Behavioral Health Symptoms Associated With Chronic Traumatic Encephalopathy: A Critical Review of the Literature and Recommendations for Treatment and Research

Martland¹ was among the first to describe a neuropsychiatric syndrome in which the individual, following a single blow or multiple blows to the head, presents as “’cuckoo,’ ‘goofy,’ ‘cutting paper dolls,’ or ‘slug nutty’.” Martland believed the syndrome was a result of one or more concussions, and that the severity of symptoms ranged from mild to severe mental and physical deterioration, and, in some cases, death. Specifically, Martland identified several long-term physical and behavioral symptoms often associated with the syndrome, including speech problems, gait disorders, Parkinsonism, vertigo, cognitive confusion, neuroses and psychoses, or even mental deterioration to a level requiring psychiatric hospitalization. At the time of Martland’s publication, the syndrome was coined “punch drunk” in the boxing arena, as the condition could occur when a boxer, after a serious blow or repeated blows to his head, would appear disoriented as if he was drunk

Since Martland’s original paper there has been an evolving understanding of the punch drunk syndrome as, primarily, a neurological condition with potential for long-term neurodegenerative effects. Martland¹ recognized the latent brain injury associated with this syndrome and attributed the long-term pathophysiological cascade to traumatic cerebral hemorrhage caused by “multiple concussion hemorrhages in the deeper portions of the cerebrum.” Half a century later, aided by advanced examination techniques, the syndrome’s late manifestations were linked to the formation of neurofibrillary tangles,² which are aggregates of hyperphosphorylated tau protein and considered a primary marker for Alzheimer’s disease. More recent research speculates that the syndrome can initiate a form of neurodegenerative tauopathy occurring years or decades following recovery from the acute or post-acute effects of head trauma.³ Specifically, repetitive axonal perturbations caused by severe hits to the head may initiate a series of metabolic, ionic, membrane, and cytoskeletal disturbances that trigger a pathological cascade evidenced by extensive tau-immunoreactive inclusions scattered throughout the cerebral cortex.⁴

The term used to describe the neuropathological effects of the punch drunk syndrome has also evolved over time. Although Martland did not, in his landmark paper, introduce a medical term for the syndrome, he recognized the resemblance of the late manifestations of the punch drunk syndrome to other brain disorders characterized by “epidemic encephalitis.” The encephalitic impact is reflected in the evolution of the syndrome’s name, from traumatic encephalopathy of pugilists⁵ to dementia pugilistica,⁶chronic progressive traumatic encephalopathy,⁷ and, most recently, chronic traumatic encephalopathy.⁸ Victoroff and Baron⁹ have compellingly argued that Parker's⁵ phrase of traumatic encephalopathy should be the preferred term for the syndrome as the term “chronic” is potentially misleading, neglects the progressive etiology of the syndrome, and instead implies a static condition. More recently, Gardner et al¹⁰ have reported on clinicopathological differences between classic and modern CTE, and argued that the modern syndrome needs a different nomenclature. However, to be consistent with the majority of the extant literature, we will use the term chronic traumatic encephalopathy (CTE) and refer to Omalu et al.’s¹¹ definition of CTE: “a progressive neurodegenerative syndrome caused by single, episodic, or repetitive blunt force impacts to the head and transfer of acceleration-deceleration forces to the brain.”

Along with the scientific advances and improved understanding of CTE, the syndrome has recently come under major scrutiny. Much of this can be linked to the enormous media coverage CTE has received in recent years, with several suicide deaths among athletes in high profile sports who have been diagnosed with CTE on postmortem examination. On the one hand, these tragic cases have helped to raise awareness of the syndrome and the associated clinical manifestations of CTE that, left untreated or treated suboptimally, can have devastating effects. On the other hand, the attention CTE has received has also emphasized the heterogeneous nature of the syndrome, and the problem of establishing clinical consensus as to the exact etiology of the condition, the clinical criteria for diagnosis, those who are most likely to be affected, how and why the severity and frequency of symptoms vary, and the most effective methods of prevention and treatment. Moreover, the continuous media coverage of athletes being linked to CTE pathology (sometimes even prematurely before sufficient evidence has been established) has perhaps also unfortunately resulted in the formation of premature conclusions about the relationship between CTE and behavioral health problems, without a thorough examination of the scientific evidence for a causal relationship. Some researchers have been particularly skeptical: McCrory and colleagues¹² recently noted that “…the speculation that repeated concussion or subconcussive impacts cause CTE remains unproven,” and that “the extent to which age-related changes, psychiatric or mental health illness, alcohol/drug use or coexisting dementing illnesses contribute to this process is largely unaccounted for in the published literature.” Randolph et al¹³ provide an alternative perspective on the etiology of cognitive decline related to repetitive blows to the head, suggesting that diminished cerebral reserve (rather than CTE) from a long history of repetitive head traumas may lead to the earlier clinical expression of an age-related neurodegenerative disease.

Understanding the exact nature of the behavioral problems related to CTE, particularly from a psychiatric perspective, is a major priority if efficacious treatment and intervention models are to be developed. This article aims to provide an improved understanding of the behavioral health symptoms related to CTE through a critical review of the extant literature. We use the term behavioral health to refer to the blending of personality, mood, and behavior—including substance addiction—which is common when discussing prevention and treatment for the purpose of providing comprehensive psychiatric services. We pose the question, “What other explanations may account for behavioral health changes among former athletes besides the onset of CTE?” We attempt to address this question and corollary issues using the current available literature. In addition, this article will provide recommendations for treatment and intervention methods for mental health professionals, as well as recommendations for future research.

Are Behavioral Health Symptoms Associated with CTE?

Despite the widely held perception that CTE is linked with changes in personality, mood, and behavior,¹⁴ there is a dearth of research addressing these behavioral health features of CTE. This is somewhat surprising as personality, mood, and/or behavior changes appear present in the majority of cases with confirmed CTE,³ and existing psychiatric treatment modalities may represent an unexplored alternative in alleviating or preventing the deterioration of these symptoms. Moreover, the behavioral health changes are often considered uncharacteristic of the person with suspected CTE¹⁵ and are among the most concerning for family members and caregivers.¹⁶

To better understand the behavioral health symptoms related to CTE, it is important to first understand who the individuals are who are developing CTE. Some investigators^17,18 have identified those at risk for CTE as individuals with high levels of exposure to repetitive head trauma; however, others argue that this is not necessarily sufficient.¹⁶ Individuals at risk include athletes in contact sports, members of the military, individuals with seizures and head-banging behavior, and those who experience repeated falls or have been in motor vehicle accidents.^17,18 Theoretically, these individuals may experience multiple pathologic cascades in response to a single or repetitive head trauma (concussive or subconcussive head injury), and this may be sufficient to initiate the neurodegenerative disease process of CTE.^3,19 The deterioration of behavioral health functioning is considered to be part of the neurodegenerative disease process, and recent research speculate that the severity of the disease process is directly related to the number of blows to the head.^20,21 Some investigators²⁰ have argued that the behavioral features of CTE are related to cumulative hits to the top-front and side of the head, which affects the basal ganglia and limbic circuits. Others have reported on the similarity of behavioral symptoms in people with CTE with individuals suffering from frontotemporal dementia.¹⁴ As we will discuss later, there also appears to be a significant overlap between behavioral symptoms described in cases with CTE and behaviors often found in people suffering from a recent traumatic brain injury (TBI) and/or post-concussion syndrome.

There are several factors that obscure the relationship between CTE and behavioral health functioning. For example, the at-risk individuals all belong to groups that commonly are exposed to significant behavioral health stressors, whether it is from participation in competitive sports, exposure to war and combat, coping with serious medical illnesses, or other potentially stress-inducing experiences. These activities can themselves cause behavioral health changes making it difficult to determine what behavioral health outcomes existed prior to the onset of the neurodegenerative disease and which developed after. Some of the behavioral manifestations (e.g., tendencies toward aggressive behavior) may have been present before any head trauma occurred and were part of the individual’s baseline personality characteristics. Also adding to the complexity of understanding the syndrome is the indication that early behavioral health symptoms of the disease differ from later symptoms.¹⁶ In fact, reports suggest that various behavioral health symptoms may not present until years or decades following the brain trauma,¹⁶ suggesting a progressive disease process that, over time, results in personality, mood, and behavior abnormalities becoming more pronounced.³ In one of the largest retrospective clinical examinations of CTE, Baugh and colleagues¹⁴ found that most behavioral health problems typically begin in midlife, between the ages of 30 and 50. This late onset of symptoms, years to decades after the injury,¹⁷ appears to distinguish CTE from the symptom patterns commonly associated with post-concussive syndrome, in which behavioral health symptoms typically present immediately or shortly after the brain trauma (more on this below).

Adding to the complexity of our current understanding of CTE is the limited empirical research on the interaction between the behavioral health symptoms and the physical and cognitive manifestations of CTE, which often are severe as well.^3,14,16,22 Thus, it is not clear whether or not this interaction of physical, cognitive, and behavioral deficits amplifies the behavioral health problems beyond what is directly related to the neurodegenerative impairment. Recent research has suggested that behavioral and cognitive deficits may represent two distinct clinical presentations of CTE.²³ Based on retrospective data on 33 subjects with neuropathologically confirmed CTE, Stern et al²³ found that 22 of the cases grouped into a subgroup characterized by reports of initial behavioral symptoms and mood changes (versus initial changes in cognitive functioning). This subgroup demonstrated symptom deficits at an earlier age (35 versus 59) and exhibited more serious behavioral symptoms (they were more explosive, out of control, and physically and verbally aggressive).

Depression, Apathy, and Suicidal Behavior

Several studies have reported on symptoms of depression in individuals who posthumously have been diagnosed with CTE. These symptoms include dysphoria, apathy, insomnia, and suicidal behavior.^18,24 In a large case review study, McKee and colleagues³ reviewed 51 neuropathologically confirmed cases of CTE and found that dysphoria was present in 48% of the cases and apathy was present in 9% of the cases. Some reports have speculated that symptoms of depression are more likely to be present early in the CTE disease process.^16,25 However, this has not been confirmed through prospective longitudinal studies, and several case studies appear to indicate that depressive symptoms may also persist or develop later in the more accelerated stages of CTE.^24,26–29

Small and colleagues³⁰ demonstrated evidence of tau deposits (as found in CTE) in five living football players (retired from the National Football League, NFL). They also found higher rates of depressive symptoms in these players when compared with control subjects. Interestingly, higher levels of tau deposits were also positively correlated with the number of concussions the athlete had experienced. Unfortunately, this study did not specifically examine if the levels of tau deposits and number of concussions were related to presentation of depressive symptoms.

In another recent study, which did not specifically examine CTE, Hart and colleagues³¹ used diffusion tensor imaging to examine white matter correlates of depression and cognitive deficits in a small sample of retired NFL players. Their findings showed a higher prevalence of depression among the retired players than what was expected from that age group (24% versus 15%), and, importantly, depression in this group versus controls was related to disrupted white matter integrity. Interestingly, however, only three of eight retired players with depression demonstrated cognitive deficits (in the total sample, 20 of 34 players were deemed to be “cognitively normal”). Moreover, the number of concussions (all but two of the retired players reported a history of concussions) and the number of years played in the NFL did not predict neurocognitive symptoms. Hart and colleagues noted that the presentation of depression was predominantly neurovegetative (e.g., disturbance of sleep and appetite) rather than overt depressed mood. They suggest that many cases of players with underlying neurological problems, including neurodegenerative disorders such as CTE, may go undetected because of poor understanding of the related clinical symptoms. In fact, the range of depressive symptoms, the level of severity of these symptoms, and whether or not individuals actually meet full criteria for depressive disorders according to the American Psychiatric Association³² is largely unclear in cases of CTE. Hart and colleagues and others³³ have recommended that future investigations include a more thorough clinical assessment of symptoms associated with CTE, as well as prospective epidemiological studies to establish the incidence of CTE, the factors associated with increased risk, and what can be done to ameliorate this.

It is important to note that case reports of individuals with confirmed CTE, diagnosed posthumously, describe the presence of various risk factors for depression, including deterioration of cognitive functioning, deterioration in socioeconomic class, bankruptcy, breakdown of intimate and family relationships, spousal separation and divorce, headaches, generalized body aches and pain, and alcohol and drug abuse.^24,27–29 Omalu and colleagues¹¹ made a syndromic profile of 17 confirmed CTE cases and demonstrated a progressive deterioration in interpersonal and familial relationships including the breakdown of relationships with spouses, children, family members, friends and coworkers; emotional and physical spousal abuse; and spousal separation resulting in divorce. They also described a progressive deterioration in financial functioning such as poor money management, deterioration of socioeconomic status, bankruptcy, and abuse of alcohol and prescription and illicit drugs. Extant research, however, has yet to address and clarify the question of whether the depressive symptoms are a direct consequence of the above risk factors or whether it is directly related to the neurological deterioration associated with CTE, a combination of the two, or entirely unrelated to CTE.

As mentioned in the introduction, suicidal behavior related to CTE has received significant media attention in recent years because of several suicides among high-profile athletes who posthumously were diagnosed with CTE. In fact, there are a number of reports suggesting that suicides and accidental deaths are disproportionately overrepresented in cases with CTE compared with rates found in the general population. Omalu and colleagues¹¹ found that of 17 subjects with CTE confirmed on autopsy, five deaths were the result of suicide. Nine of the 17 subjects’ deaths were determined to be accidental, of which five of these died from combinations of illicit and prescription drug overdose. Although speculative, these latter five deaths may also have been related to suicidal ideation or a wish to die, as research indicates that people with substance use disorders have a higher incidence of suicidal behaviors.^34,35 The last three cases in Omalu and colleagues’¹¹ study were determined to have died from natural causes (complications of alcoholism, coronary artery disease, and arrhythmia).

However, before making any conclusions about the relationship between suicidal behavior and CTE, it should be noted, as also highlighted by others,^13,36 that retired NFL players have a significantly lower risk of suicide than the general population.³⁷ In fact, there is a myriad of factors that may impact suicidal behavior, including biological, psychological, environmental, sociocultural, and demographic aspects. In order to truly demonstrate an increase of suicidal behavior in cases with confirmed CTE, studies would need to compare rates in depression, dementia, and other clinical conditions, in addition to the general population. Adding to the complexity, although suicidal behavior may be directly linked to depressive symptoms, it may also be a result of a combination of mood changes and impulse control deficits.²⁵

Impulse Control Deficits, Aggressive Behavior, and Mood Instability

Poor impulse control, aggressive tendencies, and violent behavior are among the most troubling symptoms that have been associated with the CTE syndrome (e.g.³). Family members have described a progression of aggressive outbursts in individuals with confirmed CTE, which eventually are debilitating to both the individual and the family. There is also evidence to suggest that the progression of CTE is associated with increased difficulty in impulse control, disinhibition, irritability, inappropriateness, and higher frequency of explosive outbursts of aggression.³⁸ In their aforementioned review of 51 neuropathologically confirmed cases of CTE, McKee and colleagues³ found that 70% of the cases showed behavioral changes that included aggression or violence, 39% exhibited irritability, and 24% showed agitation.

There are differing explanations of the neurological correlates of impulsive and aggressive behavior seen in individuals with CTE. Some investigators argue that damage to the hippocampal-septohypothalamic-mesencephalic circuitry (Papez circuit) may be responsible for the increased aggression and, more broadly, the emotional lability seen in individuals with CTE.^3,39 In contrast, Baugh and colleagues¹⁴ have suggested that the violent outbursts and increased aggression are associated with pathological changes observed in the amygdala and other areas of the medial temporal lobe. Others^3,4,11 report that poor impulse control and disinhibition are consistent with atrophy of the frontal lobes and orbitofrontal pathology in those with CTE. Focusing on emotional changes, Cantu⁴⁰ suggested that damage to the septum pellucidum, adjacent periventricular gray matter, and the frontal and temporal lobes was associated with the altered affect (euphoria and emotional lability) seen in people with CTE. Breedlove and colleagues²⁰ have suggested that neurodegeneration of limbic structures such as the parahippocampal gyri and the cingulate gyri may be responsible for emotional and behavioral changes in individuals with CTE.

Despite the reports of increased impulsive and aggressive behavior in individuals diagnosed posthumously with CTE, our knowledge of a causal link is, at the current time, limited. There are a number of factors that preclude us from making the assertion that increased impulsive and aggressive behaviors are directly related to the neurodegenerative cascade of CTE. First, it is important to recognize that in many of the activities in which at-risk individuals are involved (e.g., football, ice hockey, or military combat), it may be an advantage to be aggressive or to have an aggressive personality. Thus, people involved in these activities may have higher base rates of impulsivity and aggressiveness than people in the general population. Another concern is our limited knowledge of the progression of CTE; it is plausible that traumas to certain brain regions (e.g., amygdala, frontal, and orbitofrontal regions) would cause an increase in impulsive and aggressive behaviors, regardless of the development of CTE. For example, as we discuss in more detail below, TBIs are often associated with a range of inappropriate behaviors, including increases in disinhibited and aggressive behaviors.⁴¹ Other factors, such as substance abuse and addiction may also have contributed to increased impulsivity and aggression. In order to truly understand the relationship between CTE and changes in impulsive and aggressive behaviors, it is crucial that the above factors are accounted for in future prospective studies on CTE.

Other Behavioral Health Symptoms

A number of other behavioral health symptoms have also been associated with cases of individuals diagnosed posthumously with CTE. For example, Omalu and colleagues²⁴ have discussed the presence of social phobia and paranoia in some cases, and in McKee and colleagues’³ review of 51 neuropathologically confirmed cases of CTE, it was found that 42% of the cases reported paranoid ideation. In another CTE case study of a war veteran with a history of PTSD, Omalu and colleagues⁴² speculated that PTSD symptoms exhibited by that particular individual may have been due, in part, to the CTE pathology (see also⁴³).These reports suggest the presence of symptoms of anxiety spectrum disorders in some cases with CTE, which is consistent with studies showing a relatively high comorbidity of anxiety and depressive symptoms.⁴⁴

Sexual indiscretions and imprudent sexual behavior have also been related to CTE.¹¹ McKee and colleagues³ found hypersexuality to be present in three of the 51 cases in their review. Some investigators have suggested that in some cases the hypersexuality (and hyperorality) symptoms may be related to the presence of the Kluver-Bucy syndrome,³⁸ although, it is unclear if this syndrome has actually been found in people with confirmed CTE.

Some individuals with CTE have been described as having cheerful affect.³⁸ Emotional lability, euphoria, and hypomania are behavioral symptoms that have been associated with “milder” stages of CTE.³⁸ Other features found in some cases of CTE are increased religiosity²⁴ and poor insight.^25,38

CTE, TBI, and Post-Concussion Syndrome

As indicated above, the description of the “punch-drunk syndrome” has evolved from Martland’s original description to an understanding of CTE as a neuropathological cascade resulting from neurological trauma in the form of blows to the head. However, what is not entirely clear at this point is to what degree there is an overlap between the behavioral symptoms that are a result of immediate neurological impairment and the symptoms that come as a result of progressive neuropathological deterioration. In fact, Maartland’s paper appears to describe the punch drunk syndrome as a condition that can come from either repeated head blows over time (e.g., during a match, or over the career of the individual) as well as symptoms that can stem from one severe blow, not unlike a TBI.

Recent research with football players has acknowledged a possible relationship between TBI and CTE,^30,45 and neuropathological research seems to support that a single TBI may initiate the CTE process. Johnson and colleagues⁴⁶ examined postmortem brains from long-term survivors of a single TBI and compared these with uninjured, age-matched controls. In those aged 60 or younger, the brains of individuals who had experienced a single TBI were significantly more likely to show neurofibrillary tangles than controls. There were no group differences when they included cases aged 60 and above in the analyses. This finding suggests that pathological mechanisms leading to neurodegenerative disease may be initiated or accelerated by a single TBI, particularly in younger people.

In addition, there is a noticeable overlap between the reported behavioral symptoms related to TBI and those linked to CTE. For example, in a review of approximately 350 studies that reported on long-term psychiatric symptoms related to TBI (symptoms occurring at least 6 months post-injury), Hesdorffer and colleagues⁴⁷ found some evidence for an association between TBI and depression and a link between TBI and aggression. They also suggest a possible relation between TBI and completed suicide (there was insufficient evidence to make a similar conclusion for attempted suicide), a decrease in alcohol and drug use compared with preinjury levels, the development of PTSD in military populations (although there is insufficient evidence for similar results with civilian populations), and psychosis (which does not appear until after the first post-TBI year).

However, as noted by some investigators,¹⁷ what obscures the potential link between TBI and CTE related behavioral symptoms is the notion that a TBI involves a full-fledged concussion. Moreover, to meet criteria for post-concussion syndrome, which in some cases follows a TBI, an individual is required to have experienced a significant cerebral concussion.³² In contrast, CTE may be reported in cases in which the individual has experienced only subthreshold concussions, or so-called subconcussive impacts. In addition, symptoms of CTE do not usually manifest until decades after the head injury and may involve symptoms that are unique to CTE, such as gait changes that resemble Parkinsonism and progression to dementia.¹⁷ The symptoms associated with TBI may also be quite variable, with symptoms fluctuating over the period of recovery and symptom patterns differing widely between individuals. Behavioral symptoms in TBI are also often associated with the site of injury,⁴⁸ and can for example be influenced by injury to the neck and peripheral nervous system in addition to the disruptions to the cortex and brainstem.

The emerging picture suggests that there may be several different trajectories of the behavioral symptoms found in cases with CTE. Some behavioral problems may have an early onset, whereas other symptoms may not present themselves until later stages of the disease process. Some symptoms may improve over time, some may worsen, and some may initially improve before worsening. This is an important research question for future epidemiological prospective outcome studies examining CTE.

Treatment of Behavioral Health Symptoms Related to At-Risk Populations

Although our understanding of CTE is still in its infancy, and the clinical diagnostic criteria and other methods of diagnosing CTE continue to be under development (provisional research diagnostic criteria for CTE were recently published),⁴⁹ it is important to recognize that there exist various treatments for the related behavioral health symptoms. Moreover, there is a rather large research literature on effective treatments for behavioral problems in people with head injuries, such as TBI, which may be helpful in informing treatment interventions for those at high risk for developing CTE. We highlight here some of the many interventions and treatment modalities that have been reported on in individuals suffering from head injuries, more specifically TBI, with the hope that this may provide a foundation for future longitudinal outcome research that focuses on how individuals at-risk for CTE and their families can cope with the potential behavioral health changes.

For the pharmacological treatment of depression in TBI, Fann and colleagues⁵⁰ suggest selective serotonin reuptake inhibitors (SSRIs) as the first line choice. In their review of the literature, they found that sertraline might be particularly effective, with some limited evidence for citalopram. With regard to the treatment of aggressive behaviors in people with TBI, Warden and colleagues⁵¹ recommend the use of beta blockers, such as propranolol and pindolol. Warden and colleagues⁵¹ found some effectiveness in the use of olanzapine in the treatment of psychotic symptoms in the same population. Buspirone (at 45–60 mg/day) may be useful for the treatment of anxiety symptoms.^9,48 Although it is unclear if these pharmacological interventions target the underlying cause of these disturbances (e.g., neurotrauma may, in itself, disrupt dopaminergic or serotonergic neurotransmission, or indirectly influence mood and cognitive states), they may be effective for symptom management in these populations.

There is also evidence to suggest that behavioral interventions, including cognitive behavioral therapy (CBT), can be quite effective in the treatment of behavioral health problems after TBI,^50,52 as well as CBT combined with neurorehabilitation.⁵³ Referral to a caregiver support group and consideration of the availability of resources through a dementia organization may also be effective in reducing caregiver stress.

Concluding Remarks and Areas for Future Research

We have in this article critically reviewed the literature on behavioral health symptoms related to CTE. Although it is undeniable that there is a variety of behavior changes that can be identified in individuals diagnosed with CTE posthumously, our review of the current literature suggests caution against concluding that there is an empirically established causal relationship between CTE and behavioral changes. The paucity of longitudinal prospective studies on CTE, combined with a lack of commonly accepted diagnostic criteria for identifying individuals who are considered to be at risk for CTE, make it difficult to reliably establish a causal relationship.

Furthermore, as noted by others (e.g.,¹⁷), there has likely been a selection bias among athletes that have undergone autopsy. For example, it is likely that in many of the cases of individuals who have undergone autopsy to determine the presence of CTE, the families were particularly concerned about behavioral or neurocognitive impairment and may have suspected neuropathology. To our knowledge, no randomized neuropathological studies of CTE have been conducted,⁴ and there is limited information about cases of CTE in which there is no or limited behavioral and/or neurocognitive impairments. As a result, we do not know the true prevalence of cases with CTE.

Another concern is that the majority of personality and behavioral changes reported have been conveyed by family members, next-of-kin, and other acquaintances, during postmortem, semistructured interviews. There are limitations inherent to this method of data collection. Information obtained postmortem, relies in part on the memory of family members and others. In addition, the interviewees can be subject to recall bias.³⁸

New advanced imaging techniques, such as magnetic resonance spectroscopy, may offer methods that can help identify the premorbid stages of CTE in living cases (or help the early detection of pathology related to concussions, TBI, and other brain injuries). This may also help us better understand the progression of the behavioral health symptoms as they relate to the progression of the CTE disease. Moreover, this will aid with the characterization of the various factors that are associated with being at risk for CTE (including finding biomarkers that may assist in determining diagnosis), such that a commonly accepted clinical diagnosis can be established. Future research will need to take into account selection bias issues and aim to gather prospective data, using validated and reliable assessments of behavior, personality, and mood. This would allow for a better understanding of the disease process, specifically the presentation and progression of clinical symptoms occurring with CTE, while potentially allowing for earlier recognition of the disease in living persons and improved treatment and care of the related behavioral health symptoms.

Lastly, animal models and translational research that focus on genotyping and gene-expression, such as on the apolipoprotein E (ApoE) genotype, which has been associated with some, but not all, CTE cases,^3,11 and proposed as a risk factor for CTE¹⁷ and increased severity of neurological deficits,⁵⁴ may also prove important in further advancing our knowledge about CTE and associated behavioral symptoms, and provide a foundation for pharmacological interventions. To date, there is no animal model of CTE described in the literature. However, recent research has looked to animal models of repeated mild TBI to gain a better understanding of the pathophysiology of CTE. Existing animal models, such as the fluid percussion injury model, the blast TBI model, the weight-drop model, and the closed-head injury model, have been modified in an attempt to develop models that replicate the clinical features of repeated mild TBI (these models were recently reviewed by Xiong and colleagues⁵⁵). Promising results in mice, rats, and swine indicate that repeated mild head traumas, compared with single head traumas, are associated with long-term behavioral impairments, neuroinflammation, cortical neuron loss, white matter deficits, and overall poorer outcomes.⁵⁵ In one particularly relevant study, Kane and colleagues⁵⁶ used a modified weight-drop model to examine the consequences of repetitive mild traumatic brain injury in mice and found an increase in phospho-tau and glial fibrillary acidic protein after the last injury, suggesting that this may exemplify the neuropathology often associated with CTE.

Despite these promising results in animal studies, developing an animal model of CTE will be challenging. Animal models of TBI have been scrutinized for their lack of clinical translation: exciting preclinical findings of novel neuroprotective treatments have largely failed in clinical trials.^55,57 A major problem is that most animal models attempts to mimic either focal or diffuse brain injury, focusing on examining single pathophysiological events instead of treating TBI as a complex disease process that may cause significant structural damage and deficits across various functions.⁵⁵ Moreover, many animal models focus on the immediate consequences of the primary injury (the brain tissue damage that takes place at the time of the injury), instead of the secondary injury that occurs hours, weeks, and months after the primary injury (the cascade of metabolic, cellular, and molecular events that eventually can lead to cell death and white matter degeneration, as seen in CTE). The clinical reality is that human pathophysiology is heterogeneous; each person is likely to experience an individual form of brain damage that is characterized by combinations of focal and diffuse patterns of primary insults, as well as the nature of secondary insults, all of which depends on a myriad of factors (e.g., number of concussions versus subconcussions, the brain area(s) of injury, and demographic and clinical factors). Thus, as research on both repetitive TBI and CTI evolves, it is critical that new multifaceted animal models are developed that can lead to a better understanding of both the primary and secondary injury mechanisms and behavioral consequences in humans, with the ultimate goal of providing a foundation for novel interventions.