Abstract

The long-term consequences of repetitive head impacts have been described since theearly 20th century. Terms such as punch drunk and dementia pugilistica were firstused to describe the clinical syndromes experienced by boxers. A more genericdesignation, chronic traumatic encephalopathy (CTE), has been employed since themid-1900s and has been used in recent years to describe a neurodegenerative diseasefound not just in boxers but in American football players, other contact sportathletes, military veterans, and others with histories of repetitive brain trauma,including concussions and subconcussive trauma. This article reviews the literatureof the clinical manifestations of CTE from 202 published cases. The clinical featuresinclude impairments in mood (for example, depression and hopelessness), behavior (forexample, explosivity and violence), cognition (for example, impaired memory,executive functioning, attention, and dementia), and, less commonly, motorfunctioning (for example, parkinsonism, ataxia, and dysarthria). We present proposedresearch criteria for traumatic encephalopathy syndrome (TES) which consist of fourvariants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixedvariant, and TES dementia) as well as classifications of ‘probable CTE’and ‘possible CTE’. These proposed criteria are expected to be modifiedand updated as new research findings become available. They are not meant to be usedfor a clinical diagnosis. Rather, they should be viewed as research criteria that canbe employed in studies of the underlying causes, risk factors, differentialdiagnosis, prevention, and treatment of CTE and related disorders.

Introduction

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized bythe accumulation of hyperphosphorylated tau protein (p-tau) in neurons and astrocytes ina pattern that is unique from that of other tauopathies, including Alzheimer’sdisease (AD) and frontotemporal lobar degeneration. The p-tau deposition initiallyoccurs focally, as perivascular neurofibrillary tangles and neurites at the depths ofthe cerebral sulci. It spreads to involve superficial layers of adjacent cortex,eventually resulting in widespread degeneration of the medial temporal lobes, frontallobes, diencephalon, and brainstem [1],[2]. Unlike AD, there is a paucity of beta amyloid neuritic plaques. CTE has beenfound most often in professional athletes involved in contact sports (for example,boxing and American football) who have been subjected to repetitive head blows resultingin concussive and subconcussive trauma [3],[4]. Neuropathologically confirmed CTE has been reported in individuals as youngas 17 and in athletes who played sports only through high school or college. It also hasbeen found in non-athletes who have experienced repetitive head impacts, includingepileptics, developmentally disabled individuals who head-bang, and victims of physicalabuse [2]. Moreover, CTE has been neuropathologically diagnosed in military servicemembers previously deployed in Iraq and Afghanistan with histories of repetitive braintrauma [2],[5]. At this time, it is not completely clear whether all cases ofneuropathologically confirmed CTE would demonstrate a progressive course if they livedlong enough.

All cases of neuropathologically confirmed CTE reported to date have had a history ofrepetitive head impacts, although there has been some suggestion that a single traumaticbrain injury (TBI) may also lead to the neuropathological changes of CTE [6]. Although head impacts appear to be necessary for the initiation of thepathogenetic cascade that eventually leads to neurodegeneration, the history of headimpacts is not sufficient and additional risk factors (including genetic susceptibilitymarkers) remain unknown. The incidence and prevalence of CTE are also unknown, althoughthe number potentially affected could be quite large. Every year, between 1.6 and 3.8million individuals in the US experience a sports-related concussion [7], and the number of youth sports-related concussions has grown in recent years [8]. The incidence of repetitive subconcussive blows (that is, hits to the headthat produce enough force to hamper neuronal integrity but that do not result inclinical concussion symptoms) is much greater [9]. For example, a study by Broglio and colleagues [10] found that, per season, high school football players receive an average of652 head blows that exceed 15 g of force. With over 1 million high school studentsplaying American football each year and with the size and speed of football playersincreasing [11], the public health impact of CTE may be quite significant in futureyears.

In vivo diagnosis of CTE is needed to conduct research on risk factors andepidemiology and to perform clinical trials for prevention and treatment. Sensitive andspecific biomarkers for CTE are being developed and include structural and neurochemicalimaging techniques and positron emission tomography (PET) with new ligands thatselectively bind to p-tau [4],[12],[13]. These approaches hold promise to detect underlying neuropathological changesof CTE. However, the clinical features directly associated with these changes have onlyrecently been described and have been based on retrospective reports of family membersof deceased individuals who received a neuropathological diagnosis of CTE [2],[14].

In a recent article from our group [14], we examined the clinical presentation of 36 adult males selected from allcases of neuropathologically confirmed CTE at the Boston University Center for the Studyof Traumatic Encephalopathy Brain Bank. The cases were all athletes, had no comorbidneurodegenerative or motor neuron disease, and had family member informants who providedretrospective reports of history and clinical features. The semi-structured‘psychological autopsies’ were conducted blind to the subjects’neuropathological findings. Three of the 36 subjects were asymptomatic. In the remaining33 symptomatic subjects, a triad of cognitive, behavioral, and mood impairments wasfound, and cognitive changes were reported for almost all subjects at some time in thecourse of disease. However, two relatively distinct clinical presentations emerged: onegroup had initial features involving behavior (that is, explosivity, physical and verbalviolence, being ‘out of control’, and impulsivity) or mood (that is,depression and hopelessness) or both (n = 22), and another group had initialfeatures involving cognition (that is, episodic memory impairment, executivedysfunction, poor attention, and concentration) (n = 11). Symptom onset forthe ‘behavior/mood group’ occurred at a significantly younger age than forthe ‘cognition group’. Most subjects in the behavior/mood group eventuallydeveloped cognitive difficulties, although significantly fewer subjects in the cognitiongroup eventually demonstrated behavioral and mood changes. Significantly more subjectsin the cognition group developed dementia than those in the behavior/mood group. Lessthan one third of the sample had reported motor features, including parkinsonism.

Although the study by Stern and colleagues [14] involved the largest case series to date of neuropathologically confirmedcases of CTE without comorbid conditions and with clinical histories, the sample sizewas small and the generalizability of the findings was hampered by the potential bias ofa sample composed of former athletes whose family members agreed to their braindonation. This limitation notwithstanding, the finding of two possible clinical subtypesof CTE was consistent with previous literature. In the present article, we provide areview of the world’s literature on the clinical features exhibited by athleteswith histories of repetitive head impacts. After the literature review, we provideproposed research diagnostic criteria for ‘traumatic encephalopathysyndrome’ (TES), derived from this literature review and from our own researchinto the clinical presentation of CTE [1],[2],[14]. As described below, these criteria are meant to initially characterize whatis known to date and provide a foundation for developing more precise clinical criteriainformed by ongoing and future research and clinical review.

Historical terms for chronic traumatic encephalopathy

In his seminal 1928 article in theJournal of the American Medical Association,Martland [15] used the term ‘punch drunk’ to describe boxers suffering fromsymptoms he believed to be related to the repetitive blows they received in the ring.Since that time, various terms have been used to describe the clinical syndromeassociated with repetitive head impacts, predominantly in studies of boxers. In 1934,Parker [16] published an article in which he referred to the ‘traumaticencephalopathy of pugilists’. In 1937, Millspaugh [17] first used the term ‘dementia pugilistica’, which is still usedby clinicians and researchers. Other terms coined through the decades include‘traumatic encephalitis’ [18], ‘cumulative encephalopathy of the boxer’ [19], ‘psychopathic deterioration of pugilists’ [20], ‘chronic boxer’s encephalopathy’ [21], and ‘traumatic boxer’s encephalopathy’ [22]. In 1949, Critchley first used the designation ‘chronic traumaticencephalopathy’ [23], or CTE, but later modified it to ‘chronic progressive traumaticencephalopathy’ [24] because several cases apparently progressed from an early mild state tosevere dementia [23]-[25]. Johnson [26] suggested that the latter term erroneously implies that progression isinevitable. In his case series, little to no deterioration is reported in half of thecases followed for 5 years. In recent reviews of the literature, Victoroff (alone [27] and with Baron [28]) suggested using the more general and inclusive term ‘traumaticencephalopathy’.

In 2005, Omalu and colleagues [29] described the first case of neuropathologically confirmed CTE in an Americanfootball player. Since that time, there has been increasing public attention to thisdisease, and reports of CTE in deceased football players, including several well-knownathletes, have prompted a tremendous focus on what is commonly referred to asfootball’s ‘concussion crisis’. The scientific community also hasbecome dramatically more aware of CTE since it was discovered in American footballplayers. For example, a PubMed search using the terms ‘chronic traumaticencephalopathy’, ‘traumatic encephalopathy’, ‘dementiapugilistica’, or ‘punch drunk’ resulted in 14 publications in the5-year period ending in December 2001 compared with 116 publications in the 5-yearperiod ending in December 2013.

Early concepts regarding subtypes

In a 1950 editorial in theBritish Medical Journal, Jokl [30] stressed that CTE was not a single syndrome but rather two kinds of chronicimpairment, with either predominant ‘behavioral-psychopathic orneurological-psychiatric’ features. He described the behavioral-psychopathicsubtype as involving ‘viciousness’, ‘murder committed fromjealousy’, and delinquency. In contrast, he described the neurological-psychiatricsubtype as involving cognitive deficits, dementia, and motor impairment [30]-[32]. Grahmann and Ule [33] (1957) described three general subtypes: (1) a progressive dementia thattypically involved cognitive impairment and developed following a latency from the timeof boxing retirement, (2) a stable neurological presentation temporally andetiologically related to the head impacts and not representative of a progressivedisease, and (3) a paranoid and psychotic subtype absent of cognitive changes. Critchley [23] maintained that there were three commonly recurring presentations of CTE thatresembled, but could be distinguished from, (1) neurosyphilis (for example, psychopathy,altered personality, and later dementia), (2) multiple sclerosis (for example, scanningspeech, tremor, and progressive cognitive decline), and (3) frontal lobe tumor (forexample, executive impairments, headache, and eye ache). He later added a fourthpresentation: striatal parkinsonian (for example, masked facial features and tremor) [24]. In a study of 17 retired boxers, Johnson [26] described four different ‘organic psychosyndromes’: cognitiveproblems with progressive dementia, behavioral issues related to ‘morbidjealousy’, behavioral issues related to rage and personality disorders, and moodand behavioral disturbance related to persistent psychosis.

Literature search methods

To examine previous literature describing the clinical presentation of CTE associatedwith exposure to head impacts through sports participation, we conducted a literaturesearch using PubMed, PubMed Central, and Medline databases. Search terms included‘chronic traumatic encephalopathy’, ‘punch drunk’,‘traumatic encephalopathy’, ‘dementia pugilistica’,‘chronic boxer’s encephalopathy’, ‘chronic progressive traumaticencephalopathy’, ‘psychopathic deterioration of pugilists’, and‘repetitive brain injury’. In addition, bibliographies of recent literaturereviews were cross-referenced [1],[27],[34]-[39]. It should be noted that most online databases are limited to articlespublished since the 1950s. Because essential work in this field began in 1928, archivalresearch was carried out by hand, and international works were obtained with assistancefrom the Boston University Medical Library Interlibrary Loan Department. Materialsretained included articles, reviews, dissertations, society transactions, associationreports, and book chapters. To be reasonably confident about the diagnoses used, severalcriteria were used to determine inclusion in this review: (1) only case series, and notindividual case reports, were included; (2) adequate information must be provided in thereport to allow classification of cases as confirmed CTE, probable CTE, or possible CTEby using Jordan’s criteria [35],[40],[41]; and (3) only cases involving athletes were included.

Results of literature review

Following the exclusion of articles and cases that did not meet the above criteria, theliterature review resulted in 202 cases from 20 published case series, four books, andone medical dissertation. The cases are summarized in Table 1[2],[16],[22]-[26],[29],[31]-[33],[42]-[54]. Nineteen cases were published before 1950, 29 cases were published in the1950s, 49 were published in the 1960s, 13 were published in the 1970s, four werepublished in the 1980s, 19 were published in the 1990s, and 69 were published since2000. Using Jordan’s criteria [35], we approximated that 29 would have possible CTE, 90 would have probable CTE,and 83 would have definite CTE. Of the entire sample, 141 were boxers, 54 were Americanfootball players, five were ice hockey players, and two were professional wrestlers. Theclinical features described in all of the cases were classified into one of fourcategories: behavioral, mood, cognitive, and motor. Table 2summarizes the clinical features most commonly described across all cases. In 68% ofcases, the course of the clinical syndrome was described as progressive. In cases inwhich a distinction in clinical syndrome was made, the behavioral and mood features werereported to be more stable, whereas the cognitive features were described asprogressive, often resulting in dementia. Compared with cases described as progressive,cases described as stable were substantially younger. A large number of cases had aperiod of latency of several years between the end of exposure to head impacts and thepresentation of clinical signs and symptoms. In neuropathologically confirmed cases,authors described the initial clinical presentation as involving mood or behavioraldisturbance (or both) without cognitive impairment in 28%, as having cognitiveimpairment without concurrent mood or behavioral difficulties in 32%, and as havinginitial mixed cognitive and mood/behavioral disturbance in 40%.

In recent years, some authors have made the distinction between ‘classicCTE’ and ‘modern CTE’ [34],[36]. For example, McCrory and colleagues [36] define the classic CTE syndrome based on the clinical descriptions fromRoberts [49] and the neuropathological reports from Corsellis and colleagues [50]. Based on these earlier cases of boxers, classic CTE is described as havingprominent motor features, including gait disturbance, dysarthria, and pyramidalproblems, but without progressive cognitive, behavioral, or mood changes [36]. However, it is important to note that, in his monograph, Roberts [49] clarifies that he is intentionally focusing on the description andquantification of motor signs related to neurological lesions, reducing his focus on‘the evidence of dementia or personality change’ which he viewed asoccurring in a subset of cases [49]. In contrast, ‘modern CTE’ [34],[36], defined as any case report published in 2005 or later, is characterized bypredominant mood and behavioral symptoms as well as later progressive cognitive deficitsand dementia but with less prevalent motor features. We view this distinction betweenthe earlier and more recent descriptions of the clinical presentation of CTE as largelyan artifact of different sources of trauma exposure (that is, predominantly boxers inthe ‘classic’ cases and predominantly football players in the‘modern’ cases).

To explore this issue, we examined further the cases of neuropathologically confirmedpure CTE described in the series of McKee and colleagues [2] and compared the presence of motor features reported for the deceasedprofessional boxers with those reported for the professional football players. Thepercentage of professional boxers with motor features (71%) far exceeded that ofprofessional football players (13%). Additionally, it was found that in cases with themost advanced stage of CTE neuropathology, there was a striking difference in thepresence of cerebellar pathology in professional boxers (83%) and professional footballplayers (57%). The likely cause of this may be related to the differences in thebiomechanics of the head trauma that is experienced through the practice of these twodifferent sports [14].

Previously published diagnostic criteria

To date, there have been two published sets of diagnostic criteria for the clinicaldiagnosis of CTE. The first diagnostic criteria, proposed by Jordan [35],[40],[41], were developed specifically to represent the likelihood of underlying CTEneuropathology. As such, the following four diagnostic classifications are used: (1)definite CTE (‘any neurological process consistent with the clinical presentationof CTE along with pathological confirmation’), (2) probable CTE (‘anyneurological process characterized by two or more of the following conditions: cognitiveand/or behavioral impairment; cerebellar dysfunction; pyramidal tract disease orextrapyramidal disease; clinically distinguishable from any known disease process andconsistent with the clinical description of CTE’), (3) possible CTE (‘anyneurological process that is consistent with the clinical description of CTE but can bepotentially explained by other known neurological disorders’), and (4) improbableCTE (‘any neurological process that is inconsistent with the clinical descriptionof CTE and can be explained by a pathophysiological process unrelated to braintrauma’) [35].

In contrast to Jordan’s diagnostic criteria, which are focused on the predictionof underlying CTE neuropathology, the diagnostic criteria of Victoroff [27] are focused on a broad set of clinical signs and symptoms representing adiverse set of possible etiologies and are not meant to predict underlying CTEneuropathology. These provisional research diagnostic criteria for clinically probabletraumatic encephalopathy (TE) and clinically possible TE were based on the frequency ofclinical symptoms and signs reported in TE case reports published between 1928 and 2010.The Victoroff criteria represent an important addition to the literature but haveseveral limitations. For example, for a diagnosis of clinically probable TE, there is arequirement for two symptoms and three signs. However, there is tremendous overlap andredundancy between the symptoms and the ‘neurobehavioral signs’, includingthe use of the following terms included as both symptoms and signs: memory loss,irritability, apathy, impulsivity, depression, lability, euphoria, paranoia, and others.Another required criterion for clinically probable TE is the ‘persistence of bothsymptoms and signs for at least two years after the traumatic exposure’ [27]. This is not consistent with numerous cases of neuropathologically confirmedCTE for which a delayed onset of the clinical presentation is often observed,representing the neurodegenerative nature of the disease [2],[14]. An additional limitation to the Victoroff criteria is the lack of anysubtyping of the clinical presentation. That is, the same diagnosis of clinicallyprobable TE could be given to an 80-year-old with memory loss, mental slowing, headache,and nystagmus and to a 22-year-old with depression, anxiety, irritability, and anger.This lack of diagnostic subtyping for a condition with such clinically diverse signs andsymptoms would reduce the utility of the criteria for research aimed at elucidatingspecific clinico-pathological relationships or clinical trials requiring greaterspecificity of diagnosis to ensure meaningful target outcomes. The criteria arepresented in a single table without accompanying descriptive prose, makingimplementation of the criteria potentially subject to individual interpretation.Finally, the Victoroff criteria do not include or recommend the future use of objectivediagnostic tests, such as neuroimaging or other potential biomarkers, to improve uponthe diagnostic accuracy, specificity, or ability to detect CTE during life.

Proposed research diagnostic criteria for traumatic encephalopathy syndrome

We propose research diagnostic criteria that address many of the limitations of thepreviously published criteria by Jordan [35],[40],[41] and Victoroff [27]. These new criteria are derived from the previous literature on CTE reviewedabove as well as the specific findings from the studies by Stern and colleagues [14] and McKee and colleagues [2] on the clinical presentation of neuropathologically confirmed cases of CTE.The term ‘traumatic encephalopathy syndrome’ (TES) was selected instead of‘chronic traumatic encephalopathy’ (CTE) for the following reasons: (1) weview the designation ‘CTE’ as a neuropathologically defined disease (whichis defined by the characteristic deposition of p-tau pathology) rather than a clinicalsyndrome; (2) TES is meant to describe the clinical presentation of CTE as well as otherpossible long-term consequences of repetitive head impacts (for example, chronic orprogressive axonopathy without tauopathy) but is not meant to include the acute orpost-acute manifestations of a single concussion, post-concussion syndrome, or moderateto severe TBI; (3) the use of the word ‘chronic’ in CTE inaccuratelyconnotes a stable condition rather than a progressive disorder [27]; and (4) the inclusion of the term ‘syndrome’ appropriatelydescribes the cluster of clinical features that make up this condition. The proposedresearch diagnostic criteria for TES include five general criteria, three core clinicalfeatures, and nine supportive features that are used to define subtypes of TES: abehavioral/mood variant, a cognitive variant, a mixed variant, and TES dementia. Themodifiers ‘progressive course’, ‘stable course’, and‘unknown/inconsistent course’ are used to describe the clinical course, andif specific motor signs are evident, the modifier ‘with motor features’ isadded.

The selection of the five general criteria was based on the literature reviewed aboveand was designed to favor sensitivity over specificity. This decision is consistent withthe previously published diagnostic criteria [27],[35] and is appropriate at this early stage of clinical research into this area.To be included as a core clinical feature, the sign or symptom must have been reportedin a minimum of 70% of the cases in the study by Stern and colleagues [14] of neuropathologically confirmed cases of pure CTE. This is in contrast tothe algorithm employed in the Victoroff [27] diagnostic criteria for which a sign or symptom was included if it waspresent in at least 7% of the case reports he reviewed from the literature. The ninesupportive features were selected to increase specificity once the general criteria aremet and are based on features reported in the previous literature.

The clinical diagnosis of TES is not meant to imply a certainty of underlying CTEneuropathological changes (for example, p-tau accumulation). Rather, TES is meant to bea diagnosis of a clinical syndrome associated with a history of repetitive brain trauma.It is expected that some individuals with TES do indeed have CTE neuropathologicalchanges. However, it is also possible that some individuals with TES have otherunderlying causes of their clinical presentation, including, but not limited to,progressive white matter degeneration [55] or AD. For this reason, a separate diagnostic classification for‘possible CTE’, ‘probable CTE’, and ‘unlikely CTE’is included, based on the presence of additional supportive features, such asbiomarkers, which indicate the degree to which the underlying etiology of the clinicalpresentation of TES is likely due to the CTE pathophysiological process. Finally, weoffer six cases (see boxes) as exemplars of the implementation of the TES criteria; eachcase is a composite of several patients and is created specifically for thispurpose.

At this time, risk factors for CTE (above and beyond brain trauma) remain unknown. Amongpossible variables under investigation by our group and other laboratories are thequantity or severity (or both) of the brain trauma, the initial age and overall durationof head impact exposure, lifestyle factors, and genetic susceptibility. Based on currentresearch findings, it is expected that TES is the clinical manifestation of underlyingdamage or dysfunction of cortical or subcortical brain structures (or both) and isassociated with a history of repetitive brain trauma, including both symptomaticconcussions and subconcussive trauma. Although some investigators have suggested that asingle moderate to severe TBI may lead to CTE [37] or AD [56] or both, the use of the clinical diagnosis of TES at this time is meant to beused for individuals with repetitive impacts to the head, as defined below. We haveincluded a requirement for a specific minimal amount of exposure to head impacts. Thisis based on previous findings of post-mortem confirmed CTE cases [1],[2],[5],[50] and will be subject to revisions as additional research is conducted onexposure variables.

General criteria for traumatic encephalopathy syndrome

All five criteria must be met for a diagnosis of TES:

1. History of multiple impacts to the head (or to the body resulting in impulsive forcetransmitted to the head). Multiple impacts are defined based upon (a) the types ofinjuries and (b) the source of exposure.

a. Types of injuries:

i) Mild TBI or concussion, defined according to the Zurich 2012 Consensus Statement onConcussion in Sport [57] as a ‘complex pathophysiological process affecting the brain, inducedby biomechanical forces…caused either by a direct blow to the head, face, neck orelsewhere on the body with an “impulsive” force transmitted to thehead…the acute clinical symptoms largely reflect a functional disturbance ratherthan a structural injury and, as such, no abnormality is seen on standard structuralneuroimaging studies. Concussion results in a graded set of clinical symptoms that mayor may not involve loss of consciousness’. History of this form of trauma can bebased on documented records from health-care providers or on self- or informant-reports,after being given an appropriate definition of ‘concussion’ [58]. If there is no reported exposure to other repetitive hits to the head, thereshould be a minimum of four documented mild TBIs or concussions.

ii) Moderate/severe TBI, defined as having loss of consciousness of at least30 minutes, alteration of consciousness/mental state of more than 24 hours,post-traumatic amnesia of more than 24 hours, and Glasgow Coma Scale score of lessthan 13 [59]. If there is no reported exposure to other repetitive hits to the head, thereshould be a minimum of two moderate/severe TBIs.

iii) ‘Subconcussive’ trauma, defined as biomechanical force to the head orbody similar to, or less than, that required for symptomatic concussion but withoutsymptoms and clinical presentation consistent with concussion [3],[4].

b) Source of exposures:

i. Involvement in ‘high exposure’ contact sports (including, but not limitedto, boxing, American football, ice hockey, lacrosse, rugby, wrestling, and soccer) for aminimum of 6 years, including at least 2 years at the college level (orequivalent) or higher.

ii. Military service (including, but not limited to, combat exposure to blast and otherexplosions as well as non-combat exposure to explosives or to combatant or breachtraining).

iii. History of any other significant exposure to repetitive hits to the head(including, but not limited to, domestic abuse, head banging, and vocational activitiessuch as door breaching by police).

iv. For moderate/severe TBI, any activity resulting in the injury (for example, motorvehicle accident).

2) No other neurological disorder (including chronic residual symptoms from a single TBIor persistent post-concussion syndrome) that likely accounts for all clinical features,although concomitant diagnoses of substance abuse, post-traumatic stress disorder(PTSD), mood/anxiety disorders, or other neurodegenerative diseases (for example, AD andfrontotemporal dementia) or a combination of these can be present.

3) Clinical features must be present for a minimum of 12 months. However, iftreatment (for example, ‘antidepressant’ medication) results in animprovement in select symptoms, the clinician should use her or his best judgment todecide whether the symptoms would have persisted or progressed if treatment had not beeninitiated.

4) At least one of the core clinical features must be present and should be considered achange from baseline functioning.

5) At least two supportive features must be present.

Core clinical features of traumatic encephalopathy syndrome

At least one of the core clinical features must be present:

1)Cognitive. Difficulties in cognition:

a) as reported by self or informant, by history of treatment, or by clinician’sreport of decline; and

b) substantiated by impairment on standardized mental status or neuropsychological testsof episodic memory, executive function, and/or attention, as defined by scores at alevel of at least 1.5 standard deviations below appropriate norms.

2)Behavioral. Being described as emotionally explosive (for example, having a‘short fuse’ or being ‘out of control’), physically violent,and/or verbally violent, as reported by self or informant, by history of treatment, orby clinician’s report. A formal diagnosis of intermittent explosive disorder wouldmeet this criterion but is not necessary.

3)Mood. Feeling overly sad, depressed, and/or hopeless, as reported by self orinformant, by history of treatment, or by clinician’s report. A formal diagnosisof major depressive disorder or persistent depressive disorder would meet this criterionbut is not necessary.

Supportive features of traumatic encephalopathy syndrome

A minimum of two of the following features must be present for a diagnosis of TES:

1)Impulsivity. Impaired impulse control, as demonstrated by new behaviors,such as excessive gambling, increased or unusual sexual activity, substance abuse,excessive shopping or unusual purchases, or similar activities.

2)Anxiety. History of anxious mood, agitation, excessive fears, or obsessiveor compulsive behavior (or both), as reported by self or informant, history oftreatment, or clinician’s report. A formal diagnosis of anxiety disorder wouldmeet this criterion but is not necessary.

3)Apathy. Loss of interest in usual activities, loss of motivation andemotions, and/or reduction of voluntary, goal-directed behaviors, as reported by self orinformant, history of treatment, or clinician’s report.

4)Paranoia. Delusional beliefs of suspicion, persecution, and/or unwarrantedjealousy.

5)Suicidality. History of suicidal thoughts or attempts, as reported by selfor informant, history of treatment, or clinician’s report.

6)Headache. Significant and chronic headache with at least one episode permonth for a minimum of 6 months.

7)Motor signs. Dysarthria, dysgraphia, bradykinesia, tremor, rigidity, gaitdisturbance, falls, and/or other features of parkinsonism. If present, the modifier‘with motor features’ should be used (see below).

8)Documented decline. Progressive decline in function and/or a progression insymptoms and/or signs, based upon repeated formal testing, clinician examination, orother formal measurement (for example, informant questionnaire) for a minimum of1 year.

9)Delayed onset. Delayed onset of clinical features after significant headimpact exposure, usually at least 2 years and in many cases several years after theperiod of maximal exposure. It should be noted, however, that individual cases may beginto develop the clinical features of TES during their period of head impact exposure (forexample, while still actively involved in a collision sport), especially olderindividuals or those who have been engaged in the high-exposure activity for many years.It may also be difficult to differentiate the clinical presentation of prolonged orpersistent post-concussion syndrome (pPCS) from that of TES. Therefore, there could becases for whom there is overlap of resolving pPCS and the initial features of TES, thusmasking any delayed onset of TES.

Traumatic encephalopathy syndrome diagnostic subtypes}

1) TES behavioral/mood variant (TES-BMv)

a) Behavioral or mood core features (or both) without cognitive core features.

2) TES cognitive variant (TES-COGv)

a) Cognitive core features without behavioral or mood core features (or both).

3) TES mixed variant (TES-MIXv)

a) Both cognitive core features and behavioral or mood core features (or both).

4) TES dementia (TES-D)

a) Progressive course of cognitive core features with or without behavioral or mood corefeatures (or both).

b) Evidence of ‘functional impairment’, defined as cognitive impairment (orcognitive impairment exacerbated by behavioral or mood impairment or both) that issevere enough to interfere with the ability to function independently at work or inusual activities, including hobbies, and instrumental activities of daily living. Thedetermination of functional impairment is based on clinician’s judgment, takinginto account informant reports as well as consideration of individual differences withregard to level of expected responsibility and daily challenges.

c) If the clinical presentation is not distinguishable from that of dementia due to ADor another neurodegenerative disease (for example, frontotemporal dementia), bothdiagnoses may be given, either with one being ‘primary’ and the other being‘secondary’ or with the term ‘mixed’ used if neither is presumedprimary.

‘With motor features’ modifier

For each TES subtype, the modifier ‘with motor features’ should be added ifthe individual demonstrates dysarthria, dysgraphia, bradykinesia, tremor, rigidity, gaitdisturbance, falls, and/or other features of parkinsonism.

Clinical course

For each TES subtype, one of the following additional modifiers should be selected:‘stable course’, to be used when the history or objective testing (or both)indicates that there has been little if any change in symptoms, signs, or othermeasures; ‘progressive course’, to be used when there is a clear indicationof progressive worsening of clinical features for at least a 2-year period; and‘unknown/inconsistent course’, to be used when either there is too littleinformation available about the clinical course or the course has been inconsistent,with periods of stability, worsening, and/or improvement. By definition, TES dementiahas a progressive course and does not require this modifier.

‘Possible CTE’ and ‘probable CTE’

As stated above, CTE is a neuropathological diagnosis, whereas TES is a clinicaldiagnosis. As with other neurodegenerative diseases, such as AD, it is not possible atthis time to diagnose the underlying disease with certainty during life. However, againas with other neurodegenerative diseases and in keeping with the diagnostic criteria forCTE proposed by Jordan [35],[40],[41], we propose provisional diagnostic classifications of ‘probableCTE’, ‘possible CTE’, and ‘unlikely CTE’. Because thescientific study of the clinical presentation of CTE is only in its infancy, it is notyet possible to create meaningful diagnostic criteria for ‘probable CTE’based solely on clinical features and course, such as those employed for the NationalInstitute on Aging-Alzheimer’s Association (NIA-AA) AD diagnostic criteria forprobable AD dementia [60], a condition that has been carefully studied for many decades. Rather, wepropose, as a starting point, several potentialin vivo biomarkers for CTE thatcan be used to support a provisional diagnosis of ‘probable CTE’. Thisdiagnosis would be analogous to the NIA-AA diagnosis of probable AD dementia withevidence of the AD pathophysiological process [60]. However, because of the early stage of research into potential CTEbiomarkers, we refrain from using this type of nomenclature. The following list ofpotential biomarkers for underlying CTE is meant only as a guideline at this early pointin CTE diagnostic research. Many of these biomarkers are the focus of current researchbut have not yet been formally validated. Future biomarker validation studies willlikely add to or delete (or both) items on this list. Moreover, we do not in any wayrecommend that the specific tests used for these potential biomarkers be conducted forclinical purposes at this time.

Potential biomarkers for the diagnosis of probable chronic traumaticencephalopathy

1)Cavum septum pellucidum. Report of cavum septum pellucidum, cavum vergae, orfenestrations based on neuroimaging study.

2)Normal beta amyloid cerebrospinal fluid (CSF) levels. CSF beta amyloidlevels in the normal range for age and not diminished as would be suggestive of AD.

3)Elevated CSF p-tau/tau ratio. CSF p-tau/total tau ratio above the normalrange for age.

4)Negative amyloid imaging. PET amyloid imaging (for example, florbetapir andflutemetamol) in the normal range, not suggestive of AD.

5)Positive tau imaging. PET paired helical filament tau imaging suggestive ofabnormal tau deposition. It should be noted that this remains an experimental procedureand requires additional validation prior to its use as a research tool for diagnosticpurposes.

6)Cortical thinning. Based on magnetic resonance imaging (MRI) measurement,evidence of abnormal cortical thinning indicative of neurodegeneration.

7)Cortical atrophy. Based on MRI or computed tomography, generalized corticalatrophy beyond what is expected for age, and, in particular, frontal, thalamic,hippocampal, and/or amygdalar atrophy.

Chronic traumatic encephalopathy classification

1) Probable CTE. Meets classification for any TES subtype, progressive course; does notmeet diagnostic criteria for another disorder more consistently than TES; and has aminimum of one positive potential biomarker for CTE.

2) Possible CTE. Meets classification for any TES subtype, progressive course, and (1)has not undergone any potential biomarker testing, (2) has had negative results on oneor more biomarkers with the exception of PET tau imaging (that is, if a negative PET tauimaging finding, the current classification would be ‘unlikely CTE’), or (3)meets the diagnostic criteria for another disorder that, on its own, could account forthe clinical presentation.

3) Unlikely CTE. Does not meet TES diagnostic criteria or has had a negative PET tauimaging scan or both.

Case A A 45-year-old married man with a history of playing multiple contact sports,including soccer (ages 5 to 13), hockey (ages 7 to 12), and football (ages 9 to 22)presented to his primary care physician. He played college football at a Division 1university and was an offensive lineman. He had no reported or formally diagnosedconcussions, although when provided with a definition of concussion, he stated that helikely had 20 to 30 throughout high school and college. Since graduating from college,he has worked as an auditor for state government. His work performance evaluations hadbeen routinely positive, although for the past two years they have been marred byreports of ‘careless errors’, reduced productivity, and one episode ofyelling at his immediate supervisor. His wife of 16 years reports that he has had a5- to 7-year history of worsening behavior, with frequent episodes of having a‘short fuse’ and losing his temper with their two young children. Thoughalways a social drinker, he has had frequent episodes of binge drinking over the past 2to 3 years. She states that his personality has changed from a kind, even-keeled,loving man to an argumentative, explosive, and moody individual. Both he and his wifestate that he was high-functioning, without any cognitive, mood, and behavioral problemsduring the time period between college and about age 35. He recently underwent formalneuropsychological evaluation that demonstrated moderately impaired sustained attention,mildly impaired delayed recall on a word list, and moderately impaired executivefunctioning as measured by a card-sorting test. All other areas of functioning werewithin the normal range. A self-report measure of syndromal depression indicated mild tomoderate severity. Other than the recent work-performance evaluations, there were noother reports of significant functional decline. The result of a recent brain MRI wasunremarkable other than some mild, scattered white matter abnormalities. Other medicalhistory, laboratory findings, and neurological examination were unremarkable. Diagnosis:TES-MIXv, progressive course; possible CTE.

Case B A 31-year-old single female Army veteran was referred to the VA Medical CenterBehavioral Health Clinic for a 14-month history of suicidal thoughts, agitation, andaggressive behavior. She had reached the rank of staff sergeant and was a logisticsspecialist. She was honorably discharged 1 year ago, began working in herfamily’s grocery store, but had to stop working 6 months ago because of herneuropsychiatric symptoms. She had two deployments to Afghanistan and denied beingdirectly involved in combat. However, she reported that 20 months prior to herdischarge, she was thrown off a truck when it struck an improvised explosive device. Shewas told she landed on her head and lost consciousness for 2 to 3 minutes. Uponregaining consciousness, she reported ‘seeing stars’ and had a headache thatlasted 3 to 4 days. She denied these symptoms to the medic when questioned andremained on active duty. About 3 months later, a heavy box fell on her head,throwing her to the floor. She denied loss of consciousness but was nauseated and hadbalance difficulties for several hours. She complained of being in a fog and irritablefor 2 days following the accident. Her tour of duty ended 2 weeks later andshe returned home. Other than those two injuries, she denied any TBIs or concussions.These symptoms completely cleared, and she described her functioning, including hermood, as ‘completely fine’ between that time and about 14 months ago.Prior to enlisting, she was an avid ice hockey player, having played since the age of 5,and was the captain of her high school team. Her medical and psychiatric histories wereunremarkable, and laboratory results of tests ordered by her primary care physician werenormal. At the current evaluation, a mental status examination was conducted and theresults were generally within normal limits. She denied having any cognitive complaints.A psychiatric interview revealed significant overall distress, with suicidal ideationwithout any active plan. Her primary complaints included poor sleep, sadness, anxiety,agitation, and being overly aroused by loud noises. She denied having any flashbacks ornight terrors. A sibling was interviewed and corroborated the description and historybut added that for the past year she had been verbally aggressive and explosive,frequently yelling at family members for no apparent reason, and that these episodesseemed to turn off and on without any warning. The sibling stated that these abnormalbehaviors have been somewhat consistent over the past year. A PTSD specialist examinedthe patient, reported that she would not meet criteria for PTSD, and questioned whetherthe symptoms were residual from her TBIs in Afghanistan. The result of a brain MRI wasunremarkable. Diagnosis: TES-BMv, stable course; possible CTE.

Case C A 59-year-old man presented to his primary care physician with complaints ofprogressive memory and concentration problems. Prior to going to college, the patiententered the Army, where he boxed competitively for 4 years. He did not experienceany combat. He was an avid rugby player in college and continued playing in formalcompetitive clubs until the age of 54, when he stopped because of a cervical diskinjury. He received an MBA and had been a successful business consultant. He wasdivorced at the age of 45 and lived alone. He reported one concussion at the age of 30,when he briefly lost consciousness during a rugby game, although he stated he got his‘bell rung’ countless times in boxing and rugby. He reported to his primarycare physician that he had been having difficulty remembering details of conversationsand meetings at work and that this was beginning to interfere with his productivity. Hismedical history was significant for the cervical disk injury and for migraine headachesfor many years. He was referred to a local academic medical center memory clinic, wherea formal neuropsychological evaluation demonstrated moderately impaired performance on aword list recall task, compared with age and education norms, as well as severelyimpaired fine motor dexterity. All other areas were intact, although his performance ona measure of psychomotor speed and response set maintenance was slightly below expectedlevels given his history. A neurological examination revealed mild bilateral restingtremor and mild upper extremity rigidity. An MRI scan was read as normal, and alllaboratory findings were within normal limits. As part of a clinical research study, hewas given two PETs: one with a new tau radiotracer and another with an amyloid tracer.Results indicated no meaningful amyloid uptake, although his tau scan was abnormal withscattered increased tracer uptake in the dorsolateral frontal cortex and the medialtemporal lobes. Diagnosis: TES-COGv, with motor features, progressive course; probableCTE.

Case D A 69-year-old former National Football League (NFL) football player was seen inconsultation following a 10-year progressive decline. He had seen several physicians andhad been given multiple diagnoses, including frontotemporal dementia and dementia due toAD. He had played professional football for 9 years as a linebacker. He beganplaying football in high school and played for a Division 1 college for 4 years,playing both as a linebacker and as an offensive lineman. Following retirement from theNFL, he had a successful career in commercial real estate until he was forced to retireat the age of 62 because of ‘poor decision-making and judgment’. His wife of25 years stated that, in retrospect, he was demonstrating poor memory and judgmentfor about 3 years prior to his retirement and that these problems had progressivelyworsened through the years. She stated that he also began having significantdifficulties with multi-tasking and ‘numbers’ at age 61 and was havingdifficulty with household finances and hobbies. After retirement, he became increasinglywithdrawn and refused to socialize. In contrast to his previous jovial and easy-goingmanner, he became verbally aggressive toward his wife and children, ‘blowing upover small things’. On two occasions, he became physically aggressive toward hiswife, requiring her to call the police. He never demonstrated any disinhibited orsocially inappropriate behavior, nor was there any report of hallucinations or movementdisturbance. In the past 2 years, his functioning has worsened; he now has no‘short-term memory’, watches television all day long, and has an erraticsleep cycle. He is functionally impaired in all instrumental activities of daily livingas well as in some basic activities of daily living. His medical history is significantfor a myocardial infarction at age 54, hypertension, severe arthritis, and multiplelumbar disk surgeries. There is no family history of dementia. Upon examination, he wasdisoriented to time and place, was perseverative, and could not recall recent currentevents. He exhibited some frontal release signs, although the result of his motorexamination was otherwise normal. His Mini-Mental Status Exam score was 9, and hisClinical Dementia Rating was 2.0. A neuropsychological evaluation was conducted anddemonstrated severe episodic memory impairment as well as profoundly impairedperformance on most tests of executive functioning. In contrast, attentional capacitywas within normal limits and language was relatively intact. A brain MRI revealedsignificant global atrophy with marked hippocampal atrophy as well as a cavum septumpellucidum. An amyloid PET scan demonstrated only minimal uptake, not commensurate withthe degree of dementia. Diagnosis: TES-D; probable CTE.

Case E A 31-year-old male stockbroker saw his primary care physician because of an18-month history of recurrent headaches, irritability, agitation, and a worsening‘short fuse’. He had been taking oxycodone (left over from previous oralsurgery) for his headache pain. He was referred to a neurologist, who specialized inheadache and who diagnosed him with tension headache. However, when asked if he had everhad headaches previously, the patient reported that he frequently had them as a teenagerafter his varsity high school football games and when he played rugby for 2 yearsin college. Because of this history of prior exposure to repetitive head impacts andpossible symptomatic concussions, the neurologist referred him to a psychiatristcolleague to evaluate him for possible depression and suicidality, based on theneurologist’s belief that the patient might have CTE; he had recently attended atalk on sports injuries. The consulting psychiatrist interviewed the patient, whoacknowledged that he had frequent suicidal ideation following the breakup of hismarriage about 1 year earlier but that these thoughts had now diminished. Althoughthe patient formally met criteria for TES-BMv, the psychiatrist felt that the headachesymptoms, suicidality, short fuse, and irritability were likely associated with thedivorce. The patient was prescribed citalopram as well as regular therapeutic massagefor his tension headache and was seen in 3 months, at which time he reportedsubstantial improvement of his mood and behavioral symptoms and a complete resolution ofhis headaches. Diagnosis: adjustment disorder, persistent with mixed anxiety anddepressed mood; unlikely CTE.

Case F An 81-year-old widowed man enrolled in a research study examining the long-termconsequences of TBI. He reported having sustained a moderate TBI in a motor vehicleaccident at the age of 46 with loss of consciousness for approximately 1 hour. Hewas hospitalized for 3 days because of confusion and memory difficulties thatmostly resolved prior to discharge. He was unable to return to work as a high schoolphysical education teacher and coach for several weeks because of continued cognitivedifficulties, headache, and balance problems. He reported that, once he returned towork, he ‘didn’t feel normal’ for several months. He continued workinguntil retirement at age 60. He played high school and college football and reportedhaving had his ‘bell rung’ ‘all the time’. According to hisadult son (with whom he lived), he was 72 when he began having memory problems thatgradually progressed over the course of 5 to 6 years. In the past few years, thememory problems worsened significantly, such that he could not recall events thatoccurred more than an hour earlier. In addition, he had worsening problems withjudgment, decision-making, multi-tasking, and word-finding. He no longer drove and wasdependent in most areas of instrumental activities of daily living. He lacked interestin all activities and appears ‘depressed’ according to his son. His medicalhistory was significant for prostate cancer, controlled hypertension, arthritis, andglaucoma. Two brothers died in their 80s with ‘dementia’. Neuropsychologicaltesting revealed significant impairments in episodic memory, confrontation naming,psychomotor speed, and many aspects of executive functioning. Research-based MRIrevealed frontal and temporal atrophy and a pronounced cavum septum pellucidum;diffusion tensor imaging and tractography demonstrated significant reductions in corpuscallosum fiber bundles. PET amyloid imaging showed elevated uptake consistent with AD.Diagnosis: dementia due to AD pathophysiological process and TES-D, mixed; possibleCTE.

The current proposed research diagnostic criteria for TES are meant to be a startingpoint that should be modified and updated as new research findings in the field becomeavailable and as future research using these criteria are published. These proposedcriteria are not meant to be used for a clinical diagnosis or as evidence of anunderlying disease. Rather, they should be viewed as research criteria that could beemployed in studies of the underlying causes, risk factors, differential diagnosis,prevention, and treatment of TES. Future studies comparing these proposed diagnosticcategories with post-mortem neuropathological diagnoses, as well as with appropriatein vivo biomarkers for CTE and other conditions, will help lead to thetransition from ‘research’ criteria to ‘clinical’ criteria. Italso would be critical for these proposed criteria to undergo a formal expert consensusapproval process, such as that used for the NIA-AA Diagnostic Guidelines forAlzheimer’s Disease [60].

One important factor that must be addressed in future iterations of these criteria isthat of base rates. That is, the population prevalence of most of the core clinicalfeatures and many of the supplemental features of TES presented below is relativelyhigh. Therefore, it is possible to meet criteria for TES and yet have an idiopathicdisorder or a situationally based condition that is unrelated to the earlier history ofhead impact exposure. The inclusion of supportive features is meant to reduce this lackof specificity to a degree, but, at this time, we acknowledge that these criteria willlikely result in very high sensitivity at the expense of specificity. With theutilization of future research findings and subsequent criteria revisions, it is likelythat the specificity will increase. An important additional issue regarding the use ofthese criteria involves the impact of litigation or disability determination (or both)on the validity of symptom reporting and neuropsychological test performance. It istherefore recommended that this issue be taken into account when interpreting theindividual’s self-reported functioning and test performance and that formalsymptom validity checking be conducted as part of any formal evaluation. Until futureresearch yields accurate biomarkers and allows clarification and modification of theproposed criteria, the decision as to whether an individual meets the TES diagnosticcriteria and associated ‘probable CTE’ diagnostic criteria should be left upto the individual researcher, clinician, or, preferably, a multidisciplinary diagnosticadjudication process.

Conclusions

The long-term consequences of repetitive head impacts have been known since thebeginning of the 20th century. Although the clinical presentation of CTE is varied andnon-specific, there are adequate reports to date to suggest that there may be twoclinical subtypes: one subtype involving primarily behavioral or mood features(including explosivity or violence) or both, and the other involving cognitive deficits(including impairments in episodic memory, executive functioning, and attention). Manyindividuals progress to dementia, with impaired functional independence, and someindividuals develop motor impairments (including parkinsonism, ataxia, and dysarthria).We propose research diagnostic criteria for TES that we hope will facilitate researchinto this area. There are expected limitations to the development of diagnostic criteriabased primarily on a relatively small number of case reports. The goal of proposingthese criteria at this time is to facilitate research in this nascent area of study. Itis expected that these criteria will undergo modification and revision as new researchfindings become available, additional biomarkers are validated, and future researchusing these criteria are published.

Abbreviations

AD: Alzheimer’s disease

CSF: Cerebrospinal fluid

CTE: Chronic traumatic encephalopathy

MRI: Magnetic resonance imaging

NFL: National Football League

NIA-AA: National Institute on Aging-Alzheimer’s Association

PET: Positron emission tomography

pPCS: Persistent post-concussion syndrome

p-tau: Phosphorylated tau

PTSD: Post-traumatic stress disorder

TBI: Traumatic brain injury

TE: Traumatic encephalopathy

TES: Traumatic encephalopathy syndrome

TES-BMv: Traumatic encephalopathy syndrome behavioral/mood variant

TES-COGv: Traumatic encephalopathy syndrome cognitive variant

TES-D: traumatic encephalopathy syndrome dementia

TES-MIXv: Traumatic encephalopathy syndrome mixed variant

Competing interests

AEB receives royalties for published books from Elsevier (Amsterdam, The Netherlands)and Wiley-Blackwell (Hoboken, NJ, USA). RCC receives compensation from the NFL as senioradvisor to the Head Neck and Spine Committee, from the National Operating Committee onSafety of Athletic Equipment as chairman of the Scientific Advisory Committee, and fromSports Legacy Institute as co-founder and medical director for some talks given. Hereceives royalties from Houghton Mifflin Harcourt (Boston, MA, USA) and compensationfrom expert legal opinion. RAS has received research funding from the NFL and the NFLPlayers Association. He is a member of the Mackey-White Traumatic Brain Injury Committeeof the NFL Players Association. He is a paid consultant to Athena Diagnostics(Marlborough, MA, USA) and has been a consultant to Janssen Alzheimer Immunotherapy(South San Francisco, CA, USA) and Ely Lilly and Company (Indianapolis, IN, USA). Hereceives royalties for published neuropsychological tests from Psychological AssessmentResources, Inc. (Lutz, FL, USA) as well as compensation from expert legal opinion. Theother authors declare that they have no competing interests.

Contributor Information

Philip H Montenigro, Email: valmont@bu.edu.

Christine M Baugh, Email: cbaugh@bu.edu.

Daniel H Daneshvar, Email: ddanesh@bu.edu.

Jesse Mez, Email: jessemez@bu.edu.

Andrew E Budson, Email: abudson@bu.edu.

Rhoda Au, Email: rhodaau@bu.edu.

Douglas I Katz, Email: dkatz@bu.edu.

Robert C Cantu, Email: rcantu@emersonhosp.org.

Robert A Stern, Email: bobstern@bu.edu.

Acknowledgments

The authors wish to thank the following individuals for their contributions to thisarticle: Nathan Fritts, Michael McClean, David Riley, Clifford Robbins, DanielSeichepine, Julie Stamm, Yorghos Tripodis, and Florina Tynyanova. The preparation andwriting of this article were supported, in part, through the following: NationalInstitutes of Health (NIH) grants R01 NS078337 and P30 AG13846 and US Department ofDefense grant W81XWH-13-2-0064. These funding agencies played no role in the writingof the manuscript or the decision to submit it. DHD and JM receive funding throughNIH grant U01NS086659. AEB receives funding through NIH grant P30 AG13846 and the USDepartment of Veterans Affairs. RA receives funding through NIH grants AG016495-11,NS17950, AG08122,AG029451,AG033040,AG033193,HL096917, and DARPA-BAA-11-65. RASreceives funding through NIH grants R01 NS078337, R01 MH080295, R01 CA129769, U01NS086659, and P30 AG13846 and US Department of Defense grant W81XWH-13-2-0064. PHM,CMB, DIK, and RCC receive no external funding.

References