suicide has been presented as “clinically associated” with

CTE [6], over-represented in CTE cases [5], not uncommon [32], with the heightened suicidal

risk in stark contrast to other tauopathies [35]. The association between CTE and suicide has

been postulated for professional athletes [11]. Recently, concussion has also been linked to

suicide [37].

The facts are that suicide is over-represented in the CTE literature with a recent review stating

of 111 cases, 78 deaths were from natural causes; 19 accidental deaths, and 14 suicides [50].

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However, there are a number of points to consider when regarding the pathophysiology of CTE

as a cause of suicide. First, suicide was not considered a clinical feature in the first 80 years of

writing relating to CTE with the first description occurring with modern CTE cases [43, 50].

Second, there is no established causal scientific link between CTE pathophysiology and suicide

[43, 59]. Third, the case selection bias results in an over-representation of CTE cases with

neuropsychiatric comorbidities and suicide risk factors [58]. Fourth, Iverson [59] has noted that

in 10 of 52 athletes that committed suicide, 6 of 10 did not have the neuropathological features

of CTE, suggesting other potential causes for these cases. Fifth, former NFL athletes are less

likely to die by suicide than men in the general population [59]. A recent study has

demonstrated that a cohort of NFL players with 5 or more credited seasons of play had rates of

suicide that were less than half of what would be expected in a comparable sex/race/age

grouping from the general US population [60]. Sixth, many of the case histories contained

known risk factors for suicidality including but not limited to depression, substance abuse,

chronic pain, limited social connectedness, and hopelessness [61]. Iverson has stated that

depression is somewhat common in men across their lifespan, and suicidality is a cardinal

diagnostic feature of major depressive disorder [61]. Therefore, when all of the evidence is

considered, the link between suicide and CTE pathophysiology can be considered scientifically

“premature, overly simplistic, and potentially fatalistic” [61] (p. 13) and clearly precludes any

claims suggesting evidence-based relationships [58].

Another criticism related to CTE symptomology is the unverified link between symptomology

and pathophysiology. CTE researchers often comment on the link between pathophysiology

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and symptomology. It has been suggested that there is mounting evidence suggesting CTE may

be the major underlying etiology in the deaths related to neurodegeneration in NFL athletes

[37]. It has also been stated that “the symptoms of CTE, like other neurodegenerative diseases,

results from the progressive decline in functioning of neurons or of the progressive neuronal

death” [32] (p. S463). Others have stated that we “know that athletes who develop CTE develop

a progressive neurodegeneration that typically produces clinical symptoms years to decades

after retiring from the sport” [42] (p. 10). It has also been stated recently that PTSD might share

biological and pathological underpinnings with CTE [42]. Efforts have been made to link the

pathological changes described through stages I-IV with specific symptoms (e.g. memory and

executive dysfunction related to degenerative changes in the hippocampus in advanced CTE)

[15, 46]. As with many areas of CTE science, these statements have met with criticism.

Castellani [28] (p. 581) put it well: “drawing mechanistic associations between tauopathy at

autopsy, and psychiatric signs or complex behaviors such as suicide, explosive anger, impulse

control, or posttraumatic stress disorder, appears beyond the scope of neuropathological

interpretation.” Therefore, it has been assumed that CTE pathophysiology causes CTE

symptomology [38, 61] but this link has never been scientifically validated. An alternative

hypothesis proposed by Iverson and co-workers is that post-career symptomology is related to

mental health, anger control, and thinking problems unrelated to the neuropathology of CTE.

The source of these problems may be multifactorial and unrelated to neurotrauma specifically

[43].

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Finally, the explanation that neurotrauma is the sole or primary cause of CTE has been

questioned. CTE has been described as a neuropathologically distinct, progressive tauopathy

with a clear environmental etiology [10] and is the only known neurodegenerative dementia

with a specific identifiable cause; in this case, head trauma [47]. However, to date, there are no

published prospective studies relating to CTE that could generate data to support these

statements [29]. In addition, it has been noted that psychiatric problems and cognitive

impairment usually have multifactorial, not unitary causation [29]. For example, in their critical

review, Iverson et al. [43] cited several studies suggesting that men with depression show the

full spectrum of symptoms and problems that have been proposed to represent early-stage CTE

[43]. They continue that considerable overlap exists between the clinical features of CTE and

core diagnostic features of depression (e.g. sadness, hopelessness, suicidality, cognitive

difficulties; problems with concentration memory, problem solving, and thinking). We are

reminded that when considering the potential multifactorial bases for the symptomology

reported by some athletes, that when compared to the general population, athletes lead quite

different lives. Other potential factors to examine may include the effect of a relatively short

and intense career, genetics, sex, age, when collision sports were started, the use of

performance-enhancing drugs, and substance abuse [12].

ALTERNATIVE EXPLANATIONS FOR “CTE SYMPTOMATOLOGY” IN POST-CAREER ATHLETES

As Omalu et al. [8] have stated, most disease models are multifactorial and CTE is not an

exception. But what are the most important factors to consider when studying athletes with a

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substantial history in sport? Factors such as the effects of gender, genetics, and the age when

impacts were first experienced have been suggested as potential mediators [8, 12, 43]. Other

factors specific to the experience of athletes in contact sport should be considered. Specifically,

the use of substances to manage injury and chronic pain have also been noted as potential

factors [8, 12, 43]. Another element to consider is identity development in young athletes. To

date, there has been relatively little attention given to how we develop athletes and the role

that identity may play in symptomology post-retirement for athletes with foreclosed athletic

identities. This area of study has been labeled athlete career transition stress.

Athlete Career Transition Stress

Brian Kingman, a pitcher for the Oakland A’s in the 1980s stated “There’s a saying that an

athlete dies twice …Everyone gets out of the game at some point, and it’s usually involuntary. It

can be traumatic when the thing you love and have been doing so long comes to an end” [62].

Kingman’s statements are supported by a recent media survey of 763 retired NFL athletes that

reported 61% have had difficulty adjusting to life after football (61%) [63]. It may be difficult for

the non-elite athlete to understand the cognitive and emotional trauma that can occur

following a career that has brought wealth, social prominence, and a relatively early retirement.

However, the trauma is common and all too real to for elite athletes.

One potential factor may be rooted in how we form our identities. Identity theorist James

Marcia stated that successful identity formation for adolescents in western contexts is often

defined by a commitment to a vocation, a set of meaningful values, and a sexual identity [64].

21

As Kroger [64] described, there are two distinct types of commitment (achievement and

foreclosure), and two of non-commitment (diffusion and moratorium). Those adopting

achievement or foreclosure have made commitments to various social roles, however, identity

achieved individuals have done so following a crisis or decision-making period. On the other

hand, individuals with foreclosed identities have foregone the identity formation process and

adopted roles and values of childhood identification figures (e.g. an NFL football player). Marcia

also believed that foreclosed individuals are notable for their inflexibility and defensiveness in

the face of identity challenge and are drawn to the values of a parent or strong leader who can

show them the ‘right way’. They can appear to be progressing toward occupational goals and

have avoided any form of serious exploration. As a result, rigid identity structures are formed

which are impervious to challenge from new life situations [64].

Identity development requires an investment in time. However, to achieve elite athletic status,

an individual must dedicate a significant amount of time training in their specific sport at a very

young age. The timing and intensity of training varies by sport [65]. Athletic talent is often

identified in elementary school and developing elite talent becomes a central preoccupation for

both a child and caregivers [66]. For example, in European football (soccer), players as young as

five years old have been scouted and substantial contracts have been offered to 11 year olds

[67]. In American football, the recruitment process for college scholarships begins in the

freshman or sophomore years (or earlier) when athletes are advised to create online profiles

for potential coaches or recruiters [68]. For hockey in Canada, the first draft occurs at the

Bantam level (ages 13 and 14) for recruitment to the high profile junior ranks [69]. Ballie [70]

22

stated that over 80% of professional hockey and baseball players were involved in competitive

sport before 10 years of age. Elite gymnasts must commit to their sport during childhood with

most retiring in adolescence at a time when most are beginning their search for an identity

[71]. It is a widely held belief that a narrow focus on sport is necessary for competitive success.

As a result, important adult figures including sport administrators and coaches may be less

likely to support non-sporting activities that affect training time or focus on sport [72]. This

commitment to athletic excellence at such an early age benefits the athlete from a

performance perspective but may also have a significant cost in terms of identity development.

In short, in order to achieve elite athletic status, it can often be difficult to be anything other

than an athlete [73]. Aspiring elite athletes begin to define themselves as “an athlete”, with a

near complete concentration on training and competition and a near exclusion of everything

else including education, social goals, and career goals, [66, 70, 72, 73]. The definition of

oneself exclusively as an athlete has been termed “athletic identity” consisting of the cognitive,

affective, behavioral, and social concomitants of identifying with the athlete role [74].

Developing a foreclosed or athletic identity may translate to success in a sporting context, but

may be related to a number of problems in other areas of life. For example, identity foreclosure

and athletic identity were found to be inversely related to career maturity, suggesting that

foreclosure and athletic identity are separate processes, both associated with inhibited post-

athletic career decision making, failing to explore alternative roles and behaviors, and

identifying strongly and exclusively with the athlete role [72]. Elite athletic performances are

more public than most role enactments and the public reputation of most successful athletes is

23

generally positive. This can generate a high degree of social status and esteem causing one's

public athletic reputation to become enmeshed with the athlete's overall identity [66, 75]. For

some, the excitement and intensity of the experience can be addictive [75]. Some have termed

the development of an identity that is strengthened by the growth of prestige combined with

social and public acknowledgement as an identity variant termed the “glorified self” [76]. At its

extreme, this complex depiction of self has been linked to “a greedy, catchy and toxic feeling,

through which the self looks to increase its importance and escape from other dimensions into

which it might develop” [76] (p. 8) and has been linked to the loss of future orientation and

long-term planning [76].

For some, the transition from athlete to non-athlete may be relatively smooth [77]. Others have

described retirement from sport as similar to retirement from other professions, with a

percentage of athletes doing reasonably well, and others doing less well for reasons including

the amount of social support, discrimination in the job market, lack of material supports and

social contacts, level of education, and the availability of resources to assist them in career

development or job training [78]. However, the prevalence data to date suggest that the

likelihood of difficulty with transition out of sport may be significant especially for athletes with

intended or actualised careers in sport [70]. In a review of the literature, Park et al. [79] stated

that among 13,511 participants, 1768 (16%) reported adjustment difficulties during career

transition. A study on top Canadian amateur athletes who had retired from international

competition reported that 32% had a very difficult time with career transition and 46% had a

moderately difficult time [73]. Another study reported that 46.2% of retired athletes reported

24

that a difficult retirement was "quite characteristic" or "very characteristic" of their experience

[66]. In a study of young retired gymnasts, most described their disengagement from

gymnastics as profoundly traumatic [71]. Therefore it appears that for some athletes, the

transition to retirement can be perceived as negative and difficult.

A number of variables have been identified as important indicators of a difficult transition to

retirement including “athletic identity, demographic issues, voluntariness of retirement

decision, injuries/health problems, career/personal development, sport career achievement,

educational status, financial status, self-perception, control of life, disengagement/drop-out,

time passed after retirement, relationship with coach, life changes and balance of life” [79]

(p.33). Others have noted that the type of sport involvement is important with Olympic and

college athletes making smoother transitions than professional athletes [70]. Those with abrupt

retirements, due to injury or being de-selected have had worse post-retirement outcomes [65,

66, 70, 80-82]. Coping style or resources may also affect post-career adjustment [78, 82-84].

However, it is the strength of the athletic identity that has been shown to be the primary factor

related to career transition stress [65, 66] because of its narrowing effect on other aspects of

life such as education, friend networks, sport specific social and emotional support by families,

and limitation of experience and social contacts outside of sport [78].

In their review of the literature, Park et al. [79] identified 34 studies indicating that both a

strong athletic identity and high tendency towards identity foreclosure were negatively

associated with the quality of athletes’ career transitions. Importantly, these studies indicate

25

that the retired athletes experienced a loss of identity when they had a strong athletic identity

at the time of their sport career termination requiring a longer period of time to adjust to post-

sport life. Consistent with this position is a study by Webb and colleagues [66] who reported a

positive relationship between the strength of athletic identity and retirement difficulty.

Another study reported similar findings suggesting that individuals who maintain a strong and

exclusive athletic identity up to the point of retirement may be vulnerable to career transition

difficulties [83]. Conversely, those who begin the transition from athlete to non-athlete prior to

retirement have reported increased levels of life satisfaction [80]. A number of other studies

also point to the strength of athletic identity as a prominent factor in career transition

difficulties [77, 85]. How the retirement was characterised in the media may also impact the

quality of adjustment to life after elite competition [86, 87].

The qualitative research literature also contains substantial commentary on the struggle to find

meaning following retirement from sport. Retired gymnasts reported feeling lost post-

retirement, had difficulties with starting again in the real world/fitting in, and had deep sense of

disappointment/loss that could not be faced [71, 85]. A common theme reported by athletes

was that they may never find a replacement for the pleasure, intensity, and passion provided by

involvement in their sport [70, 75, 85]. Athletes reported feeling unprepared, or even unwilling,

to re-create their identity [75]. They also reported missing the public recognition, adoration of

fans, and connection to team-mates [75]. They reported having a sense of uncertainty

regarding who they were outside of their sport [71].

26

The literature on athletic identity and retirement from sport is relevant to the CTE literature for

a number of reasons. First, while most athletes who struggle with loss of athletic identity adjust

within a few years, some struggle for 10 or more years post retirement [70, 73]. This time frame

is consistent with the window of symptom onset for CTE. Many of the CTE cases described to

date reference retirement with most describing symptom onset as the athlete nears

retirement, or within 10 years of retirement [3, 7, 9, 10, 44, 47]. Interestingly, the first case

described by Omalu [44] was diagnosed with adjustment disorder, a diagnosis consistent with

loss of identity following retirement. Another interesting point regarding two asymptomatic

CTE cases described by Stern et al., [46] was that they obtained “advanced graduate degrees,

were very successful in their professional careers, and were described as extremely intelligent.”

(p.1127). The authors attributed the asymptomatic status to the fact that they were intelligent

and therefore had significant “cognitive reserve”. An alternative hypothesis is that they had less

developed athletic identities (seeing themselves as more than athletes), allowing them to

transition into post-career life without a dramatic increase in CTE symptomology. The same

general pattern of adequate post-career adjustment has been shown for ex-professional

Swedish tennis players all of whom obtained employment as tennis coaches, managers,

consultants and sport commentators [88].

Other parallels exist between the CTE and identity literatures regarding symptomology. For

example, athletes with difficult transitions from sport related to a strong athletic identity have

reported coping via substance use or abuse [87, 89], anxiety symptoms [79, 83], aggression and

emotionality [73, 83] and depression [73, 75, 84, 87, 90]. In addition, there is a well-established

27

and substantial link between suicide and factors experienced by elite athletes post-retirement

such as a loss of identity, challenges with mental health, and a loss of social support networks.

For example, it is well known that individuals with affective disorders have a markedly

increased risk of suicide [e.g. 91, 92]. Substance use disorders have also been linked with

suicide in with a number of studies yielding odds ratio estimates ranging from 3.3 to 10.7 [91].

Further, the social isolation and low belongingness experienced by some athletes post-career

have been linked to increased suicidal ideation in young adults [93, 94]. Of particular relevance,

the presence of identity stress has also been reported to increase the risk of suicidal ideation

[92, 95] in non-athletes and athletes. For instance, acculturative stress associated with an

ethnic minority identity has been associated with depression and suicidal ideation in some

college students [96]. Gender identity issues have been linked to increased rates of suicidal

behaviour in youth who die by suicide [97], in transgendered veterans with gender identity

disorder [98], in female college students [99], in sexual minority youth [100] and in military

personnel with a history of same sex behaviour [101]. The loss of identity as a farmer has been

associated with suicide and has been described as an international phenomenon [102]. Military

personnel have been reported to undergo stress when transitioning to civilian life. This problem

has been noted for reservists [103] and regular force members, particularly those with a

foreclosed military identity [104]. A shift in identity may be particularly relevant to members of

the armed forces returning from active service, who may become disconnected from the values

of society and in some cases believe that their service was unappreciated [105, 106]. Brewin

and Andrews [105] reported an association between negative changes in perceptions of the

world, PTSD and suicidal behaviour in military veterans. It is possible that this type of stress is

28

experienced by in military veterans who experience neurotrauma [5]. Schmidt and West [106]

liken the military identity to a strong athletic identity and discussed how both can be related to

and increased risk of suicide. For athletes with a strong athletic identity, an increased rate of

suicide attempts has been reported following retirement [107]. This trend may particularly

relevant for athletes for masculine sports that emphasize risk-taking, including some degree of

tolerance for health-compromising behaviors [108]. The latter is consistent with the recent

statements of the high profile MMA fighter Rhonda Rousey who following a one-sided loss,

recalled thinking “…what am I anymore if I’m not this? … I was literally sitting there … thinking

about killing myself … I’m nothing … what do I do anymore?” [109]. Table 1 summarises the

common symptomology for athlete career transition stress and CTE.

Chronic Pain

Chronic pain is a common problem affecting 19% of the adult population in Europe and Canada

and 30% in the USA [110]. Chronic pain is a more prevalent problem in retired athletes who

have sustained multiple injuries during their careers. For example, a case reported by Omalu

and co-workers had numerous musculoskeletal and cartilage injuries requiring knee, elbow and

shoulder surgeries [44]. Another had spinal surgery with many musculoskeletal injuries [8]. Yet

another suffered chronic musculoskeletal pain and constant headaches [9]. The latter two cases

had evidence of pain prescription overuse; a common problem with chronic pain patients. The

link between chronic pain and abuse substance use/abuse was recently described in a study of

ex-NFL athletes [111]. Nearly half (47%) of the 644 athletes polled had had three or more NFL

injuries, most reported undiagnosed concussions (81%), half (55%) reported a career-ending

29

injury, with 6% reporting current use of an assistive mobility device. Players also reported that

approximately one-third (29.4%) of their teammates misused prescription pain medication

[111].

Nes et al., [112] have described the complex interactions between executive functioning, the

capacity for self-regulation, and chronic pain management. They stated that self-regulatory

capacity varies and is a limited resource that can be fatigued. Chronic pain management can

affect self-regulatory ability resulting in cognitive difficulties, fatigue, sleep disturbance,

tension, and emotional and social distress. The decrease in cognitive ability during pain flare-

ups is the first indication that pain interferes with the ability to self-regulate. The potential for a

downward spiral in which self-regulatory demands cause self-regulatory fatigue, reduce

executive cognitive resources for further self-regulation, and thereby increase difficulty in

meeting further demands occurs with increased pain symptoms. A history of repetitive

neurotrauma may worsen executive functioning, resulting in problems controlling and

regulating behavior, leading to additional difficulty in functioning [112].

Chronic pain has been linked to symptomology that parallels CTE cases. For example, a wide

array of cognitive abilities can be affected with chronic pain including attention, concentration,

speed processing, working memory, psychomotor ability, decision-making, and executive

functioning [113, 114]. Post-traumatic headaches that can occur following concussion have

been reported to cause confusion and loss of concentration and overuse of pain medication

[115, 116]. Altered sleep patterns and sleep deprivation (that can affect mood and cognition)

30

are commonly reported with chronic pain [112, 117]. Chronic pain can also lead to dependence

on prescription medication as reported in some CTE cases [8, 9] and in studies on chronic pain

patients [118]. Emotional dysregulation including anger, irritability, sadness, and fear symptoms

have been reported in those with chronic pain [112, 119]. Chronic pain has been shown to

increase anxiety-like behaviour in animal models [110, 113] and anxiety symptoms in human

studies [112, 119, 120]. A number of authors have reported the reciprocal relation between

depression and chronic pain [113, 118, 120] and their relation to CTE [61]. The reciprocal

relation between chronic pain and depression has been demonstrated in animal models [110,

113] and in chronic pain patients [112], with both linked to common dopamine pathways [110,

120]. Finally, there are links between chronic pain and suicidal behaviour [61, 118]. For

example, the lifetime prevalence of suicide attempts was between 5% and 14% in individuals

with chronic pain, with the prevalence of suicidal ideation being approximately 20% [121].

Other studies reported that pain was an independent risk factor for suicide, particularly among

those with head pain or multiple forms of co-occurring pain [122, 123] as reported in CTE cases

and retired athletes who participated in contact sport. Table 1 summarises the common

symptomology for chronic pain and CTE.

Substance Use and Abuse

The unique lives of athletes can in some cases lead to the development of specific types of

substance use and/or abuse. For example, following the deaths of three National Hockey

League (NHL) athletes, a series of now public emails were produced by members of the NHL

league office. One email stated that the role of enforcer is “not the same role as it was in the

31

80's and 90's… Fighters used to aspire to become regular players. Train and practice to move

from 4th line to 3rd. Now they train and practice becoming fearsome fighters. They used to

take alcohol or cocaine to cope… Now they take pills. Pills to sleep. Pills to wake up. Pills to ease

pain. Pills to amp up. Getting them online." [14]. These statements have been supported by

recently retired enforcer Daniel Carcillo speaks about substance abuse, depression and loss

following his career as an NHL enforcer [124].

Evidence of substance use in sport is not limited to ex-hockey enforcers. Evidence of alcohol

use, abuse, and addiction can be found in a number of the CTE case histories [e.g. 6, 7, 9].

Cottler et al. [111] reported that 52% of retired football players used opioids during their NFL

career with 71% of those respondents reporting misuse. Substance abuse and addiction have

been linked to accidental and intentional death in CTE cases [7, 32]. Evidence of past anabolic-

androgenic steroid (AAS) abuse have been reported in CTE cases [8, 44] with at least one case

revealing an exogenous testosterone source in the body at time of death [8]. It has been

reported that an estimated 20% of CTE cases had a documented history of substance abuse

prior to or co-morbid with symptomatic CTE presentation including the use of alcohol,

prescription opioids, AAS, cocaine, methamphetamine, and cannabis [50]. CTE researchers have

attempted to address this issue by suggesting that athletes may in some cases develop

“problems with drug abuse as a consequence of the loss of inhibitory control caused by the

neurodegenerative disease” [47] (p.183) however no objective evidence has been advanced to

support this claim. Others have reported that no relation between CTE symptomology and

32

steroid use [6, 37] but again, it is difficult to determine how these data were derived in the

original publication based on the information provided.

Substance use, abuse, and addiction in its many forms can result in acute and long-term

changes that are similar to some of the symptomology attributed solely to CTE. For instance,

excessive alcohol use has been associated with the culture of certain sports and is used during

and following some athletic careers [125]. It is also linked to specific elements unique to sport

such as poorly developed coping strategies and injury management [125]. While not a general

trend, a percentage of people will either resume alcohol abuse or will develop a new alcohol

use disorder following TBI due to a combination of negative affective states, impaired decision

making, social pressures, and alterations in neurochemical signaling [126]. Social stressors, such

as adjustment to retirement, may cause activation of the corticotrophin releasing factor (CRF)

system is necessary for this social stress-induced escalation of alcohol consumption [127].

Alcohol use is linked to general health problems such as respiratory dysfunction and infection

[128]. It is also correlated with co-morbid psychiatric problems such as antisocial behavior [129]

and anxiety and mood disorders, the latter being reduced with abstinence [130]. Animal models

have shown that alcohol may lead to the distortion of social signals from benign to threatening

which in turn can lead to the emergence of aggressive behavior [127]. Prolonged alcohol

exposure has been associated with impairments in executive processes such as top-down

inhibitory control, decision-making, and behavioral flexibility possibly related to altered

dopamine (DA) function in pre-frontal cortex (PFC) [131,132]. Lifetime alcohol use has been

33

shown to correlate with reduced dorsolateral PFC and anterior cingulate cortex (ACC) gray

matter density of up to 20% leading to problems with attention, decision-making, error

monitoring, and impulse control [132]. It is also well-established that alcohol use is a potential

risk factor for attempted and completed suicide among individuals both with and without a

history of alcohol abuse or dependence, and when combined with other substances such as

opiates, can lead to accidental overdose via respiratory depression [130]. Alcohol use, abuse,

and alcohol-related accidental overdose have been reported in some CTE cases.

The use of recreational substances such as cannabis and cocaine also have the potential to

affect symptomology in retired athletes. Moderate polydrug use such as cannabis,

amphetamine, and cocaine has been shown to elevate psychiatric symptom profiles [133].

Evidence of a dose–response relation has been reported between cannabis use and psychotic

outcome [134,135]. Cocaine use is related to various cerebrovascular events that can occur in

every brain region and may in some cases increase the risk of developing Parkinsonism [136].

Cannabis use may affect broad cognitive domains including memory, attention, decision-

making, psychomotor speed, and inhibitory control [134]. Similarly, chronic cocaine use is

linked to problems with executive function, decision-making, increased impulsivity, visual

perception, psychomotor speed, manual dexterity, verbal learning, memory function, insight

and judgment, foresight, and disinhibition related to dopamine dysfunctions in the prefrontal

cortex [134, 137]. Small but significant lingering effects have been reported for long-term

cocaine abstinence over many cognitive domains [138]. Cocaine dependence may also be

associated with impaired recognition of fearful facial expressions and the perception of anger

34

[139]. Chronic cocaine use may cause long-term hippocampal-dependent learning and memory

impairments associated with elevated HPA axis activity [140] and changes in N—methyl-D-

aspartate receptor activity [141].

Prescription and non-prescription opioid use in sport increases as injuries occur and associated

chronic pain mounts [111]. Interestingly, opioid use has also been increasing in military

populations in response to war-related injuries that exceed the rise of civilian opioid use and

abuse [142]. Long-term opioid use may be associated with a number of negative outcomes

including tolerance, opioid induced hyperalgesia, physical and psychological dependence, and

higher rates of depression [143, 144]. Additional problems may arise when continued opioid

use is expanded to manage the pain-related negative emotions associated with prolonged use

leading to a spiral of use and elevated pain and dependence [145]. To add to the problem,

opioids are often prescribed for pain conditions where they have little to no effect (i.e.

headache) [146, 147] meaning that few of these patients will benefit and many will be exposed

to significant harms [144]. Cognitive and sedative effects for those experiencing long-term

opioid therapy for chronic non-malignant pain may be as high as 60% [148, 149]. Cognitive

effects of prolonged opioid use include problems with attention, concentration, affect,

memory, executive functioning, perception, psychomotor functioning, and delirium [148, 149].

Sedation effects can include somnolence, lethargy, and sleep disorders [148]. Delirium can

occur when opioid use is initiated or following dose escalation and may be greater in patients

with pre-existing cognitive impairment [148, 149]. Additional negative outcomes related to the

problematic use of opioids include hypogonadism [150], depression and other mental health

35

diagnoses [143, 144, 149]. The risk of accidental death by overdose is increased in patients who

are prescribed opioids for pain [143, 149, 151] as is suicidal ideation [118]. Finally, opioid use

may have long-term effects on brain structure. Hyperphosphorylated tau positive neuropil

threads, not unlike those found in CTE case studies, have been observed in a number of brain

areas in those who overuse opioids [152, 153].

Anabolic androgenic steroids (AAS) are used by some athletes during their careers to improve

elements of sport performance and to recover more rapidly from fatigue and injury. The

increased popularity of these products has led to the development of synthetic AAS which have

not undergone appropriate testing in humans or animals and therefore may represent an even

more serious health risk than the more traditionally used AAS [154]. The acute effects of AAS

administration have been studied prospectively in volunteer participants. Acute AAS use has

been associated with increases in positive mood, negative mood (including irritability), mood

swings, violent feelings, anger, and hostility, and cognitive symptoms such as distractibility,

forgetfulness, and confusion [155] not attributable to prior substance abuse, familial history of

mental illness, or substance abuse [155]. A subsequent prospective study administered

prednisone to participants for 5 consecutive days and observed that 75% of participants

developed diverse and fluctuating behavioral changes which had discrete onsets during the

prednisone administration period including depression, irritability, anger, sleep problems,

tearfulness, mood elevation, increased energy, confusion, with some associated changes in

EEG, and significantly higher rate of errors of commission during a test of recognition memory

[156]. Hypomania, aggression, or violence have been shown in occasional users [157]. Long-

36

term AAS use results in a more well-established presence of symptoms of aggressiveness,

anxiety, depression, and potentially psychosis linked to functional change in monoamine and

peptidergic systems with evidence of hippocampal involvement [158-161]. A review of the

negative outcomes associated with AAS described a link between AAS use and higher rates of

attempted suicide and homicide [154]. AAS-induced hypogonadism may require normalization

of neuroendocrine function that can include antidepressant treatments and reversal of

dependence via mechanisms shared with other addictive substances [162]. Hypogonadism

induced by androgen withdrawal may occasionally produce severe depression in some men

[157]. Animal models suggest that AAS has significant effects on neural systems that control

reproductive function [163]. Some males regret AAS use because of the negative impact on

future fertility [164].

A substantial body of evidence exists pointing to the addictive properties of AAS that have a

shared neural basis with other addictive substances [154, 157, 159]. AAS dependence may

share mechanisms of opioid dependence in humans and therefore it is not surprising that some

retired athletes continue the use of AAS beyond the duration of their careers [154]. There is

also substantial evidence to suggest that substance use, including opioids, cannabis, alcohol,

amphetamines, and cocaine co-occur with AAS use [154, 157, 159]. Long-term use of AAS may

result in neural damage via apoptosis [157]. In adolescents, AAS use may cause persistent

changes in neural structures and neurotransmitter function that may cause increased

aggressiveness and perceived threat during a social encounter [165]. Animal models have

demonstrated AAS effects on the expression of NGF and its receptors in the hippocampus and

37

basal forebrain [166], show axonal injury and microgliosis increases when ASS use co-occurs

with repetitive neurotrauma [167], and decreased performance in multiple aspects of

behavioral flexibility including both set-shifting and reversal learning [168]. In humans AAS

users have had significant impairments in visuospatial memory correlated to the lifetime AAS

dose, problems with inhibitory control and attention, larger right amygdalas, and higher

glutamine/glutamate ratios [159].

A THEORETICAL MODEL TO EXPLAIN CTE SYMPTOMATOLOGY IN RETIRED ATHLETES

It is evident that some athletes experience career transition stress (related to a strong athletic

identity), chronic pain, and substance use/abuse as they enter retirement. It is also evident that

there is significant overlap between the case reports of athletes with post-mortem diagnoses of

CTE, and symptom profiles with those with a history of substance use, chronic pain, and athlete

career transition stress. Table 1 provides a summary of research on the athletic identity/career

transition stress, chronic pain, and substance use/abuse and how each independently may

result in symptomology in athletes that has been attributed primarily to neurotrauma and CTE.

Figure 1 represent a theoretical model intended to explain some of the symptoms that athletes

experience at the end of their careers or during retirement. Stern et al., [46] described two

major clinical variants of CTE. Variant 1 described patients who died earlier, exhibited more

pronounced behavioral or mood disturbances, were significantly more explosive, out of control,

physically and verbally violent, and depressed. Variant 2 described patients who were older at

their time of death, who exhibited cognitive impairment including impaired episodic memory,

38

and were significantly more likely to progress to dementia that overlaps with other age-

associated cognitive disorders, such as Alzheimer’s disease (AD) [31, 35, 36, 45, 46]. The Athlete

Post-Career Adjustment (AP-CA) model shown in Figure 1 is most consistent with the

symptomology of the patients with Variant 1 (behavioural and mood disturbances).

Based on the existing literature, it is clear that any one of the four elements of the AP-CA model

can account for a significant number of Variant 1 CTE symptoms. In addition, depression can be

a chronic lifelong co-morbid condition that may be present prior to neurotrauma, or may be

developed secondary to any of the model elements as shown in Figure 1. Notably, neurotrauma

is a necessary, but not a sufficient condition, for the development of Variant 1 CTE

symptomology because at minimum, a history of neurotrauma must be present for an

individual, or a family, to suspect the CTE. It is important to recognize that the science for each

of the factors within the AP-CA model have been presented as independent elements. We do

not as yet have substantial information regarding how symptomology is affected when more

than one element is present. For example, it is possible, that the effects of neurotrauma and

chronic pain affect the emotional responses to identity transition and pain management. The

exaggerated patterns of emotional response in some retired athletes may be due to the

interactions between each model element. Finally and of note, there is no inclusion of a genetic

factor in the AP-CA model at this time. The rationale for this exclusion is that based on the

available literature, it is difficult to identify a definitive link between the APOE e4 allele and the

development of CTE independent of other neurodegenerative diseases [e.g. 50].

39

It is hoped that the AP-CA model will allow for the development of specific hypotheses related

to post-career symptomology in retired athletes. If the model holds, athletes with elevated CTE

symptomology should score highly on at least one of the model elements, with the inclusion of

more elements related to increased symptomology. As noted, some of the CTE cases describe

precisely that.

CONCLUSIONS

In their criticisms of CTE research to date, Meehan III et al., [38] stated, “The scientific method

dictates that in our quest to discover the truth we must (1) make an observation, (2) develop an

hypothesis that explains the observation, (3) test that hypothesis in varying situations, and (4)

reach a conclusion based on the findings of those tests.” [38] (p.1509). With this in mind,

statements such as “Participating in a contact sport is now thought to increase an individual’s

risk for later-life impairment and possibly developing CTE” [37] (p. 304) and ‘‘CTE is the only

known neurodegenerative dementia with a specific identifiable cause; in this case, head

trauma’’ [47] (p. 184) are highly problematic. These statements are based on highly selected

case evidence and equate all symptomology with one primary mechanism. It is clear, from a

thorough review of the scientific literature, that the development of symptoms post-athletic

career is multi-factorial in nature and at minimum includes career transition stress mediated by

athletic identity, chronic pain, and substance use/abuse.

It is necessary to separate CTE pathophysiology detected post-mortem, from the CTE

symptomology that in most cases was obtained retrospectively. There is no prospective

40

scientific basis that can be used to support this link; only speculation based on highly selective

and potentially biased case data. As scientists, we have a responsibility be thorough and

accurate in our presentation of facts. To ignore the non-neurotrauma elements in the AP-CA

model as important factors that have been demonstrated to cause symptomology attributed

almost exclusively to CTE by some researchers is irresponsible. We must consider the unique

developmental and situational factors that athletes face as they enter retirement. If we hope to

limit the severity and prevalence of these problems, we must also understand that our current

practices for developing athletes are problematic.

Future studies must be prospective in nature and less reliant on case data. Identification of

biomarkers that can be correlated with neurotrauma are ongoing but in their early stages [169].

Unfortunately, large ongoing CTE studies such as the UNITE and LEGEND appear to be fraught

with similar problems as those described here. Restricting a participant pool to only those who

had a history of repetitive head impacts during sport or military careers [170] limits the

identification of other factors that produce CTE pathophysiology. Case data based on the

criteria developed in this manner have been inconclusive [171]. The use of convenience

sampling that targets individuals with perceived problems related to participation in contact

sport [172] potentially creates problems with generalizability and sampling bias. In future

studies, we must invest in proper methodology and move away from a focus on case data and

neurotrauma if we intend to correctly identify and address the bases for the significant

symptomology experienced by some athletes following retirement. It is hoped that

development of models such as AP-CA will be the first step toward development and testing of

specific hypotheses in this population.

41

ACKNOWLEDGEMENTS

I would like to acknowledge the many athletes and coaches who have influenced the form this

manuscript has taken. I would also like to acknowledge My-Phoung Ngo for her patience and

support.

42

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62

CAPTIONS TO ILLUSTRATIONS

TABLE 1. OVERLAP IN SYMPTOMOLOGY BETWEEN CTE, CHRONIC PAIN, SUBSTANCE USE, AND

FORECLOSED ATHLETIC IDENTITY.

FIGURE 1. A THEORETICAL MODEL TO ACCOUNT FOR CTE SYMPTOMATOLOGY IN RETIRED

ATHLETES.

63

64

TABLES AND FIGURES

CTE Symptomatology

Other factors CTE Features (e.g. Stern et al., 2013; Montenigro et al., 2015)

Cognitive:

Memory

impairment;

executive

dysfunction;

attention and

concentration

difficulties;

language

impairment;

visuospatial

difficulties

Behavioural:

Explosivity;

impulse control

problems; “out of

control”; Physically

violent;

Disinhibited

speech;

disinhibited

behaviour; socially

inappropriate;

paranoia

Mood:

Sadness;

depression;

anxiety; agitation;

manic behaviour;

mania; suicidal

ideation; suicide

attempts;

hopelessness;

apathy

Motor

Parkinsonism; gait

difficulties; ataxia;

dysarthria; tremor;

masked facies;

rigidity; weakness;

spasticity; clonus

65

Athletic

Identity

Grove et al., 1997;

Werthner & Orlick,

1986.

Brewer, 1993;

Cosh et al., 2015;

Gearing, 1999;

Grove et al., 1997;

Joiner Jr. et al.,

2009; Ogilvie,

1987; Park et al.,

2013; Schmidt &

West 2015; Van

Orden et al., 2008;

Werthner & Orlick,

1986; Wooten,

1994.

Chronic Pain Lane, 2000; Lane &

Arciniegas, 2002;

Liu and Chen,

2014; Moriarity &

Finn, 2014;

Garland, 2012; Nes

et al., 2009;

Braden & Sullivan,

2008; Cheatle,

2011; Garland,

2012; Ilgen et al.,

2008; Jarcho et al.,

2012; Liu and

Chen, 2014 Nes et

al., 2009; Tang &

Crane, 2006

66

Substance

Use/abuse

Cadet & Bisagno,

2016; Dhingra et

al., 2015;

Grönbladh et al.,

2016; Harned &

Sloan, 2016; Potvin

et al., 2014;

Spronk et al.,

2013; Yang et al.,

2016

Cunningham et al.,

2013; Dubovsky et

al., 2012; Ersche et

al., 2015;

Grönbladh et al.,

2016; Hallberg,

2011; Miczak et

al., 2015;

Piacentino et al.,

2015

Cadet & Bisagno,

2016; Cheatle,

2015; Chen & Lin,

2009; Cobaugh et

al., 2014; Connor

et al., 2016;

Harned & Sloan,

2016; Stannard,

2016; Trantham-

Davidson &

Chandler, 2015;

Parrott et al.,

2012; Yang et al.,

2016

Büttner, 2011