Neuropsychological and Psychiatric Comorbidities of Mild Traumatic Brain Injury

C H A P T E R

8 Neuropsychological and Psychiatric Comorbidities of Mild Traumatic Brain Injury Jeffrey P. Staab, MD, MS and Matthew R. Powell, PhD, LP Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States

INTRODUCTION In this chapter, we will review the neuropsychological and psychiatric sequelae of mild traumatic brain injury (mTBI). We will confine our discussion to mTBI because it is by far the most common severity of brain injury, constituting at least 80% of identifiable cases,1 and because the association of neuropsychological and psychiatric problems with mTBI is far more controversial than similar sequelae of more severe brain injuries. One area of controversy is the definition and extent of mTBI. In this chapter, we will use the definition of mTBI promulgated by the US Department of Veterans Affairs and Department of Defense (VA/DoD) in a comprehensive guideline for diagnosis and management of military service members and veterans with histories of brain injury.2 The events that may cause mTBIs include blunt force blows to the head (i.e., head striking an object or an object striking the head), whiplash type of injuries (i.e., abrupt acceleration/deceleration movement without a direct blow to the head), and direct exposure to other external forces that do not cause objects to penetrate the skull (e.g., blasts or explosions). Penetrating brain injuries are by definition moderate or severe because they cause gross structural damage to the brain. Following any of these events, mTBI is defined by any alteration in mental state or focal neurological deficits with loss of consciousness of 30 minutes or less, altered consciousness of 24 hours or less, posttraumatic amnesia of 24 hours or less, Glasgow Coma Scale score of 13 15 within the first 24 hours, and absence of structural lesions on clinical neuroimaging.2 The VA/DoD definition is the most common one in current use in clinical and research settings. The Mayo Classification System for TBI Severity subdivides the VA/DoD mTBI group into two classes: Mild (probable) TBI which includes individuals with loss of consciousness lasting less than 30 minutes, posttraumatic amnesia lasting less

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than 24 hours, or nonpenetrating injury to the skull with intact dura, and Symptomatic (possible) TBI which includes those with no loss or consciousness, posttraumatic amnesia, or injury to the skull, but at least one symptom of feeling dazed or confused, headache, nausea, dizziness, blurred vision, or transient focal neurologic symptoms after exposure to a brain injury event.3 This subdivision is meant to separate patients who have symptoms and signs thought to be more specific for injuries to the brain, itself, from patients with symptoms and signs that might arise from other causes following one of the brain injury events listed earlier.4 A second area of controversy and a much more difficult problem is the diagnostic classification of patients with persistent post-mTBI symptoms. There are no established biomarkers for mTBI. As a result, patients, family members, and friends; healthcare professionals of many specialties and disciplines; lawyers, judges, and juries; and representatives of healthcare and disability systems often battle across the divide between neurological (real brain injury) and psychological (not real brain injury) causes of symptoms. This struggle is rooted in mind-body dualism and is tainted by the dichotomous hierarchy of the 20th century that reified “objective” diagnostic tests despite the fact that they have limited power to predict the daily level of functioning or quality of life of individual patients with any chronic medical condition. In all major clinical specialties, long-term outcomes have a very human variability that is not captured well by blood work, imaging, or standardized diagnostic tests. These statements are not meant to denigrate the everexpanding range of biomarkers of human physiology in health and disease that have been developed over the last several decades, but rather to put them in proper perspective. They each measure one aspect of human disease. Emerging biomarkers of mTBI will do the same. They will not rid us of the difficult problem of trying to understand why one person fares well after the same type of brain injury event that fells another quite badly. At the same time, it is just as important to realize that the answer to this dilemma does not lie exclusively within the psychological realm, though the logic of the dichotomous hierarchy would place it there. Psychological assessments, like their structural counterparts, have limitations that fall well short of predicting individual outcomes. Thus, the care of patients who have sustained TBIs will continue to be a combination of structural, functional, and psychological assessments and treatment interventions tailored as best possible to the needs of individuals who are living in their own personal contexts with the consequences of their injuries.

ACUTE NEUROCOGNITIVE EFFECTS OF MILD TRAUMATIC BRAIN INJURY For an excellent discussion of the complex pathophysiological changes that occur within the brain at the time of injury and during the early postacute (subacute) recovery period, please see the review by Giza and Hovda.5 For 80% 90% patients with histories of mTBI, acute mental status changes and focal neurological symptoms resolve relatively quickly.6 Cognitive symptoms recover gradually over a period of 1 2 weeks on average, with minor residua lasting no more than 3 months for most individuals.7,8 During recovery, patients often experience slowed cognition, attention problems, and memory difficulties.

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Functional neuroimaging research in humans and physiologic studies in animals suggest that brain recovery follows a similar time course,5 but there is some suggestion that full brain recovery may lag behind symptom resolution. If healing of the brain lags symptom recovery, then there would be obvious but currently unknowable implications for clinical management, particularly for return to activities with the potential for reinjury (e.g., athletics, military service, physically demanding occupations). Investigations into the timeframe of brain recovery are ongoing.9,10

POSTACUTE NEUROCOGNITIVE RECOVERY OF MILD TRAUMATIC BRAIN INJURY The sport concussion research paradigm that sprang forth in the mid-1980s was a turning point in understanding subacute and later postacute neuropsychological recovery following mTBI.11 Investigators were able to test athletes involved in contact sports at predetermined baselines (e.g., the start of a season) and then compare those players who suffered mTBIs against matched controls on variables of interest. Although there are some limitations to the generalizability of this research (i.e., most athletes are younger and healthier than the general population), this methodology permitted prospective and well controlled investigations of mTBI from the moment of injury until maximal recovery while tracking symptomatic, cognitive, and neurophysiological measures.12 These methods were applied more recently to United States and allied miltary service members deployed to the combat zones of Iraq and Afghanistan.13,14 Studies of military cohorts also offered well matched comparisons between individuals who suffered mTBIs and those who did not, but these investigations also have limitations in applying their results to the general populace. Combat veterans, like athletes, are younger and healthier than the civilian population at large, men still outnumber women in military units, and high force explosives may produce different injuries than lower impact blunt force trauma (although combat veterans also are at increased risk for accidents, assaults, and falls that mimic the most common brain injuries suffered by civilians1,2). There have been a number of meta-analyses of neuropsychological data obtained from these lines of inquiry. In most prospective, well controlled group studies, postacute neuropsychological effects of mTBI appear to resolve by 3 months,12,15 17 though some experts have argued that over-reliance on group data in meta-analyses obscures persisting effects for individuals or subgroups of patients.18 For example, patients recruited from clinicbased samples or from medicolegal cohorts may have longer recovery periods.19 It is possible that medical comorbidities (e.g., coexisting orthopedic injuries), more severe postmTBI symptoms that prompt patients to seek medical care, and social factors such as involvement in litigation or applications for disability may prolong their cognitive recovery.20 A small number of patients report new or worsening cognitive symptoms that develop weeks, months or even years post-mTBI. This subset of patients often has preexisting physical or psychiatric illnesses or problems such as depression, anxiety, or chronic pain after injury. They also tend to have complicated psychosocial circumstances such as limited support or involvement in legal or disability proceedings.19,21 23 McCrea8 conceptualized the postacute recovery period following mTBI within a neurobiopsychsocial

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framework. He emphasized that interactions among neurobiological, emotional, cognitive, occupational, and legal factors (i.e., structural, functional, and psychological variables and patients’ context) all affect recovery and outcome.

PERSISTING NEUROCOGNITIVE AND PSYCHIATRIC EFFECTS OF MILD TRAUMATIC BRAIN INJURY Approximately 10% 20% of individuals experience post-mTBI symptoms that persist beyond the expected window of recovery of 3 months, even if they have had an opportunity for appropriate treatment and rehabilitative interventions.1,2,6 8 This condition is called postconcussion syndrome (PCS) (aka postconcussive or postconcussional syndrome). A validated set of diagnostic criteria for PCS does not yet exist, but it is commonly characterized as in the International Classification of Diseases, 10th edition24 or the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)25 by a constellation of cognitive, somatic, vegetative, behavioral, and emotional symptoms that develop following a mTBI. The most common symptoms of PCS are listed in the first column of Table 8.1. TABLE 8.1 Symptoms of PCS and Common Post-mTBI Psychiatric Disorders

PTSD

Major Depressive Episode

Depressed mood

X

X

Irritability

X

X

Apathy

X

X

Anxiety

X

X

X

Reduced tolerance for stress or emotional excitement

X

X

x

X

X

X

X

X

Memory problems

X

X

Loss of concentration

X

X

PCS

Generalized Anxiety Disorder/ Panic Disorder

EMOTIONAL AND BEHAVIORAL SYMPTOMS

X

VEGETATIVE PROBLEMS Fatigue Insomnia COGNITIVE COMPLAINTS

X

SOMATIC SYMPTOMS Dizziness

X

Headache

x

X, Symptom is explicitly listed in the DSM-5 diagnostic criteria for these conditions26; x, symptom is described as commonly occurring with these conditions.26

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Of note, the DSM-5 does not define PCS. It only contains diagnostic criteria for major and minor cognitive disorders following TBI.26 PCS should not be diagnosed until an individual experiences symptoms for 3 months or more.25 Patients with residual deficits following moderate to severe brain injury should not be diagnosed with PCS. PCS appears to be a heterogenous condition; some individuals report very circumscribed clinical symptoms (i.e., only headache), whereas others report symptoms that span the full range listed in Table 8.1 and more (e.g., chronic tinnitus, photophobia, or hyperacusis). Despite controversies about the nature and extent of PCS, there is evidence from animal studies that mild brain injury can cause cognitive deficits and pathological changes in the brain.27 For example, rats with mild brain injury were found to have decreased synaptic density in specific hippocampal regions relative to controls. These changes were subtler than the lesions found on gross inspection in mice with severe brain injuries, yet the mice with mild injuries performed just as poorly as their more severely injured counterparts on certain experimental memory tasks.27 In humans, there is not a distinct neuropsychological profile that is universally associated with PCS, highlighting the fact that cognitive tests cannot be used as a diagnostic standard for PCS. Coexisting problems such as depression, medication side-effects, and other confounds, explain an equal amount (or more) of the variance in cognitive performance in patients during the postconcussive period when compared against acute concussion, making it difficult to interpret the cause of abnormal test results in those who present for examination temporally remote from their brain injury events.7 Nevertheless, neuropsychometric tests can be useful to quantify the state of an individual’s neurocognitive functioning at a given point during recovery, as long as appropriate confounds are carefully considered during the interpretation of the results. The most common cognitive symptoms reported by patients beyond 3 months after mTBI are attention problems, slowed information processing speed,28 and reduced memory functioning.28,29 It has been hypothesized that mTBI may be associated with persisting cognitive symptoms because of underlying microscopic neuropathologic abnormalities, particularly diffuse axonal injury.30 Mild brain injury stresses frontal-subcortical networks and decreases axonal integrity in the acute phase of injury, which is thought to correlate with persisting cognitive symptoms.5 Research using functional magnetic resonance imaging demonstrated that disruption of right hemisphere attentional networks correlated with cognitive symptom reported by athletes in the acute period following mTBI, but not the postacute period.31 Axonal injury assessed via serum biomarkers drawn at time of injury was associated with subjective cognitive complaints at 6 months postinjury.32 Initial and subsequent analysis of biomarkers of axonal injury in boxers failed to correlate with cognitive function, but was associated with slowed reaction time at 2 weeks after concussion.33 This mix of structural and biochemical results presents an intriguing but quite incomplete picture of the neurobiology of PCS. Questions about how long postconcussive cognitive (and other) symptoms may persist due to the direct effects of neurobiological factors and what roles cognitive reserve34 and psychosocial stressors play in the clinical manifestations of PCS remain unanswered. Despite all the technology available today, including advanced neuroimaging, serum markers, and genetic studies, there is still not a compelling, comprehensive neurobiological explanation for PCS. In planning future research, it has been recommended that multiple neuroimaging technologies be combined with

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biomarkers in prospective investigations to better characterize any biological underpinnings to PCS and then examine subgroups of the syndrome.35 To that, we would suggest equal attention to psychosocial variables. Factors other than strutural brain deficits can explain persisting symptoms following mTBI.20 The symptoms of PCS are nonspecific. They may occur in healthy individuals, though usually transiently and not in aggregate. More importantly, they may occur in patients experiencing other sequelae of brain injury events including posttraumatic stress disorder (PTSD), major depressive disorder, anxiety disorders, substance use disorders, and chronic pain.36 39 Persisting complaints have been correlated with female gender, positive premorbid psychiatric history, comorbid depressive symptoms, and posttraumatic anxiety.40 Table 8.1 gives a side by side comparison of the symptoms of PCS, PTSD, major depressive episodes, and anxiety disorders, which illustrates their overlapping nature. This may create difficult diagnostic dilemmas. For example, in a study of 4462 Vietnam veterans, more patients with PTSD, anxiety, or depressive disorders (50% 57%) met DSMIV criteria for PCS than patients with mTBI (32%).41 In disability and forensic settings, data like these have been used to discount diagnoses of PCS for given patients, and sometimes to argue against the construct of PCS, in general. The problem with this line of reasoning is that it uses commonalities to blur distinctions. Even measurable signs such as body temperature are nonspecific as evidenced by the wide differential diagnosis of fever. In situations like the evaluation of fever of unknown origin,42 the diagnostic dilemma cannot be solved by focusing on common elements in an attempt to rule out illnesses, but by identifying distinctive features that allow active conditions to be ruled in. This approach has been applied to PCS. In a study of 213 veterans from Iraq and Afghanistan, Morrisette et al.43 used structural equation modeling to show that nonoverlapping features of PCS mediated the effects of TBI on coexisting PTSD and depression. Table 8.2 lists clinical features that overlap least among PCS and common post-mTBI psychiatric disorders. It is important to interpret Table 8.2 properly. The presence of the listed features suggests the existence of the associated diagnoses (possible rule in), but their absence does not exclude the diagnosis (cannot rule out). For example, a patient with multiple PCS symptoms and recurrent suicidal thoughts after a mTBI does not have PCS alone, but also a coexisting depressive or related disorder that explains his suicidal ideation. In contrast, the absence of suicidal ideation does not preclude a diagnosis of a depressive disorder if all other features are present, even if some overlap with PCS symptoms. Similarly, a patient with all of the major symptoms of PTSD and chronic daily headache and dizziness after a mTBI does not have PTSD alone, but likely a component of PCS, posttraumatic headache, or chronic vestibular syndrome to explain her daily headache and dizziness. Psychological adjustment to injury can influence speed of recovery following mTBI.3,37 Depression affects the experience and reporting of PCS symptoms. Outpatients with a history of mTBI plus depression reported more PCS symptoms than patients without depression or patients with depression but no history of mTBI.44 Coexisting clinical diagnoses of depression, anxiety, and pain disorders as well as self-perceived cognitive disturbances affected disability and work status.45 Psychiatric comorbidity, especially PTSD, increased utilization of psychotherapy services among military veterans with histories of mTBI.46 Misattributing all post-mTBI symptoms to a diagnosis of structural brain injury rather than apportioning them to PTSD, depression, anxiety, or pain when these problem coexist

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TABLE 8.2 Features That May Distinguish PCS From Common Post-mTBI Psychiatric Disorders PCS

PTSD

Major Depressive Generalized Anxiety Episode Disorder/Panic Disorder

Headache (chronic daily headache or frequent migraine headache) Dizziness (often a chronic symptom exacerbated by exercise) Intrusion symptoms related to mTBI (flashbacks, nightmares) Excessive avoidance of reminders of the mTBI Suicidal ideations, plans, or behaviors Excessive feelings of worthlessness Chronic worry about multiple topics (often predates mTBI) Frequent, unexpected panic attacks (unrelated to mTBI)

may lead patients to the erroneous conclusion that their problems are permanent.2 How can one recover from a damaged brain? The resulting decrease in self-efficacy can serve to maintain PCS symptoms.2,37 Patients, like their clinicians, may fall into the trap of the dichotomous hierarchy, spending inordinate time and effort searching for the person or test that will reveal their suspected brain damage, while giving short shrift to properly addressing psychological morbidity. The resultant frustration may exacerbate their symptoms and alienate them from needed medical, and especially psychological care, potentially increasing their disability.

PSYCHIATRIC DISORDERS FOLLOWING MILD TRAUMATIC BRAIN INJURY Epidemiological and clinical studies have used various methods to investigate the psychiatric sequelae of TBI over many years. Unfortunately, most older reports have been small and of modest quality. In 2009, Carlson et al.47 performed a comprehensive review of 1107 references for the VA. The largest and most detailed study that they identified was conducted by the RAND Corporation on approximately 2000 US service members and

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veterans of deployments to Iraq and Afghanistan. That investigation reported a point prevalence of 19.5% for probable TBI, 13.8% for PTSD, and 6.6% for coexisting probable TBI and PTSD. The rate of coexisting probable TBI and PTSD was 2.4 times the rate of a chance cooccurrence indicating that a probable TBI more than doubled the risk of developing PTSD above and beyond other exposures associated with deployment. In a more recent study, Lagarde et al.48 compared the development of PTSD and PCS in 534 civilian accident victims who sustained mTBIs compared to 827 patients with nonhead injuries who were followed prospectively after emergency department evaluations. At 3 months after injury, 8.8% of patients with mTBIs and 2.2% of patients without brain injuries met diagnostic criteria for PTSD, again suggesting that mTBI carries an increased risk of PTSD compared to other exposures (odds ratio, 4.47; 95% CI: 2.38 8.40). In additional findings that stirred doubts about the validity of PCS as a unique construct, Lagarde et al.48 reported that 21.2% of patients with mTBI and 16.3% of the comparison group without head injuries met the DSM-IV diagnosis of PCS with exposure to mTBI carrying no added risk for PCS (odds ratio, 1.13; 95% CI: 0.82 1.55). They further concluded from a correspondence analysis that PCS symptoms acted like PTSD hyperarousal symptoms, which is where the two syndromes have the greatest overlap (i.e., shared symptoms of irritability, concentration problems, and insomnia). However, they found no clustering of other PCS symptoms or unique relationships to mTBI. The incidence and prevalence of major depression also are increased among individuals who have sustained mTBIs. Hoge et al.14 investigated 2525 US Army infantry soldiers 3 4 months after their return from a 1-year deployment to Iraq. In that cohort, 124 soldiers (4.9%) reported injuries with loss of consciousness—that is, mild (probable) TBI in the Mayo classification.3 An additional 260 soldiers (10.3%) reported injuries with altered mental status—that is, Symptomatic (possible) TBI in the Mayo classification.3 Rates of major depression were significantly increased in the former group at 22.9%, but not in the latter group at only 8.4%, which was comparable to the remainder of the study cohort. Studies of civilians have reported a wide range for the prevalence of major depression after TBI, but best estimates suggest an incidence of 18%49 and prevalence of 33% 42% within 1 year after injury.50 A 5-year prospective study of patients with moderate to severe (not mild) TBI illustrated the time course of post-TBI psychiatric morbidity.51 In 161 civilians, three-quarters of those who developed depressive, anxiety, or substance use disorders did so within the first year after injury. This was followed by a natural decline in psychiatric morbidity of about one-quarter per year from the second through fifth years. Depressive and substance use disorders were more likely to persist than anxiety disorders. Other psychiatric consequences of brain injury events are more circumscribed but potentially disruptive problems such as specific phobias. An example is a specific phobia of driving or riding in an automobile after a motor vehicle accident that severely limits a person’s mobility.52 The VA/DoD clinical practice guidelines strongly recommends screening patients with post-mTBI symptoms for psychiatric morbidity including PTSD, depression, substance use disorders, and suicidality.2 That recommendation is well-suited to civilian populations as well and could be extended to include anxiety disorders. To aid in the identification of psychiatric morbidity in patients with histories of mTBI, widely available self-report questionnaires and clinician-rated instruments for PTSD, depression, anxiety disorders, and

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substance use disorders may be used—for example, the 9-item Patient Health Questionnaire (PHQ-9) for depression. Two caveats must be kept in mind. First, there have been no studies that fully tested the validity of these measures in patients with mTBI.47 Second, positive self-report scores or clinician-rated findings do not necessarily mean that the identified traumatic stress, depressive, or anxiety symptoms are secondary to the mTBI. Proper diagnosis would depend on full consideration of premorbid medical and psychiatric history and other potential sequelae of brain injury events—for example, other physical injuries, persistent pain, and family, occupational, financial, and legal consequences.53

LATE NEUROCOGNITIVE OF MILD TRAUMATIC BRAIN INJURY A third major area of controversy is the potential for brain injury to be a risk factor for later development of neurodegenerative disorders. Here we will not cover pugilistic parkinsonism or chronic traumatic encephalopathy (CTE) in detail. For those interested in more information, please see the review of CTE by Iverson et al.54 and refer to the article by Giza and Hovda5 for an evidence-based discussion of potential pathophysiological mechanisms that may link repetitive mTBI to an increased risk of neurodegeneration. Apart from the cases of Muhammed Ali and former National Football League players that have captured headlines,55 the existing body of epidemiological evidence is mixed regarding a potential association between the duration of exposure to subconcussive blows (e.g., years of participation in contact sports) and later life neurodegenerative disorders.56,57 While there is some evidence that a history of mTBI, cumulative effects of repetitive mTBI,5 and more serious levels of brain injury18 may be risk factors for development of neurodegeneration, it is not yet known if exposure to a single mTBI with loss of consciousness or a limited number of incidental mTBIs leads to an acceleration of amyloid deposition and increased risk of Alzheimer’s disease. In one study,58 a self-reported history of brain injury with loss of consciousness was linked to amyloid deposition, but variability in the results suggested that some individuals may have inherent vulnerabilities, whereas others may possess intrinsic protective factors, none of which is well understood. Taken together, these incomplete and inconsistent results illustrate the urgent need for more definitive research and serve as a reminder that caution is still warranted before drawing any firm conclusions for individual patients between their histories of mTBI and risk of neurodegenerative disorders.54

TREATMENT OF NEUROPSYCHOLOGICAL AND PSYCHIATRIC SYMPTOMS FOLLOWING MILD TRAUMATIC BRAIN INJURY Treatment of patients with histories of mTBI depends on the length of time it has been since the brain injury event that prompted their symptoms. Within the first few weeks after injury, it is best to separate incident symptoms (i.e., those that developed de novo after the brain injury event) from preexisting problems that may have been exacerbated by injury. For incident symptoms, the first step is to set reasonable expectations for recovery.

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Most patients will improve substantially within the first 2 weeks and at least 80% will recover within the first 3 months after their brain injury events. During this time, the recovery environment is important.59 Patients should be encouraged to set regular schedules to ensure adequate sleep and nutrition. They also should be supported in maintaining activities of daily living, work, and recreation, though these activities may have to be paced with breaks during the recovery period. Activities inside and outside the home that risk reinjury are best avoided until symptoms and signs of injury have resolved. There is a great deal of research underway on test procedures to guide return to play, work, and duty for individuals involved in high risk activities (e.g., athletics, physical labor, military service), but these investigations have not yet coalesced around specific metrics. For more information on these topics, please see the review by Cancelliere et al.,60 guidelines from the US Centers for Disease Control and Prevention (https://www.cdc.gov/ headsup/providers/return_to_activities.html), and patient education information from the Brain Injury Association of America (https://www.biausa.org/brain-injury/about-braininjury/concussion/return-to-play). For patients who have preexisting illnesses (e.g., mood, anxiety, traumatic stress, substance use, or cogntive disorders) that were exacerbated by the brain injury event, the first step is to reassess the efficacy of the preexisting treatment plan. If the increase in symptoms is mild, then the conservative measures just described may be enough to restore adequate control. If the exacerbation of preexisting problems is more than mild, then the brain injury event may have exposed vulnerabilites in treatment. In the latter situation, it may be necessary to reexam the efficacy of pharmacotherapy or provide added sessions of psychotherapy. For post-mTBI cognitive, emotional, or behavioral symptoms that remain problematic after a few weeks (B30 days), further evaluation is indicated.2 There is no global intervention for emerging PCS symptoms or developing psychiatric comorbidity. Rather, treatment is directed at specific symptom clusters (e.g., cognitive complaints) or identifiable disorders (e.g., PTSD, major depressive, anxiety, or substance use disorders). For cognitive symptoms, formal neuropsychological assessment may be useful to ascertain functional limitations and identify targets for treatment.2 A course of therapist-directed cognitive rehabilitation may be indicated and is the treatment option with the best supporting evidence.61,62 A variety of medications have been used off-label over the years in an effort to promote recovery from neurocognitive symptoms following brain injury. Examples include psychostimulants (methylphenidate and amphetamines) and nonamphetamine stimulants (modafanil) for attention and concentration problems and fatigue, memory preserving medications (primarily donepezil and memantine) and dietary supplements (gingko biloba) for memory complaints, and antidepressants (selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) to promote brain recovery across multiple domains. There are no data from large scale randomized controlled trials to support the efficacy of these pharmaceuticals. Available evidence has been obtained from small samples of patients with TBI severity ranging from mild to severe who were treated during acute, postacute, and chronic periods after injury. As a result, the VA/DoD practice guidelines,2 reinforced at a consensus conference in 2017,63 recommend against offering medications or supplements to treat neurocognitive symptoms in patients with histories of mTBI. In contrast, Talsky et al.64 prepared a succinct summary of medication

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options and Wortzel and Arciniegas65 offered an overly optimistic review of pharmacologic treatment choices. For post-mTBI psychiatric morbidity (i.e., major mood, anxiety, traumatic stress, and substance use disorders) the VA/DoD guideline2 recommends following standards of care for those disorders as established for patients without brain injuries. The VA consensus conference in 201763 updated this recommendation and cited emerging evidence that cognitive behavioral therapy is just as effective for PTSD in patients with TBI as it is in patients without TBI and that it also improves depressive symptoms, insomnia, general PCS symptom burden, and psychosocial functioning.63,66,67 In contrast, there have not been adequate clinical trials that compared the relative efficacy of medications indicated for major mood, anxiety, traumatic stress, and substance use disorders in patients with histories of TBI versus uninjured cohorts. Therefore, current practice is to purse medication management based on general treatment guidelines for psychiatric disorders identified in patients with histories of mTBI, whether they emerged de novo or existed prior to brain injury events. Hammer and Sauve´68 wrote a concise review of this topic. Research has begun on other treatments for the sequelae of TBI, including neuropsychological and psychiatric symptoms. The first reports on transcranial magnetic stimulation and transcranial direct current stimulation,69 and hyperbaric oxygen therapy70 indicate potential benefit, but await confirmation in more definitive trails.

References 1. Centers for Disease Control and Prevention (CDC), National Center for Injury Prevention and Control. Report to Congress on mild traumatic brain injury in the United States: steps to prevent a serious public health problem. Atlanta, GA: Centers for Disease Control and Prevention; 2003. 2. VA/DoD clinical practice guideline for the Management of Concussion-Mild Traumatic Brain Injury. ,https://www. healthquality.va.gov/guidelines/Rehab/mtbi/mTBICPGFullCPG50821816.pdf.; 2017 [accessed 10.12.17]. 3. Malec JF, Brown AW, Leibson CL, Flaada JT, Mandrekar JN, Diehl NN, et al. The Mayo classification system for traumatic brain injury severity. J Neurotrauma 2007;24(9):1417 24. 4. Friedland DP. Improving the classification of traumatic brain injury: the Mayo classification system for traumatic brain injury severity. J Spine 2003;S4:0051. 5. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery 2014;75(suppl 4):S24 33. 6. Katz DI, Cohen SI, Alexander MP. Mild traumatic brain injury. Handb Clin Neurol 2015;127:131 56. Available from: https://doi.org/10.1016/B978-0-444-52892-6.00009-X. 7. Iverson GL. Outcome from mild traumatic brain injury. Curr Opin Psychiatry 2005;18(3):301 17. 8. McCrea M. Mild traumatic brain injury and post-concussion syndrome: the new evidence base for diagnosis and treatment. New York: Oxford Press; 2008. 9. Barr WB, Prichep LS, Chabot R, Powell MR, McCrea M. Measuring brain electrical activity to track recovery from sport-related concussion. Brain Inj 2012;26(1):58 66. 10. Kamins J, Bigler E, Covassin T, Henry L, Kemp S, Leddy JJ, et al. What is the physiological time to recovery after concussion? A systematic review. Br J Sports Med 2017;51(12):935 40. 11. Barth JT, Alves W, Ryan T, Macciocchi S, Rimel R, Jane JJ. Mild head injury in sports: neuropsychological sequelae and recovery of function. In: Levin H, Eisenberg J, Benton A, editors. Mild head injury. Oxford: New York; 1989. p. 257 75. 12. Belanger HG, Vanderploeg RD. The neuropsychological impact of sports-related concussion: a meta-analysis. J Int Neuropsychol Soc 2005;11(4):345 57. 13. Morissette SB, Woodward M, Kimbrel NA, Meyer EC, Kruse MI, Dolan S, et al. Deployment-related TBI, persistent postconcussive symptoms, PTSD, and depression in OEF/OIF veterans. Rehabil Psychol 2011;56:340 50.

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110

8. NEUROPSYCHOLOGICAL AND PSYCHIATRIC COMORBIDITIES OF MILD TRAUMATIC BRAIN INJURY

14. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 2008;358:453 63. 15. Schretlen DJ, Shapiro AM. A quantitative review of the effects of traumatic brain injury on cognitive functioning. Int Rev Psychiatry 2003;15(4):341 9. 16. McCrea M, Iverson GL, McAllister TW, Hammeke TA, Powell MR, Barr WB, et al. An integrated review of recovery after mild traumatic brain injury (MTBI): implications for clinical management. Clin Neuropsychol. In press. 17. Frencham KA, Fox AM, Maybery MT. Neuropsychological studies of mild traumatic brain injury: a metaanalytic review of research since 1995. J Clin Exp Neuropsychol 2005;27(3):334 51. 18. Bigler ED. Traumatic brain injury, neuroimaging, and neurodegeneration. Front Hum Neurosci. 2013;7:395. 19. Belanger HG, Curtiss G, Demery JA, Lebowitz BK, Vanderploeg RD. Factors moderating neuropsychological outcomes following mild traumatic brain injury: a meta-analysis. J Int Neuropsychol Soc 2005;11(3):215 27. 20. Tarsh MJ, Royston C. A follow-up study of accident neurosis. Br J Psychiatry 1985;146:18 25. 21. Vanderploeg RD, Curtiss G, Belanger HG. Long-term neuropsychological outcomes following mild traumatic brain injury. J Int Neuropsychol Soc 2005;11(3):228 36. 22. Lange RT, Brickell TA, Ivins B, Vanderploeg RD, French LM. Variable, not always persistent, postconcussion symptoms after mild TBI in U.S. Military service members: a five-year cross-sectional outcome study. J Neurotrauma 2013;30(11):958 69. 23. Binder LM, Rohling ML, Larrabee GJ. A review of mild head trauma. Part i: meta-analytic review of neuropsychological studies. J Clin Exp Neuropsychol 1997;19(3):421 31. 24. World Health Organization. International classification of diseases, 10th edition, postconcussional syndrome (F07.81). ,http://www.icd10data.com/ICD10CM/Codes/F01-F99/F01-F09/F07-/F07.81.; 2018 [accessed 20.03.18]. 25. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 26. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5). 5th ed. Washington, DC: American Psychiatric Association; 2013. 27. Darwish H, Mahmood A, Schallert T, Chopp M, Therrien B. Mild traumatic brain injury (MTBI) leads to spatial learning deficits. Brain Inj 2012;26(2):151 65. 28. Bigler ED. Neuropsychological results and neuropathological findings at autopsy in a case of mild traumatic brain injury. J Int Neuropsychol Soc 2004;10(5):794 806. 29. Anderson SD. Mild traumatic brain injury and memory impairment. Arch Phys Med Rehabil 2004;85(5):862. 30. Bigler ED. Neurobiology and neuropathology underlie the neuropsychological deficits associated with traumatic brain injury. Arch Clin Neuropsychol 2003;18(6):595 621 discussion 3-7. 31. Hammeke TA, McCrea M, Coats SM, Verber MD, Durgerian S, Flora K, et al. Acute and subacute changes in neural activation during the recovery from sport-related concussion. J Int Neuropsychol Soc 2013;19(8):863 72. 32. De Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Rutten J, Twijnstra A. Prediction of post-traumatic complaints after mild traumatic brain injury: early symptoms and biochemical markers. J Neurol Neurosurg Psychiatry 2002;73(6):727 32. 33. Neselius S, Brisby H, Marcusson J, Zetterberg H, Blennow K, Karlsson T. Neurological assessment and its relationship to CSF biomarkers in amateur boxers. PLoS One 2014;9(6):e99870. 34. Oldenburg C, Lundin A, Edman G, Nygren-de Boussard C, Bartfai A. Cognitive reserve and persistent postconcussion symptoms—a prospective mild traumatic brain injury (mTBI) cohort study. Brain Inj 2016;30 (2):146 55. 35. Shenton ME, Hamoda HM, Schneiderman JS, Bouix S, Pasternak O, Rathi Y, et al. A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav 2012;6(2):137 92. 36. Iverson GL, Lange RT, Gaetz M, Zasler ND, Mild TBI. In: Zasler ND, Katz D, Zafonte RD, editors. Brain injury medicine. New York: Demos Medical Publishing; 2007. p. 333 71. 37. Iverson GL, Zasler ND, Lange RT. Post-concussive disorder. In: Zasler ND, Katz DI, Zafonte RD, editors. Brain injury medicine: principles and practice. New York: Demos Medical Publishing; 2007. p. 373 405. 38. Iverson GL, Lange RT, Franzen MD. Effects of mild traumatic brain injury cannot be differentiated from substance abuse. Brain Inj 2005;19(1):11 18. 39. Iverson GL, McCracken LM. ‘Postconcussive’ symptoms in persons with chronic pain. Brain Inj 1997;11 (11):783 90.

II. OVERVIEW OF NEUROSENSORY CONSEQUENCES

REFERENCES

111

40. Scheenen ME, Spikman JM, de Koning ME, van der Horn HJ, Roks G, Hageman G, et al. Patients “at risk” of suffering from persistent complaints after mild traumatic brain injury: the role of coping, mood disorders, and post-traumatic stress. J Neurotrauma 2017;34(1):31 7. 41. Donnell AJ, Kim MS, Silva MA, Vanderploeg RD. Incidence of postconcussion symptoms in psychiatric diagnostic groups, mild traumatic brain injury, and comorbid conditions. Clin Neuropsychol 2012;26:1092 101. 42. FUO. 43. Morissette SB, Woodward M, Kimbrel NA, Meyer EC, Kruse MI, Dolan S, et al. Deployment-related TBI, persistent postconcussive symptoms, PTSD, and depression in OEF/OIF veterans. Rehabil Psychol 2011;56: 340 50. 44. Lange RT, Iverson GL, Rose A. Depression strongly influences postconcussion symptom reporting following mild traumatic brain injury. J Head Trauma Rehabil 2011;26:127 37. 45. Xiong C, Martin T, Sravanapudi A, Colantonio A, Mollayeva T. Factors associated with return to work in men and women with work-related traumatic brain injury. Disabil Health J 2016;9:439 48. 46. Miles SR, Harik JM, Hundt NE, Mignogna J, Pastorek NJ, Thompson KE, et al. Delivery of mental health treatment to combat veterans with psychiatric diagnoses and TBI histories. PLoS One 2017;12:e0184265. 47. Carlson K, Kehle S, Meis L, Greer N, MacDonald R, Rutks I, et al. The assessment and treatment of individuals with history of traumatic brain injury and post-traumatic stress disorder: a systematic review of the evidence. Washington, DC: U.S. Department of Veterans Affairs, Evidence-based Synthesis Program; 2009. 48. Lagarde E, Salmi L-R, Holm LW, Contrand B, Masson F, Ribe´reau-Gayon R, et al. Association of symptoms following mild traumatic brain injury with posttraumatic stress disorder vs postconcussion syndrome. JAMA Psychiatry 2014;71(9):1032 40. 49. Rao V, Bertrand M, Rosenberg P, Makley M, Schretlen DJ, Brandt J, et al. Predictors of new-onset depression after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci 2010;22:100 4. 50. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major depression following traumatic brain injury. Arch Gen Psychiatry 2004;61:42 50. 51. Alway Y, Gould KR, Johnston L, McKenzie D, Ponsford J. A prospective examination of Axis I psychiatric disorders in the first 5 years following moderate to severe traumatic brain injury. Psychol Med 2016;46:1331 41. 52. Sutherland J, Middleton J, Ornstein TJ, Lawson K, Vickers K. Assessing accident phobia in mild traumatic brain injury: the accident fear questionnaire. Rehabil Psychol 2016;61:317 27. 53. Donders J, Pendery A. Clinical utility of the patient health questionnaire-9 in the assessment of major depression after broad-spectrum traumatic brain injury. Arch Phys Med Rehabil 2017;98:2514 19. 54. Iverson GL, Gardner AJ, McCrory P, Zafonte R, Castellani RJ. A critical review of chronic traumatic encephalopathy. Neurosci Biobehav Rev 2015;56:276 93. 55. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology 2012;79(19):1970 4. 56. Janssen PH, Mandrekar J, Mielke MM, Ahlskog JE, Boeve BF, Josephs K, et al. High school football and latelife risk of neurodegenerative syndromes, 1956 1970. Mayo Clin Proc 2017;92(1):66 71. 57. Savica R, Parisi JE, Wold LE, Josephs KA, Ahlskog JE. High school football and risk of neurodegeneration: a community-based study. Mayo Clin Proc 2012;87(4):335 40. 58. Mielke MM, Savica R, Wiste HJ, Weigand SD, Vemuri P, Knopman DS, et al. Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study. Neurology 2014;82(1):70 6. 59. Mittenberg W, DiGiulio DV, Perrin S, Bass AE. Symptoms following mild head injury: expectation as aetiology. J Neurol Neurosurg Psychiatry 1992;55(3):200 4. 60. Cancelliere C, Hincapie´ CA, Keightley M, Godbolt AK, Coˆte´ P, Kristman VL, et al. Systematic review of prognosis and return to play after sport concussion: results of the international collaboration on mild traumatic brain injury prognosis. Arch Phys Med Rehabil 2014;95(3 Suppl):S210 29. 61. Cooper DB, Bowles AO, Kennedy JE, Curtiss G, French LM, Tate DF, et al. Cognitive rehabilitation for military service members with mild traumatic brain injury: a randomized clinical trial. J Head Trauma Rehabil 2017;32(3):E1 15. 62. Mittenberg W, Tremont G, Zielinski RE, Fichera S, Rayls KR. Cognitive-behavioral prevention of postconcussion syndrome. Arch Clin Neuropsychol 1996;11(2):139 45. 63. Scholten J, Vasterling JJ, Grimes JB. Traumatic brain injury clinical practice guidelines and best practices from the VA state of the art conference. Brain Injury 2017;31(9):1246 51.

II. OVERVIEW OF NEUROSENSORY CONSEQUENCES

112

8. NEUROPSYCHOLOGICAL AND PSYCHIATRIC COMORBIDITIES OF MILD TRAUMATIC BRAIN INJURY

64. Talsky A, Pacione LR, Shaw T, Wasserman L, Lenny A, Verma A, et al. Pharmacological interventions for traumatic brain injury. Br Columb Med J 2010;53(1):26 31. 65. Wortzel HS, Arciniegas DB. Treatment of post-traumatic cognitive impairments. Curr Treat Options Neurol 2012;14(5):493 508. 66. Ponsford J, Lee NK, Wong D, McKay A, Haines K, Alway Y, et al. Efficacy of motivational interviewing and cognitive behavioral therapy for anxiety and depression symptoms following traumatic brain injury. Psychol Med 2016;46:1079 90. 67. Bryant R. Post-traumatic stress disorder vs traumatic brain injury. Dialog Clin Neurosci 2011;13(3):251 62. 68. Hammer PS, Sauve´ WM. Psychopharmacology in treating posttraumatic stress disorder with co-occuring mild traumatic brain injury. Primary Psychiatry, July 8, 2014. 69. Dhaliwal SK, Meek BP, Modirrousta MM. Non-invasive brain stimulation for the treatment of symptoms following traumatic brain injury. Front Psychiatry 2015;6:119. 70. Harch PG, Andrews SR, Fogarty EF, Amen D, Pezzullo JC, Lucarini J, et al. A phase I study of low-pressure hyperbaric oxygen therapy for blast-induced post-concussion syndrome and post-traumatic stress disorder. J Neurotrauma 2012;29:168 85.

II. OVERVIEW OF NEUROSENSORY CONSEQUENCES