Post-traumatic stress disorder and traumatic brain injury.

Handbook of Clinical Neurology, Vol. 128 (3rd series) Traumatic Brain Injury, Part II J. Grafman and A.M. Salazar, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 39

Post-traumatic stress disorder and traumatic brain injury JULIAN C. MOTZKIN1,2 AND MICHAEL R. KOENIGS3* Neuroscience Training Program, University of Wisconsin — Madison, Madison, WI, USA

1 2

Medical Scientist Training Program, University of Wisconsin — Madison, Madison, WI, USA 3

Department of Psychiatry, University of Wisconsin — Madison, Madison, WI, USA

INTRODUCTION Since the time “shell shock” was first recognized in veterans returning from World War I, clinicians and researchers have struggled to disentangle the effects of physical, or “organic,” brain damage from psychological distress (Jones et al., 2007). In recent decades, the comorbidity of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) has taken center stage in the nearly century-old debate concerning the interaction between neurologic and psychiatric reactions to trauma (Bryant, 2008). Some investigators and clinicians have proposed that a strict interpretation of contradictions inherent in the diagnostic criteria for TBI and PTSD would preclude a dual diagnosis (O’Brien and Nutt, 1998). Specifically, it was thought that posttraumatic amnesia in TBI would prevent the encoding of memories essential for forming the intrusive symptoms necessary for a diagnosis of PTSD (Sbordone and Liter, 1995). More recently, it has become apparent that these conditions do indeed coexist, and that individuals with a dual diagnosis present unique clinical challenges (Bryant, 2001a; Harvey et al., 2003). A dual diagnosis of mild TBI (mTBI) and PTSD is emerging as a signature injury of veterans returning from conflicts in Iraq and Afghanistan, and will undoubtedly garner increasing attention over the coming years (Okie, 2005; Warden, 2006). Both disorders are associated with a variety of common behavioral sequelae, including substance abuse (Mills et al., 2006; Graham and Cardon, 2008), depression (Kim et al., 2007; Carlson et al., 2010), and suicidal behavior (Sareen et al., 2007; Simpson and Tate, 2007; Desai et al., 2008; Gutierrez et al., 2008), in addition to a host of somatic and cognitive complaints (McCauley et al., 2001). These implications

highlight the need to better understand the interaction between TBI and PTSD. In the following chapter, we define and review the diagnostic criteria for PTSD and TBI. We present evidence that a dual diagnosis is not only possible, but is in fact quite common. Next, we describe neurocircuitry and cognitive models of PTSD, highlighting how neuropathologic states germane to TBI can promote or protect against the development of PTSD. Finally, we discuss how the interaction between organic brain damage (TBI) and psychiatric reactions to severe stress (PTSD) contribute to the development of adverse outcomes, with careful consideration of the unique challenges in diagnosis, patient education, and treatment in patients with the dual diagnosis.

DEFINITION OF TERMS Post-traumatic stress disorder PTSD is an anxiety disorder that can develop after an individual is exposed to a traumatic or life-threatening event. Most cases of PTSD stem from events such as military combat, traffic accidents, and assault – lifethreatening situations that may also be accompanied by an increased likelihood of TBI (Breslau et al., 2004; Langlois et al., 2006; Galea et al., 2008). The lifetime prevalence of PTSD in the general population is approximately 7%, whereas the reported prevalence in military populations is between 10% and 30% (Kessler et al., 1995; Hoge et al., 2008). The diagnostic criteria for PTSD, as outlined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 2000), include five major criteria. First,

*Correspondence to: Michael R. Koenigs, PhD, Assistant Professor, Department of Psychiatry, University of Wisconsin, 6001 Research Park Blvd, Madison, WI 53719, USA. Tel: +1-608-263-1679, E-mail: [email protected]

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an individual must have experienced, or witnessed first-hand, an event that posed a significant risk of death or serious injury, and this traumatic experience must have been accompanied by feelings of intense fear or helplessness. Second, the traumatic event must be persistently re-experienced, either through intrusive recollections, dreams, and flashbacks, or through intense psychological distress or physiologic arousal to cues resembling the traumatic event. Third, the affected individual must engage in persistent avoidance of traumaassociated thoughts, feelings, or situations, have an inability to recall aspects of the trauma, withdraw from others, or demonstrate general emotional numbing and detachment. Fourth, there must be symptoms of persistent hyperarousal, including insomnia, irritability, hypervigilance, or exaggerated startle response. Finally, the symptoms must cause significant distress and/or impairment and must persist for at least 1 month after the trauma. To meet the diagnostic criteria for PTSD, an individual must have at least one re-experience symptom, three avoidance symptoms, and two hyperarousal symptoms.

A recent systematic review of ASD suggests that approximately 17% of those who experience an emotionally traumatic event go on to satisfy the diagnostic criteria for ASD, with approximately 26% satisfying at least three of the symptom clusters (Bryant, 2011). Of these individuals, approximately half will subsequently meet the criteria for PTSD. However, ASD is not a sensitive indicator of subsequent PTSD. More than half of trauma survivors who eventually meet the diagnostic criteria for PTSD do not meet the diagnostic criteria for ASD (Bryant, 2011). If dissociative symptoms are ignored, a diagnosis of ASD is significantly more accurate in predicting subsequent PTSD. This suggests that PTSD-like symptoms within the first month after a traumatic experience may be a better predictor of the progression to PTSD than ASD per se (Bryant et al., 2012). Despite the failure of the diagnosis to effectively identify trauma survivors at risk for subsequent PTSD, ASD appears to be particularly good at predicting subsequent PTSD in individuals with a TBI (Harvey and Bryant, 2000, 2002). The implications for ASD following TBI will be discussed in subsequent sections.

Acute stress disorder

Changes to post-traumatic stress disorder and acute stress disorder in the DSM-5

In light of temporal constraints in the diagnostic criteria of PTSD that preclude a diagnosis within the first month, a second diagnosis was introduced to capture acute stress reactions that occur in the immediate aftermath of a traumatic event (Bryant and Harvey, 2000). Clinicians hoped that such a diagnosis would help them identify individuals at high risk for PTSD for psychiatric care, to deploy early interventions and stave off progression to more persistent symptoms (Bryant et al., 2000; Harvey and Bryant, 2002). Acute stress disorder (ASD) first appeared in the DSM-IV (American Psychiatric Association, 2000) as a more acute form of PTSD, lasting for at least 2 days and no more than 4 weeks after the traumatic event. ASD is qualitatively very similar to PTSD and includes many of the re-experiencing, avoidance, and arousal criteria from the PTSD diagnosis. However, in addition to the temporal constraints that set ASD apart from PTSD, ASD places a greater emphasis on dissociative symptoms. The diagnosis of ASD requires at least three of the following: (1) subjective sense of numbing or detachment, (2) reduced awareness of surroundings, (3) derealization, (4) depersonalization, or (5) dissociative amnesia (Bryant and Harvey, 1997). The motivation for this distinction is grounded in the theoretical assertion that dissociation is the primary mechanism for coping with the extreme stress in the days and weeks following a traumatic experience (Bryant and Harvey, 1997).

In the most recent version of the DSM (DSM-5) (American Psychiatric Association, 2013), PTSD and ASD have been relocated from “anxiety disorders” to a new class of “trauma and stress-related disorders,” reflecting the shared etiology across conditions within the class (i.e., trauma). Despite the change in class heading, the diagnostic criteria for both PTSD and ASD remain quite similar. In sum, the changes respond to heterogeneity in the symptom expression and are more permissive of variable clinical manifestations of distress. Notably, the DSM-5 has de-emphasized the role of dissociative symptoms in the ASD diagnosis. This change reflects the heterogeneity of the acute phase response, and is in line with previous work showing that ASD is a better predictor of PTSD when dissociative criteria are relaxed (Bryant et al., 2012).

Traumatic brain injury TBI occurs when mechanical or biomechanical forces are applied to the brain at a sufficient magnitude to elicit organic neurologic damage. More than 1.5 million Americans suffer a traumatic brain injury each year, and approximately 5 million live with persistent disabilities resulting from TBI (Langlois et al., 2006). Traumatic brain injuries are typically accompanied by a host of neurologic and behavioral sequelae, many of which persist long after the initial insult (Levin et al., 1990; Landre et al., 2006; McAllister, 2011). Although

POST-TRAUMATIC STRESS DISORDER AND TRAUMATIC BRAIN INJURY 635 there is no universally accepted definition for TBI, a clinin which an individual can acquire a TBI also tend to be ical diagnosis is most commonly made on the basis of an rather psychologically traumatic and/or life-threatening alteration or loss of consciousness (LOC) immediately (e.g., automobile accidents, assault, armed conflict), this after the injury, post-traumatic amnesia (PTA) for a point is an important one to consider. period of time after the traumatic event, and in some Perhaps the most significant implication of the overcases, retrograde amnesia (RA) for events leading up lap between ASD/PTSD and postconcussive syndrome is to the trauma (Bryant, 2001a). LOC and PTA can be brief the difficulty in retrospectively assigning symptoms to or more persistent, and there are often “islands of organic (i.e., neurologic) or psychological causes memory” that emerge before anterograde amnesia (Bryant, 2001a; Stein and McAllister, 2009; Vasterling (i.e., PTA) fades back into ongoing and continuous et al., 2009). This complicates efforts by clinicians and recollection (King, 2008). researchers to firmly establish the mechanism underlyThe duration of PTA is the most commonly used ing the functional disturbance. In particular, many of metric to assess the severity of TBI, typically classified the dissociative, avoidance, and hyperarousal criteria as mild, moderate, or severe (Ellenberg et al., 1996) (see of ASD, including amnesia and concentration problems, Ch. 2 for further discussion). Although the effects of can be misattributed to organic causes. Thus, a retromoderate and severe TBI on postinjury psychiatric funcspective diagnosis of TBI can be made based solely on tion and PTSD merit consideration, the majority of work symptoms attributable to the acute stress reaction on the dual diagnosis has been performed in individuals (Bryant, 2008). with mild TBI (mTBI). These studies include individuals To further exacerbate the problems of overlapping in whom PTA was generally less than 24 hours, LOC was diagnostic criteria between conditions, a diagnosis of generally less than 30 minutes, and the lowest recorded postconcussive syndrome seems to rely more on ASD Glasgow Coma Scale rating was no less than 13 (Rees, and PTSD symptoms than organic brain damage. 2003). Although the following sections are most relevant Indeed, persistent postconcussive syndrome symptoms to the comorbidity of mTBI and PTSD, the implications have been shown to occur in trauma-exposed individuals of more severe TBI on the progression of PTSD will be without TBI (Meares et al., 2008, 2011). Notably, in a discussed in relevant sections. series of studies conducted by Dikmen and colleagues, researchers were unable to find significant differences Postconcussive syndrome in long-term cognitive deficits between a TBI group and noninjury (Dikmen et al., 1986) and other injury Importantly, TBI is associated with a host of cognitive, (Dikmen et al., 1995) comparison groups 1 year after psychological, and somatic symptoms that arise after injury. Recent work suggests that PTSD and other psythe insult, in some cases persisting for months or years. chiatric symptoms are the best predictors of postconcusThe most commonly observed constellation of symptoms sive symptoms after a TBI, even after the overlapping that arise after TBI make up a so-called postconcussive symptoms are removed from the analysis (Hoge et al., syndrome. The symptoms of postconcussive syndrome 2008). Taken together, these findings suggest that psyare typically organized into three categories: (1) cognitive chiatric symptoms characteristic of the stress response symptoms, including impairments in memory, attention, play a key role in the progression of postconcussive and concentration, (2) somatic symptoms, including headsymptoms, in some cases even mimicking these sympache, fatigue, insomnia, dizziness, tinnitus, sensitivity to toms in individuals without TBI. noise or light, and (3) affective complaints, including There is justifiable concern within the neuropsychodepression, irritability, and anxiety (McCauley et al., logical community regarding the assignment of over2001; McAllister and Arciniegas, 2002). Approximately lapping symptoms to the appropriate diagnosis. 80–100% of mTBI patients will experience at least one Undoubtedly, there is an interaction between organic of these symptoms immediately after injury (Levin and psychiatric causes in the development of the dual et al., 1987). In a smaller subset of individuals, these sympdiagnosis, but the significant overlap in symptoms raises toms become more persistent and disabling (McAllister important questions about the predictive value of studies and Arciniegas, 2002). that retrospectively assign either diagnosis. Further, the mechanism of injury may have significant implications DIAGNOSTIC CHALLENGES: SYMPTOM for treatment selection, patient education, and prognoOVERLAP sis. Therefore, it is important to consider the unique conThe symptoms of postconcussive syndrome are notable tributions of organic brain injury and psychiatric for their significant overlap with several of the diagnosdisturbance, and how each may promote or protect tic criteria for ASD and PTSD, across cognitive, somatic, against the other. These considerations will be addressed and affective domains (Table 39.1). Given that situations in subsequent sections of this chapter.

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Table 39.1 Symptom overlap of acute stress disorder, post-traumatic stress disorder, and postconcussive syndrome Criterion

ASD

PTSD

PCS

Re-experience Intrusive images Dreams/flashbacks Distress with reminders Avoidance Avoid thoughts/people/places Amnesia Emotional numbing Withdrawal from others Diminished interest Foreshortened future Hyperarousal Insomnia Irritability Concentration problems Hypervigilance Elevated startle Dissociation Reduced awareness Depersonalization Derealization Somatic Headache Sensitivity to light Dizziness

At least one of: x x x Marked: x D D

At least one of: x x x At least three of: x x x x x x At least two of: x x x x x NA

Present:

Marked: x x x x At least three of: x x x NA

NA

Overlap

N N N Present: x x x x x Present: x x x

Present: x x x Present: x x x

Y Y Y Y Y N Y Y Y N N Y Y Y N N N

The table depicts the overlap between acute stress disorder (ASD), post-traumatic stress disorder (PTSD), and postconcussive syndrome (PCS; long-term sequelae of some TBIs). The letter “x” indicates that the symptom is present, a minus sign “ ” indicates that the symptom is not present, and the letter D (in the avoidance criteria under ASD) indicates that the symptoms are present, but typically included under the heading of “Dissociation.” Above each criterion is the number of symptoms required for a diagnosis (e.g. at least one symptom, marked symptoms, or symptoms present). The last column indicates whether there is (Y) or is not (N) an overlap between neurologic (PCS) and psychiatric (ASD/PTSD) symptoms. The table demonstrates significant symptom overlap across avoidance, hyperarousal, and dissociation criteria. (Adapted from Bryant, 2001a.)

EVIDENCE FOR THE DUAL DIAGNOSIS Theoretical background Preliminary reports investigating the comorbidity of TBI and PTSD suggested that LOC during TBI would prevent the encoding of trauma memories during the event (Sbordone and Liter, 1995; O’Brien and Nutt, 1998). Given the central role of re-experiencing symptoms in PTSD, it was thought that TBI with LOC and PTA would preclude a PTSD diagnosis (Klein et al., 2003). The assumption inherent in this line of reasoning is that overt recollection of the traumatic event is required to induce feelings of anxiety. These reports ignored the possibility that intrusive memories from other sources, including spared “islands of memory” or confabulated accounts, could form the foundation of a reconstructed narrative

(Bryant, 2001a; King, 2008). Further, the diagnostic criteria in the DMS-IV elaborated upon the originally proposed re-experiencing criteria (in the DSM-III) to include psychological and physiologic distress to cues that symbolize or resemble the traumatic event, a process that may persist in the absence of explicit traumatic memories. Indeed, the majority of individuals who meet the re-experiencing criteria for PTSD after a severe TBI experience marked psychological distress in response to reminders of the trauma in the absence of documented intrusive recollections (Bryant and Harvey, 1995; Bryant et al., 2001; Feinstein et al., 2002). The low rate of intrusive memories in this sample stands in stark contrast to the high rates of intrusive memories in PTSD without TBI (Bryant and Harvey, 1995). Despite the qualitatively different pattern of PTSD symptoms in individuals with

POST-TRAUMATIC STRESS DISORDER AND TRAUMATIC BRAIN INJURY 637 TBI, it is clear that many individuals who suffer a TBI go and TBI after trauma in both civilian and military on to experience chronic stress reactions consistent with populations. Further, many of the data seem to suggest PTSD even in the absence of intrusive episodic memories that mTBI acts as a “permissive gateway” that increases of the event. the relative risk of a host of psychiatric symptoms, including PTSD (McAllister and Stein, 2010).

Epidemiology of post-traumatic stress disorder and traumatic brain injury Perhaps the strongest evidence for the existence of the dual diagnosis comes from the aggregation of epidemiologic data linking TBI to increased risk of PTSD. There is good evidence that PTSD and TBI are comorbid in up to 33% of TBI cases (Ohry et al., 1996; Bryant, 2001b; Williams et al., 2002; Ashman et al., 2004; Bryant et al., 2004; Sojka et al., 2006). Several studies in civilian samples suggest that TBI is associated with comparable, or in some cases higher, rates of PTSD relative to individuals without TBI (Layton and Wardi-Zonna, 1995; Bryant, 1996; Hickling et al., 1998). Bryant and colleagues (Bryant, 2011) estimate that mTBI is associated with a significant increase in the risk of developing a range of psychiatric disorders, including PTSD (see Ch. 38 for a further discussion of personality and mood changes after TBI). A study by Mayou and colleagues (2000) found that among individuals with mTBI and definite LOC, 48% had PTSD 3 months after injury. When the LOC criteria were relaxed, a third of subjects with mTBI had PTSD 1 year after injury. These studies suggest that mTBI is associated with a significantly increased risk of developing PTSD. Recent US military reports from the operations in Afghanistan and Iraq have played an essential role in shining a spotlight on the prevalence of the dual diagnosis. In veterans returning from Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF), those reporting mTBI had higher rates of PTSD than veterans reporting no head injury or no injuries at all, controlling for combat severity, mechanism of injury, hospitalization, and other demographic factors (Hoge et al., 2008). Another study by Schneiderman and colleagues found that mild TBI approximately doubled the risk of developing PTSD (Schneiderman et al., 2008; Carlson et al., 2010). A more recent study suggests that veterans with TBI were three times more likely to develop PTSD than those without TBI (Carlson et al., 2010). However, this study was based on a retrospective screening instrument that may have overestimated the rate of TBI in the sample endorsing PTSD. These findings are consistent with prior studies of veterans in other conflicts, suggesting that mTBI increases the risk of PTSD and the severity of PTSD symptoms (Chemtob et al., 1998; Vanderploeg et al., 2005; Bryant et al., 2009). Taken together, there is significant evidence to support the coexistence of PTSD

LINK BETWEEN TRAUMATIC BRAIN INJURY SEVERITYAND POSTTRAUMATIC STRESS DISORDER Among individuals with documented TBI, there appears to be an inverse relationship between the severity of TBI and the risk of developing PTSD. In particular, more severe TBIs are associated with a decreased risk of developing PTSD (Feinstein et al., 2002; Klein et al., 2003; Vasterling et al., 2009). Researchers speculate that this inverse relationship between TBI severity and PTSD risk in individuals with a brain injury is a result of the profound lack of memory for the event in the most severe cases of TBI. Indeed, the length of post-traumatic amnesia is negatively associated with the strength of intrusive (re-experiencing) and avoidant symptoms relating to the trauma (Feinstein et al., 2002). However, while the rate of intrusive recollections decreases over time in non-TBI patients, intrusions appear to become more prevalent over time among individuals who suffered a TBI (Bryant, 2001a; Bryant et al., 2001). These data suggest that studies performed in the early stages of recovery from TBI may miss a PTSD diagnosis if symptoms have not yet developed. Further, these studies highlight the possibility that PTSD follows a unique developmental trajectory following TBI. Although a wealth of studies have demonstrated comparable or increased risk of PTSD following TBI, some reports suggest that TBI confers decreased risk of PTSD. In many of these accounts, which tend to observe astonishingly low rates of PTSD in brain-injured samples, TBI was moderate to severe (Malt, 1988; Warden et al., 1997) and all victims reported loss of consciousness (Mayou et al., 1993). In some cases, although a diagnosis of PTSD was not made, other psychiatric problems were present (Malt, 1988; Warden et al., 1997). In one study of Vietnam veterans, Koenigs and colleagues (2008) found that patients with penetrating brain injuries with focal damage to the medial prefrontal cortex or anterior temporal lobes were significantly less likely to develop PTSD. Therefore, in addition to the most severe closed-head injuries, penetrating brain damage in certain focal locations also appears to reduce the risk of developing PTSD. The implications of this finding will be discussed further in the context of brain mechanisms of TBI and PTSD, outlined below.

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TRAJECTORY OF POST-TRAUMATIC STRESS DISORDER FOLLOWING TRAUMATIC BRAIN INJURY Despite the significant overlap between ASD symptoms and postconcussive symptoms, these conditions each appear to have important prognostic implications for PTSD and subsequent health problems. In one study, 82% of mTBI patients with ASD symptoms went on to develop PTSD at 6 months. In a 2 year follow-up, 80% of mTBI patients who met the ASD criteria still met the criteria for PTSD (Harvey and Bryant, 2000). This is markedly higher than the rates of progression from ASD to PTSD observed in nonbrain-injured populations (Harvey and Bryant, 2002), indicating that early stress reactions satisfying the criteria for ASD are particularly relevant in individuals who have suffered a TBI. Some investigators suggest that TBI may decrease that ability to effectively manage the acute stress reaction, promoting the increased progression from ASD to PTSD in TBI populations (Harvey and Bryant, 2002; Bryant, 2011). Just as acute stress reactions following TBI appear to be a good predictor of subsequent PTSD symptoms, it is also becoming apparent that psychiatric sequelae following TBI have a significant impact on long-term cognitive and somatic symptoms of TBI. Notably, PTSD is associated with a significant increase of persistent postconcussive symptoms in individuals with a TBI (Bryant and Harvey, 1998, 1999b; Harvey and Bryant, 1998a, b, 1999). Among individuals with PTSD, those with TBI endorse significantly more postconcussive symptoms than those without TBI (Bryant and Harvey, 1999a; McAllister and Arciniegas, 2002). More recent estimates suggest that individuals with PTSD are up to three times more likely to develop persistent postconcussive syndrome after TBI than individuals without PTSD (McCauley et al., 2001; Schneiderman et al., 2008). When symptoms common to both TBI and PTSD are removed from analysis, PTSD becomes the strongest predictor of postconcussive symptoms (Hoge et al., 2008; Meares et al., 2008, 2011). However, ascribing postconcussive symptoms to the direct effects of neuronal injury following TBI or to secondary behavioral reactions to trauma remains extremely difficult (McAllister and Arciniegas, 2002). Taken together these findings suggest that psychiatric responses to trauma play an essential role in the progression of TBI to postconcussive syndrome. These data have important implications for the management of postconcussive symptoms in individuals with TBI and PTSD, particularly in the domain of intervention and treatment. Specifically, these data suggest that treatments aimed at modulating the patient’s psychiatric symptoms may prove effective in mitigating the progression of long-term postconcussive symptoms.

Although the data above suggest that PTSD can and does occur after a TBI, there appear to be significant differences in the way individuals with and without TBI develop and express the symptoms of PTSD. It is likely that the organic neurologic damage that results from TBI interacts in some way with the neurologic substrates involved in the pathogenesis of PTSD. Similarly, it is apparent that a psychiatric diagnosis of PTSD significantly affects the progression of “organic” neurologic symptoms. In all likelihood, the reciprocal interaction between “organic” brain injury and “functional” psychiatric disturbance reflects the unique pathology of individuals with a dual diagnosis of PTSD and TBI. For the remainder of the chapter, we will address how TBI may increase or decrease the risk of PTSD. Further, we will address the unique challenges posed by the dual diagnosis, with special attention paid to the contribution of each condition to adverse outcomes commonly observed following TBI.

MODELS OF POST-TRAUMATIC STRESS DISORDER Neurocircuitry models of anxiety/posttraumatic stress disorder Neurocircuitry models of PTSD marshal convergent evidence from research in animal models and human subjects to support a conceptual link between the neural basis of fear and the neurocircuitry of PTSD (Milad et al., 2006; Rauch et al., 2006; Shin et al., 2006). The driving feature behind these models is the apparent phenomenological similarity of PTSD symptoms (i.e., re-experience, avoidance, hyperarousal) and processes instantiated during classic fear conditioning. The model proposes that neural circuits involved in the pathogenesis of PTSD likely reflect the neural circuitry implicated in the processes of fear acquisition and extinction. In animal models of classic Pavlovian fear conditioning, a conditioned fear response is established through the repeated pairing of a conditioned stimulus (CS) – a perceptual cue with no intrinsic fearful qualities like a tone or light – with an unconditioned stimulus (US), usually an intrinsically painful or startling stimulus such as an electric shock. After repeated pairings of the CS and US, the CS alone becomes capable of eliciting a fear response (e.g., freezing, startle, autonomic/neuroendocrine changes). However, if the CS is presented repeatedly without its associated US, the fear response eventually becomes extinguished. Although the language used to describe this phenomenon (i.e., extinction) seems to suggest that the initial memory is lost during this period, evidence from the animal literature suggests that fear extinction is a unique process that relies on the

POST-TRAUMATIC STRESS DISORDER AND TRAUMATIC BRAIN INJURY formation of new memories coding the safety of the extinguished CS. In other words, during the extinction period, the animal forms a new memory trace linking the CS to its new association, safety. For an individual with PTSD, the sights, sounds, smells, and internal states accompanying a traumatic event can all serve as unwelcome reminders (CSs) that reactivate the intense fear and helplessness experienced during the initial traumatic event (US). In these models, the pathologic process inherent in the emergence of PTSD is analogous to a deficit of fear extinction, such that cues associated with the initial event elicit a potent and improperly inhibited fear response. The initial US, or emotional trauma, is so powerful that the link between the fear response and the CS becomes over-represented and resistant to extinction. Continued exposure to situations with similar perceptual characteristics to the emotional trauma, even long after the event, serves to reactivate and potentially strengthen the initial association. Convergent evidence from animal models and human studies highlights the role of a network of brain regions thought to be essential for the acquisition and extinction of fear memories, namely, the amygdala, prefrontal cortex, and hippocampus (Fig. 39.1) (Rauch et al., 2006; Shin et al., 2006). Briefly, the neurocircuitry model posits that

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PTSD is the result of amygdala hyperactivity in response to threat-related cues, accompanied by impaired topdown regulation and contextualization of the amygdala response by the prefrontal cortex. Hippocampal dysfunction is thought to contribute to explicit memory problems and impairments in identifying contextual cues as safe. The role of each of these structures will be discussed, and evidence implicating each region in PTSD will be presented.

AMYGDALA The underlying supposition of neurocircuitry models of PTSD is that amygdala activity is causally involved in the experience of negative emotional states such as fear and anxiety. The amygdala is known to be an important brain region mediating the recognition of, and subsequent coordination of behavior toward, emotionally salient stimuli, particularly threat (Anderson and Phelps, 2001; Davidson, 2002). Importantly, the amygdala plays a critical role in the acquisition of conditioned fear (LeDoux, 2000). Human studies support and elaborate on the conclusions of the animal literature. Amygdala activity has been linked to the expression of the conditioned fear response in human fMRI studies (Phelps et al., 2004; Phelps and LeDoux, 2005), and neurologic patients with

Fig. 39.1. Locations of functional abnormalities in post-traumatic stress disorder (PTSD) superimposed on the typical patterns of brain damage in traumatic brain injury (TBI). Areas shaded dark gray are particularly vulnerable to damage following a TBI, including: anterior lateral and medial prefrontal cortex, anterior lateral and ventromedial temporal cortex, subfrontal white matter, and hippocampus. Ovals with horizontal bars indicate the approximate location of hypofunction and/or atrophy in PTSD, including: ventromedial prefrontal cortex, rostral anterior cingulate, and hippocampus. Ovals with vertical bars, in the bilateral amygdala, are regions of hyperfunction in PTSD. PTSD-associated functional changes are approximate representations derived from a meta-analysis of PTSD (Etkin and Wager, 2007).

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lesions involving the amygdala demonstrate impaired acquisition of conditioned fear (Bechara et al., 1995; LaBar et al., 1998). The amygdala is one of the brain regions most consistently implicated in the pathogenesis of PTSD (Shin et al., 2006; Etkin and Wager, 2007). Individuals with PTSD exhibit profound dysfunction in amygdalamediated processes, demonstrating hypervigilance to threatening stimuli and more readily acquiring conditioned fear responses. A recent meta-analysis of human functional imaging studies found that amygdala hyperactivity is the most common and reliable neurobiological finding observed in individuals suffering from PTSD (Etkin and Wager, 2007). Hyperactivity has been observed across a variety of experimental contexts, including recall of traumatic memories and passive viewing of unrelated affective stimuli (Bremner et al., 1999; Shin et al., 2005; Phan et al., 2006). Importantly, amygdala activity in PTSD is positively correlated with both PTSD symptom severity (Rauch et al., 1996; Shin et al., 2004) and self-reported anxiety (Pissiota et al., 2002; Fredrikson and Furmark, 2003).

PREFRONTAL CORTEX The ventromedial prefrontal cortex (vmPFC), encompassing the rostral anterior cingulate cortex, medial prefrontal cortex, subgenual cingulate cortex, and orbitofrontal cortex, has been shown to play a key role in the extinction of conditioned fear responses, and importantly, in the maintenance of fear extinction over time (Milad and Quirk, 2002; Milad et al., 2006; Shin et al., 2006). The vmPFC is extensively and reciprocally interconnected with the amygdala (Amaral and Price, 1984; Ghashghaei et al., 2007), and stimulation of a region homologous to vmPFC in rodents facilitates the extinction of conditioned fear (Quirk et al., 2003; Rosenkranz et al., 2003). Further, damage to this structure in rodents leads to deficits in fear extinction, accompanied by amygdala hyperactivity (Morgan and LeDoux, 1995; Quirk et al., 2000). Although the homology of prefrontal cortical structures between humans and other mammals remains the subject of debate, human studies of vmPFC function converge on similar conclusions to those reached in the animal literature. Namely, vmPFC activity is associated with extinction of fear (Phelps et al., 2004). Similarly, structural MRI studies in humans demonstrate an association between cortical thickness in the vmPFC and the retention of fear extinction in healthy subjects (Milad et al., 2005; Rauch et al., 2005). A complimentary literature on emotion regulation, in which participants are instructed to attenuate their emotional responses to affective images, highlights the inverse relationship between amygdala and vmPFC

in affective control processes (Urry et al., 2006; Johnstone et al., 2007). When healthy subjects are instructed to reduce their experienced negative affect to anxiety-provoking stimuli, increases in vmPFC activity are associated with decreased amygdala activity and a decrease in self-reported negative affect. A recent meta-analysis of functional neuroimaging studies suggests that vmPFC hypoactivity is a reliable neural correlate of PTSD (Etkin and Wager, 2007). Across several experimental contexts, including cued recall of trauma-associated memories, negative emotional pictures, and tasks designed to test cognitive processes, individuals with PTSD activate the vmPFC less than comparison subjects (Bremner et al., 1999; Etkin and Wager, 2007). A subset of these studies observed an inverse relationship between vmPFC activity and PTSD symptom severity, with greater vmPFC activity associated with milder symptoms (Shin et al., 2004, 2005; Williams et al., 2006). PTSD is also commonly associated with a reduction in cortical volume within the prefrontal cortex (Shin et al., 2006), and some studies have observed a significant anticorrelation between cortical volume in the anterior cingulate cortex (a subregion of the vmPFC) and the severity of PTSD symptomatology (Woodward et al., 2006). Taken together, the vmPFC appears to be a critical node of dysfunction in PTSD.

HIPPOCAMPUS Given its well-described role in the encoding of explicit memory, the hippocampus is thought to be critical for establishing environmental context during a traumatic experience. The hippocampus and amygdala work together during the establishment of fear conditioning, and it is thought that hippocampal activation in novel contexts should provide contextual information regarding the safety of the current environment (Rauch et al., 2006; Shin et al., 2006). In the context of PTSD, the most common neuroanatomical finding is reduced hippocampal volume. Hippocampal volume in PTSD is negatively correlated with a host of measures, including combat severity, PTSD symptom severity, and verbal memory deficits (Sapolsky, 2000). However, it is unclear if reduced hippocampal volume is a cause or consequence of the disorder. In a study of identical twins in which only one twin was exposed to trauma, unexposed twins of PTSD sufferers had smaller hippocampal volumes than unexposed twins of individuals without PTSD (Gilbertson et al., 2002). Interestingly, PTSD symptom severity in the exposed twin was negatively correlated with hippocampal volume in the unexposed twin, suggesting a genetic, predispositional role of hippocampal volume, in which smaller hippocampal volumes are a risk

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factor for developing PTSD. Further, combat veterans with attention deficit, hyperactivity, and learning problems in childhood, as well as those with lower IQ scores at the time of enlistment, are more likely to develop PTSD (Gurvits et al., 1993; Macklin et al., 1998). To the extent that general intelligence and learning ability reflect hippocampal function, these findings support assertions that smaller hippocampal volumes are a risk factor, rather than a consequence, of PTSD. In contrast, animal models and some human conditions (e.g., Cushing’s syndrome) link exposure to chronic stress and high levels of circulating glucocorticoids (a stress hormone) with hippocampal atrophy (Sapolsky, 2000). In the context of TBI, the traumatic event may promote hippocampal atrophy, which in turn may contribute to the development of PTSD. However, prospective studies of hippocampal volume following PTSD have repeatedly failed to observe a significant decline in volume following psychological trauma (Bremner et al., 1997). Similarly, many studies have failed to observe a difference in hippocampal volume between trauma survivors with and without PTSD (Gurvits et al., 1996; Stein et al., 1997). Therefore, it is possible that hippocampal atrophy represents a common response to trauma, only promoting PTSD when other potent risk factors, neurologic or otherwise, are present.

reserve” to manage and cope with traumatic memories. Consistent with this assertion, individuals with a low IQ are at a greater risk of developing PTSD (Macklin et al., 1998). This assertion bears directly on the neural substrates of cognitive reappraisal and strategic flexibility, which overlap significantly with structures involved in fear extinction and contextual memory, namely, the prefrontal cortex and hippocampus. Whereas more medial regions of the prefrontal cortex are implicated in fear extinction and emotion regulation, executive functions, including working memory, decision-making, and cognitive flexibility, are typically ascribed to dorsolateral prefrontal regions (Mansouri et al., 2009). In concert with the hippocampus, the dorsolateral prefrontal cortex likely contributes to the integration of the traumatic memory into the present context (Mansouri et al., 2007). Dysfunction in any of these processes may promote the deployment of negative appraisals consistent with those described in cognitive models of PTSD (McAllister, 2011). Although there are no reliable data implicating dorsolateral prefrontal cortex dysfunction in PTSD, hippocampal atrophy has been linked to deficits in explicit memory and to higher rates of dissociative symptoms, indicating a failure of integration of aspects of self with memory (Stein et al., 1997). Thus hippocampal dysfunction may be a reliable neuroanatomical correlate of cognitive models of PTSD.

Cognitive models of post-traumatic stress disorder

NEUROPATHOLOGY OF TRAUMATIC BRAIN INJURY

Although cognitive models of PTSD are often subsumed within the larger neuroanatomical framework of risk and resilience in anxiety disorders, they present some unique considerations regarding the interaction between TBI and PTSD. Cognitive models of PTSD suggest that dysfunction in PTSD is related to an impairment in the reappraisal of stimuli as nonthreatening (Ehlers and Clark, 2000). The model suggests that individuals with PTSD deploy counterproductive appraisals of events surrounding the trauma, ascribing global negative implications to the trauma and failing to see the event as a time-limited. The negative appraisals serve to impair the proper integration of the trauma to its appropriate context in time and place, creating a sense of real and serious current threat. The symptoms of PTSD become entrenched as individuals begin to selectively recall information consistent with their appraisals. In other words, cognitive models highlight the inability to reason through traumatic memories or cues reminiscent of the traumatic context to ascertain the safety of current situations. The neurobiological correlates of the cognitive model are not typically enumerated. Instead, the model proposes that PTSD reflects a lack of adequate “cognitive

There is apparent overlap between the patterns of brain damage typically observed in TBI and brain regions implicated in the behavioral and cognitive sequelae that arise after injury (Fig. 39.1). At the outset, it is important to distinguish between injuries that penetrate into the brain and “closed” head injuries resulting from contact or inertial forces. Whereas closed head injuries elicit characteristic patterns of damage, the spatial distribution of penetrating brain damage depends significantly on the location and trajectory of the penetrating object (McAllister, 2011). In the context of risk for PTSD, it is important to understand the regional specificity of brain damage following TBI. Below, we summarize the structural and functional patterns of brain damage reported in human neuroimaging studies of individuals with closed head injuries.

Brain structure GRAY MATTER/CORTEX Gross cortical damage in TBI is generally caused by: (1) contact forces as the brain rubs against the bony anatomy of the skull, or (2) contrecoup injuries from sudden

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acceleration or deceleration of the brain within the skull. The rough bony anatomy of the anterior and middle cranial fossae and the mobility of the brain within the cranium increase the likelihood of damage to frontotemporal regions in particular (Bigler, 2007, 2008). The most vulnerable regions for this type of brain damage include the ventral anterior, medial, and lateral frontal and temporal cortices (see Fig. 39.1) (Bigler, 2007). Neuroimaging studies of human cortical morphology in TBI typically utilize a technique known as voxel-based morphometry (VBM). This method uses high-resolution structural MRI images to compare the regional concentration of gray matter between groups. Recent VBM studies reveal diffuse reductions in gray matter concentration across the brain following TBI, including bilateral frontal, temporal, and parietal lobes, as well as in the cerebellum (Gale et al., 2005). This study also revealed significant reductions in gray matter concentration in the right medial temporal lobe, including the parahippocampal gyrus. Studies examining gross morphology of subcortical structures after TBI reveal consistent reductions in hippocampal volume following TBI (Karl et al., 2006). Damage to other subcortical regions, including the amygdala and thalamus, has been proposed, but data are inconsistent.

WHITE MATTER Angular acceleration and deceleration elicit shearing forces that place significant strain on subcortical white matter as axons and small blood vessels stretch beyond their tolerated thresholds. The shearing forces that accompany most TBIs have the capacity to induce diffuse axonal injury in the subcortical white matter, disrupting connections between overlying cortical regions. The most common sites of white matter damage are at gray–white matter junctions near the cortex and in the corpus collosum (Bigler, 2001). Gray–white junctions in the frontal and temporal lobes are particularly vulnerable, affecting the connectivity of subcortical structures (e.g., amygdala) with white matter projections to the frontal cortex. Although these studies highlight prefrontal and temporal structures, damage following TBI tends to be rather diffuse. Further, damage in TBI appears to evolve over time, becoming exacerbated by the inflammatory milieu that accompanies tissue injury. It is speculated that acute neuronal injury causes a massive release of neurotransmitters, leading to secondary excitotoxic brain injury (McAllister, 2011). Some structures, including the hippocampus, are especially vulnerable to secondary brain injuries mediated by excitotoxicity, hypoxia, and ischemia (McAllister and Stein, 2010). Secondary reactions to brain injury create an evolving set of

lesions, which likely interact with psychological and somatic states in the recovery period. Taken together, the pattern of structural damage in TBI involves a combination of diffuse brain injury and focal gray and white matter damage in regions particularly relevant to the pathogenesis of PTSD.

Brain function Recently, functional brain imaging studies using positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional MRI (fMRI), have been used to quantify brain metabolism in individuals with a TBI. Data from these studies have led investigators to suggest that significant changes in function may be present even when structural imaging is negative. These studies converge on similar brain regions to those highlighted in the structural imaging literature; notably, frontal and temporal cortices are significantly hypometabolic in TBI patients (Humayun et al., 1989; Gross et al., 1996; Kato et al., 2007). Further, metabolic activity, particularly in temporal regions including the hippocampus, is associated with abnormalities in cognitive function and persistence of postconcussive symptoms (Gross et al., 1996). A recent meta-analysis of fMRI studies in TBI populations suggests that TBI is associated with a typical pattern of dysfunction across a variety of cognitive tasks (Simmons and Matthews, 2012). The investigators identified several clusters in the superior and middle frontal gyri, medial frontal cortex, superior and inferior parietal lobules, and superior temporal gyrus, that were activated differently in individuals with TBI. The interpretations of these data are complicated by several methodological issues common in TBI research, including small sample sizes, retrospective biases in diagnosis, heterogeneous samples, and variability in task demands for the fMRI studies. Despite their limitations, these data converge to implicate the medial prefrontal and temporal lobes as key nodes of dysfunction following TBI.

OVERLAP IN NEUROBIOLOGICAL SUBSTRATES Neurologic risk factors for post-traumatic stress disorder As outlined above, the pattern of organic neurologic damage characteristic of TBI is particularly relevant to the emergence of psychiatric symptoms in the postinjury period. Although TBI elicits diffuse cortical and axonal damage, frontal and subcortical regions involved in fear conditioning, social and affective behavior,

POST-TRAUMATIC STRESS DISORDER AND TRAUMATIC BRAIN INJURY 643 and cognition appear to be especially susceptible. Given essential to investigate the causal link between vmPFC the putative roles of frontal and temporal cortices and damage and amygdala hyperactivity in individuals with underlying white matter in the pathogenesis of PTSD, TBI and PTSD. the preponderance of findings in these areas suggests Hippocampal dysfunction is perhaps the most reliable that the neuropathology of TBI may directly contribute neurobiological correlate common to both TBI and to the development of PTSD. The overlapping neural PTSD. TBI has been consistently linked to hippocampal substrates common to TBI and PTSD are depicted in atrophy and reduced hippocampal volume is one of the Figure 39.1. most commonly cited risk factors for PTSD (Sapolsky, Of particular interest is the convergence of findings 2000; Karl et al., 2006). Hippocampal damage following in the vmPFC and subcortical white matter. These TBI may contribute to the development of PTSD by proregions are particularly vulnerable damage in a TBI moting contextually inappropriate fear responses and (Bigler, 2008), which may explain the high rates of impaired integration of traumatic memories into their emotional and behavioral dysregulation observed after appropriate context in time and place (McAllister, traumatic injury (Stein and McAllister, 2009). However, 2011). The ability to retrieve specific memories of posicounter to the predictions of the neurocircuitry model, a tive experiences in the acute post-trauma phase is a recent study of war veterans with focal lesions to the strong predictor of PTSD, suggesting that hippocampal vmPFC suggests that damage to this region is actually damage in TBI, to the extent that it results in impaired protective against developing PTSD. Veterans with penretrieval of trauma-proximal memories, may be a predisetrating brain lesions encompassing the vmPFC were far posing factor in the development of PTSD (Harvey less likely to develop PTSD than individuals with damage et al., 1998). outside the vmPFC and amygdala (Koenigs et al., 2008). General cognitive impairment is a reliable predictor These data directly contravene the predominant neuroof PTSD (Macklin et al., 1998). Most individuals who circuitry models of PTSD, which predict that vmPFC suffer a TBI demonstrate acute cognitive impairment, damage would promote amygdala hyperactivity and with a sizable minority demonstrating persistent impairexacerbate PTSD symptomatology. Although this findment (Landre et al., 2006; Bigler, 2008). The data are ing appears to call into question the veracity of amygdaconsistent with cognitive models of PTSD that highlight lacentric models of fear extinction and emotion the importance of a “cognitive reserve” in promoting regulation, it is not entirely incompatible in light of funcresilience to the effects of trauma (Ehlers and Clark, tional attributions made to subregions of the vmPFC. In 2000). Therefore, cognitive impairment following a particular, more dorsal regions of the vmPFC have been TBI may contribute to the increased risk of PTSD. Howlinked to metarepresentations of emotional experience ever, the link between cognitive function and a particular and awareness of emotional states (Lane, 2008). Therebrain area is tenuous. Although the hippocampus and fore, these findings suggest that penetrating focal damdorsolateral prefrontal cortex are consistently impliage to the vmPFC may protect against anxiety by cated in a range of cognitive processes, including infordecreasing the subjective feeling of this state. More submation processing, short-term memory, attention, and tle patterns of dysfunction, thinning, and subcortical executive function, it may be premature to ascribe defwhite matter damage, as are commonly observed in icits in executive and cognitive measures to either of TBI, may elicit the expected phenotype. these regions. Despite unclear links to neurobiology, The neurocircuitry model would also predict that cognitive impairment relative to preinjury functioning frontal dysfunction following TBI would lead to amygafter a TBI deserves consideration as an important neudala hyperactivity. However, amygdala dysfunction has ropsychological risk factor for PTSD. not yet been observed in individuals with a TBI. In one To date, no studies have explicitly tested the relationstudy of Vietnam veterans with penetrating damage to ship between the location of damage and dysfunction the amygdala and overlying temporal cortex, the risk after TBI and emergence of PTSD symptoms. However, of PTSD was significantly reduced; none of the patients the data presented above converge to implicate the with damage encompassing the amygdala met the diagmedial prefrontal cortex and hippocampus in the nostic criteria for PTSD (Koenigs et al., 2008). Although pathogenesis of PTSD after a TBI. Future work, using this study suffers from limitations in generalizability to prospective study designs to follow the trajectory of closed head injuries, it is consistent with neurocircuitry organic damage and psychological dysfunction, will model of PTSD in suggesting that the amygdala is critbe necessary to link patterns of brain damage and dysical for the development of psychiatric sequelae after function characteristic of TBI to PTSD. In light of the TBI. As such, a TBI causing amygdala damage or hypodata presented above, it seems likely that TBI-induced function should protect against the development of organic brain damage acts as a permissive gateway PTSD. Future functional imaging studies will be for the development of PTSD.

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FUTURE DIRECTIONS AND IMPLICATIONS FOR TREATMENT The studies reviewed in this chapter provide convincing evidence that PTSD and TBI can co-occur in individuals exposed to trauma. Furthermore, it is clear that these conditions interact in complex ways. This interplay manifests in a unique profile of PTSD symptoms distinct from those observed nonbrain-injured individuals, one in which intrusive symptoms are de-emphasized and avoidance and hyperarousal symptoms are more prominent (Vasterling et al., 2009). A traumatic event with sufficient biomechanical force to elicit a TBI results in some degree of “organic” structural and functional damage, accompanied by an acute psychological reaction to the intense stress of the traumatic event (Bigler, 2007). As noted, many symptoms of the acute stress reaction, particularly amnesia, irritability, and concentration problems, overlap significantly with symptoms typically ascribed to neurologic damage (Table 39.1) (Bryant, 2001a). Despite the overlap in symptoms, it is clear that individuals who suffer a TBI and an accompanying stress reaction are significantly more likely to develop PTSD (Harvey and Bryant, 2000). The pattern of brain damage typically observed in TBI involves several brain regions implicated in the pathogenesis in PTSD, especially the prefrontal cortex and hippocampus (see Fig. 39.1). These data suggest that the progression of psychological symptoms may be related to neurologic damage incurred during the trauma. However, this assertion remains untested and requires careful prospective experimental designs to determine the causality of neurologic insult in the development of psychiatric symptoms. It is likely that the acute psychological reaction to trauma exacerbates the initial neurologic insult, impairing healing and neural plasticity, ultimately leading to persistence of postconcussive symptoms. Indeed, PTSD and other psychiatric responses to trauma appear to be far better predictors of neurologic and cognitive outcomes than symptoms directly ascribed to TBI (Hoge et al., 2008; Pietrzak et al., 2009). Perhaps the most important implications of these findings relate to patient education and treatment selection. The data summarized above provide convincing evidence that psychological factors play a key role in all stages of the progression of TBI. Furthermore, recent work suggests that psychiatric symptoms, and not organic neurologic damage, may be the proximal cause of the somatic and cognitive sequelae commonly attributed to TBI. Although TBI predicts a range of health outcomes, including poor general health, missed workdays, medical visits, and postconcussive symptoms, the relationship becomes nonsignificant when PTSD and depression are included in the analysis (Hoge et al., 2008;

Pietrzak et al., 2009). In light of the strong link between PTSD and the development of postconcussive symptoms and poor health outcomes after a TBI, it seems likely that persistent dysfunction reflects the compounding effects of psychiatric symptoms on brain and body. Misattribution of persistent symptoms to neurologic rather than psychiatric causes may have unfortunate implications for individuals with a TBI and PTSD (Bryant, 2008). Ascribing symptoms to neurologic damage may encourage a belief in their permanence, leading to an expectation of poor recovery. These patients will be more likely to attribute the common stress reactions subsumed by the diagnostic criteria for ASD and PTSD to the effects of brain injury, preventing them from seeking counseling or other psychiatric interventions that may be effective. Indeed, available evidence suggests that psychiatric interventions (e.g., cognitive behavioral therapy) and educational programs are highly effective in alleviating cognitive and somatic sequelae of TBI (Mittenberg et al., 1996). For example, antidepressant treatments and behavioral interventions have been shown to reverse the effects of stress on hippocampal neurogenesis (Bremner et al., 2008); both paroxetine and phenytoin have proven effective in increasing hippocampal volume in individuals with PTSD. However, some antidepressants (e.g., tricyclics) increase the risk of seizures, which would likely be a contraindication for individuals with a TBI. Unfortunately, carefully controlled studies examining the efficacy of pharmacologic and behavioral psychiatric interventions have not yet been conducted in individuals with TBI and PTSD. Considering the unique trajectory of PTSD after a TBI, it remains unclear whether traditional treatments that have proven efficacy in PTSD will be similarly effective in cases complicated by TBI. Patient education to discourage misattribution of stress reactions to neurologic damage, in concert with evidence-based strategies to mitigate psychiatric symptoms, should help to promote resilience and self-efficacy in patients with TBI.

CONCLUSIONS Although much remains to be learned about the interaction between TBI and PTSD, researchers and clinicians are beginning to appreciate the importance of understanding the effects of organic neurologic damage and psychological responses to stress in the context of each individual’s experience. Going forward, a team approach to patient management will be necessary to integrate the expertise of neurologists, psychiatrists, and neuropsychologists. At this stage, there are several critical issues that need attention. First, operational definitions for TBI need to be put forward and standardized in order

POST-TRAUMATIC STRESS DISORDER AND TRAUMATIC BRAIN INJURY to address the significant overlap between acute reactions to organic brain damage and acute psychological stress reactions. Second, prospective studies must be carried out to assess the causal relationship between damage and dysfunction incurred during a TBI and subsequent PTSD. Finally, the efficacy of standard treatments for PTSD must be assessed in individuals with TBI in order to determine conclusively whether psychiatric interventions can improve the cognitive symptoms typical of the postconcussive syndrome. Together, these advances will enable researchers and clinicians to better understand the unique course of PTSD after a TBI.

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Traumatic brain injury and posttraumatic stress disorder.

OND Veterans.

Functional Neuroimaging Distinguishes Posttraumatic Stress Disorder from Traumatic Brain Injury in Focused and Large Community Datasets.

Glucocorticoid functioning in male combat veterans with posttraumatic stress disorder and mild traumatic brain injury.

Combat-Acquired Traumatic Brain Injury, Posttraumatic Stress Disorder, and Their Relative Associations With Postdeployment Binge Drinking.

Positive Psychological Aspects on Posttraumatic Stress Disorder after Traumatic Brain Injury.

Altered Microstructural Caudate Integrity in Posttraumatic Stress Disorder but Not Traumatic Brain Injury.

Association of symptoms following mild traumatic brain injury with posttraumatic stress disorder vs. postconcussion syndrome.

OIF veterans.

Interdisciplinary residential treatment of posttraumatic stress disorder and traumatic brain injury: effects on symptom severity and occupational performance and satisfaction.

Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans.

The temporal relationship between posttraumatic stress disorder and problem alcohol use following traumatic injury.

Specificity of cognitive and behavioral complaints in post-traumatic stress disorder and mild traumatic brain injury.

White Matter Changes in Posttraumatic Stress Disorder Following Mild Traumatic Brain Injury: A Prospective Longitudinal Diffusion Tensor Imaging Study.

Afghanistan war veterans.

The Evolution of Post-Traumatic Stress Disorder following Moderate-to-Severe Traumatic Brain Injury.

Psychotic disorder caused by traumatic brain injury.

Bipolar disorder after traumatic brain injury.

Predictors of posttraumatic stress disorder after burn injury.

Posttraumatic stress disorder.

Disrupted Functional Brain Connectome in Patients with Posttraumatic Stress Disorder.

Brain-derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress.

Posttraumatic Stress Disorder: The Misappropriation of Military Suicide Causation and Medication Treatment of Posttraumatic Stress Disorder.

Measuring secondary traumatic stress symptoms in military spouses with the posttraumatic stress disorder checklist military version.