Alcohol abuse after traumatic brain injury: Experimental and clinical ...

Neuroscience and Biobehavioral Reviews 62 (2016) 89–99

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Alcohol abuse after traumatic brain injury: Experimental and clinical evidence Zachary M. Weil a,∗ , John D. Corrigan b , Kate Karelina a a b

Department of Neuroscience and Group in Behavioral Neuroendocrinology, Columbus, OH, USA Physical Medicine and Rehabilitation, The Ohio State University Medical Center, Columbus, OH, USA

a r t i c l e

i n f o

Article history: Received 13 October 2015 Received in revised form 16 December 2015 Accepted 21 January 2016 Available online 24 January 2016 Keywords: Traumatic brain injury Alcohol Inflammation Substance abuse Rehabilitation Reward

a b s t r a c t Brain injury survivors, particularly those injured early in life are very likely to abuse drugs and alcohol later in life. Alcohol abuse following traumatic brain injury (TBI) is associated with poorer rehabilitation outcomes and a greatly increased chance of suffering future head trauma. Thus, substance abuse among persons with brain injury reduces the chances for positive long-term outcomes and greatly increases the societal costs. In this review, we discuss the evidence for modulation of drinking behavior after TBI and the costs of problem drinking after TBI from both a biomedical and economic perspective. Further, we review the existing animal models of drinking after brain injury and consider the potential underlying psychosocial and neurobiological mediators of this phenomenon. In particular, we highlight the potential interactions among TBI, neuroinflammation and alcohol abuse. Substance abuse is a major problem in this vulnerable patient population and a greater understanding of the underlying biology has the potential to greatly improve outcomes. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Does alcohol abuse increase after TBI? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.1. Military personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 2.2. Childhood injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Alcohol abuse after TBI produces negative outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Animal models of posttraumatic drinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Potential mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 5.1. Neuropsychological basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 5.2. Self medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 5.3. Cognitive deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 5.4. Neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 5.5. Dopaminergic dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

1. Introduction Traumatic brain injury (TBI) is a major public health problem. Annually, in the United States alone approximately 1.7 million peo-

∗ Corresponding author at: Biomedical Research Tower #618, 460 West 12th Ave, Columbus, OH, USA. Fax: +1 614 688 8742. E-mail address: [email protected] (Z.M. Weil). http://dx.doi.org/10.1016/j.neubiorev.2016.01.005 0149-7634/© 2016 Elsevier Ltd. All rights reserved.

ple sustain a TBI and this will result in hundreds of thousands of emergency room visits, hospitalizations and as many as 50,000 deaths (Coronado et al., 2012; Faul et al., 2010). Estimates of the total number of TBI are probably low as many patients never seek medical treatment and these numbers do not include the military. The economic cost of TBI is staggering with some estimates ranging into the hundreds of billions of dollars annually (Silver et al., 2011). Further, previous estimates indicated that there are up to five million TBI survivors living in the US (Centers for Disease Control and

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Prevention, 1999; Zaloshnja et al., 2008); however, recent population surveys suggest that as many as 20% to 25% of adults in the general population may have experienced at least one TBI with loss of consciousness sometime in their lifetime (Ilie et al., 2015; Whiteneck et al., 2015). Alcohol use and misuse are inextricably linked to TBIs, as alcohol intoxication is a proximate cause of an enormous subset of injuries. By some accounts more than half of all TBIs are either directly or indirectly caused by alcohol with large percentages of patients presenting with elevated blood alcohol (Tagliaferri et al., 2006). Importantly, binge drinking, often defined as 5 or more drinks on one occasion, appears to be associated with TBI more than chronic drinking (Centers for Disease Control and Prevention, 1990; Chikritzhs et al., 2001), and produces an odds ratio of 3.4 for sustaining an injury in general, and a greater risk factor for TBIs (Savola et al., 2005). Although abuse of other drugs is a problem among the TBI population, this review will focus on the role of alcohol because of its strong relationship with TBI and because it is the preferred drug of most TBI patients. TBIs caused by alcohol are mainly falls, moving vehicle crashes and assaults. Nearly all assaulted patients were either intoxicated at the time of assault, or met the diagnostic criteria for an alcohol use disorder (Brismar et al., 1983; Savola et al., 2005). Interestingly, although high blood alcohol is a common finding in all trauma patients it is much more common in head injured patients. For instance, bicycle accidents are more common in intoxicated riders and being intoxicated increased the likelihood that a bicycle accident would result in TBIs (Li et al., 2001). Presumably, sober cyclists are able to avoid head injury and in the event of an accident are more likely to present with extremity injuries. The loss of psychomotor control associated with intoxication thus both increases the chances for an accident overall and increases the likelihood that the accident will result in a TBI (Savola et al., 2005). Critically, alcohol misuse after TBI can reduce the efficacy of rehabilitation and increase the chances of developing seizures, mood, and anxiety disorders, as well as greatly increasing the likelihood of subsequent TBIs (Ilie et al., 2014a; Salcido and Costich, 1992; Winqvist et al., 2006). Problem alcohol usage is extremely common both prior to and after TBI. Therefore understanding the independent contributions of TBI to the risk of developing or exacerbating alcohol use disorders has been difficult. In this review, we will evaluate the existing clinical and animal evidence that TBIs, particularly those that occur early in development, increase the lifelong propensity for alcohol abuse and discuss the potential underlying neurobiological mechanisms.

2. Does alcohol abuse increase after TBI? Although a complete evaluation of this issue is beyond the scope of this review, we will summarize some of the existing evidence for increased problem drinking after TBI in at least a subset of patients particularly those injured early in life. For an excellent in depth review see (Bjork and Grant, 2009). Additionally, as summarized below, drinking after TBI can produce significant negative psychosocial, health and employment consequences, thus the relatively high levels of problem drinking in TBI populations is troubling even if they are not greater than in the general population. The vast majority of TBI research has focused on the role of alcohol as a cause or risk factor for TBI rather than the other way around. Several unique features of this population complicate epidemiological research into alcohol consumption following TBI. First, there are a very high percentage of patients that are already alcohol abusers before injury (Corrigan, 1995; De Guise et al., 2009). Further, the populations with the highest rates of substance abuse and the highest rates of TBI are partially overlapping. Specifically,

young males are both the most likely to suffer a TBI and have the highest rates of substance abuse. Further complicating this issue is that there has been an impression from the clinical literature that more severe injuries are associated with lower rates of substance abuse, however, this likely represents, at least in part, that individuals with the most severe injuries may not have direct physical access to alcohol or drugs and, depending on the degree of disability, might require assistance to administer substances (Taylor et al., 2003). Additionally, patients with the most severe injuries that require prolonged (or permanent) institutional care may also not be allowed to take drugs or alcohol because of environmental restrictions (Taylor et al., 2003). Beyond that there is little evidence that TBI subtypes produce differential alcohol outcomes. There is substantial evidence that alcohol use drops immediately after injury because of a combination of disability, hospitalization and other acute factors (Bombardier et al., 2003; Kreutzer and Harris, 1990; Ponsford et al., 2007). Thus, to get a fuller sense of the relationship between TBI and alcohol abuse, researchers must track patients across time. However, there is strong evidence from clinical studies that tracking TBI patients with substance abuse issues is very difficult and that these individuals are often lost to follow-up and thus could result in skewed results (Corrigan et al., 1997). In any case, there is evidence that despite the large negative costs of drinking after TBI, some proportion of patients still drink heavily and some evidence indicates increased or new problem drinking after TBI. The Center for Disease Control and Prevention in collaboration with the TBI Model Systems program has published estimates of pre- and post-injury characteristics of the U.S. population over the age of 16 who receive inpatient rehabilitation for a primary diagnosis of TBI. In the year prior to injury, 22.9% have misused alcohol (Cuthbert et al., 2015). By 5 years post-injury, among those discharged from the hospital who are still alive, 14.1% are misusing alcohol (Corrigan et al., 2014). This decline in the percentage may in part be due to persons who misuse having a greater likelihood to die or be lost to follow-up in the first 5 years post-injury; however, it is also due to some proportion of individuals stopping use because of injury-related impairments or reduced access to alcohol because of disability. Several characteristics of adult TBI patients drinking after injury are clear. First, most studies have reported that alcohol drinking declines precipitously during the first few months after injury and that this represents a window of opportunity for substance abuse treatment/prevention in the TBI population. Second, multiple studies have reported that the rates of alcohol abstinence increase from pre-injury to post-injury indicating that some percentage of patients are heeding their doctor’s advice to avoid alcohol. Third, some patients return to drinking heavily over time after injury. Finally, problem drinking before injury is highly predictive of drinking after injury (Bombardier et al., 2003; Dikmen et al., 1995; Kreutzer and Harris, 1990; Ponsford et al., 2007). There is some suggestion that aspects of substance abuse may be enhanced by TBI in adulthood. For instance, an examination of billing records from a health management organization database revealed a significant difference in the substance abuse rates among patients with a history of psychiatric illness or substance abuse in the year prior to their injury. Patients with no recent pre-injury psychiatric care had an odds ratio of 4.5 for substance abuse in the year following their injuries, before declining over the subsequent 36 months to 1.4 (Fann et al., 2004). Results from the New Haven NIMH Epidemiological Catchment study reported increased drinking behavior after injury, compared to community samples, and increased rates of drug abuse even after controlling for alcohol abuse (Silver et al., 2001). Finally, in a consecutive sample of patients referred to a treatment program for substance abuse after TBI, nearly 20% of patients that had been light drinkers or abstain-


ers prior to injury, showed heavy use after injury (Corrigan et al., 1995). 2.1. Military personnel The large numbers of TBIs in the recent conflicts in Iraq and Afghanistan have yielded conflicting results on post-TBI drinking behavior. Multiple studies have reported that combat-injured service members are more likely to misuse alcohol upon return from deployment (Adams et al., 2012, 2016; Johnson et al., 2015; Rona et al., 2012), with only one study not finding greater alcohol abuse among brain injured soldiers when compared to those who suffered other injuries (Heltemes et al., 2011). However, some studies have found post-traumatic stress disorder (PTSD) to account for the relationship (Miles et al., 2015; Polusny et al., 2011), while others have found a significant association persists when PTSD is accounted for. Analysis of over 13,000 soldiers who had served in Iraq and/or Afghanistan, indicated that soldiers who had experienced a confirmed TBI during active duty were nearly 3 times as likely to present with a substance abuse problem (Carlson et al., 2010). Similarly, among more than 4,000 British soldiers returning from Afghanistan and/or Iraq, those that experienced a TBI were 2.3 times as likely to report alcohol misuse (Rona et al., 2012). A third study investigating binge drinking in active duty military personnel following combat deployment reported that TBI was a risk factor for binge drinking even after controlling for PTSD and demographics, with an odds ratio of 1.48 (Adams et al., 2012, 2016). Why exactly there is stronger evidence of post-TBI alcohol abuse in the military population is not clear. The high level of comorbid posttraumatic stress disorder associated with combatacquired injuries may at least partially explain this phenomenon (Friedemann-Sanchez et al., 2008). Enlisted personnel are the ones most likely to experience drinking issues during active duty but they are also largely young and male, and experience high rates of deployment, all of which are independent risk factors for problem drinking (Bray and Hourani, 2005; Bray et al., 2009). It is also likely that multiple factors interact with the culture of drinking among service personnel, increasing the incidence of both brain injuries and alcohol misuse (Bray et al., 2009) 2.2. Childhood injuries If injuries during development are considered alone the story is quite different. High school students who experienced a TBI with loss of consciousness were 2.3 times as likely to engage in binge drinking and 2.4 times as likely to abuse alcohol overall (Ilie et al., 2014b). In a birth cohort study from New Zealand, children injured before age five were 3.6 times more likely to abuse substances during adolescence than uninjured children. These children were also much more likely to display externalizing behavioral disorders indicating that this kind of injury produces permanent and significant long term disruption (McKinlay et al., 2009). In a TBI model systems database analysis of patients in inpatient rehabilitation for TBI, those patients who had experienced a previous TBI, especially before age 16, were more than twice as likely to have substance abuse issues than those without a previous injury (Corrigan et al., 2013) The differential effects of injury during development compared to adulthood likely represents a combination of factors. First, injuries during childhood occur while significant neurodevelopmental events including myelination, synaptic pruning and the establishment and crystallization of circuitry, particularly in the prefrontal cortex, is still ongoing (Eslinger et al., 1992; Giedd et al., 1999). Further, children may lack the coping and adaptation skills (including the competent use of self-talk to calm negative emotions, goal directed problem solving, self awareness of internal

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emotional states and a better ability to match coping strategy to the specific stressor presented) that develop later in childhood, adolescence or early adulthood (Anderson et al., 2005; Compas et al., 2001). There may be differences in the type and severity of injuries experienced by children, as children are more likely to be injured in falls and injuries induced by abuse than patients injured at other ages (Duhaime et al., 1992; Leventhal et al., 2010). Experience of child abuse is also a risk factor for later alcohol abuse and inversely, parental drinking (and thus the presence of genetic risk factors for alcohol abuse) are risk factors for child abuse (Hawkins et al., 1992) and these factors likely interact with TBI and age to increase the risk of problem drinking. Finally, if TBI reduces behavioral inhibition and impairs judgment (see below) during adolescence, the riskiest time for the development of substance abuse issues, this may lead to an overall increase in the rate of substance abuse later in life (Chambers et al., 2003). One risk factor that younger children likely do not experience, however, is intoxication prior to- or at the time of injury. This hypothesis requires further testing but alcohol use does increase during childhood and into adolescence. Alcohol abuse prior to injury is a major risk factor for abuse afterwards and thus greater drinking in childhood TBI survivors may be independent of the effects of prior problem drinking.

3. Alcohol abuse after TBI produces negative outcomes There has been substantial investigation of the long-term outcomes as a consequence of intoxication at the time of injury. However, much less attention has been paid to the functional consequences of problem drinking after TBI. Much like in the general population, chronic or binge drinking of alcohol causes significant negative psychosocial, cognitive and health consequences in TBI patients (Bouchery et al., 2011; Clark et al., 2001; Nixon et al., 1992; Stavro et al., 2013). However, because the head injured patient has unique challenges not common to the general population it is necessary to consider the role of post-traumatic drinking separately. TBI populations comprise patients ranging from those with relatively mild injuries not requiring formal rehabilitation through patients with severe injuries that may be comatose and require both acute medical care and inpatient rehabilitation. Importantly, the link between TBI and alcohol intoxication is overwhelming, with some studies reporting that alcohol is a proximate cause of nearly 70% of all brain injuries (Corrigan and Mysiw, 2012). Therefore the TBI population consists disproportionally of patients with alcohol use disorders (Corrigan, 1995). Acutely after injury, alcohol consumption tends to drop, probably due in part to lack of access to alcohol in the care environment and the physical disabilities associated with TBI and potential advice from health care providers, especially when prescribed psychoactive medications. Additionally a proportion of individuals report reduced tolerance to the effects of alcohol after TBI (Oddy et al., 1985). However, in the months and years following injury, alcohol consumption tends to return to pre-injury levels, at least in some patients. Studies in clinical populations of patients with brain injury have indicated that alcohol use, even at social levels, produces impairments in both auditory evoked potentials and neuropsychological indices of executive function over and above the deficits detected in brain injured patients who abstained from alcohol (Baguley et al., 1997; Ponsford et al., 2013). Chronic, sustained drinking or repeated binge drinking has been shown to produce a neurodegenerative condition that is associated with neuroinflammation, loss of neurons, demyelination and significant cognitive impairments (He and Crews, 2008; Stavro et al., 2013). Importantly, neurodegeneration in alcohol use disorders appears to be centered around frontal and limbic structures already impaired in TBI (Harper et al., 2003;

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Ikegami et al., 2003) indicating that the deleterious consequences of heavy drinking may be worse in patients with impairments due to TBI and/or previous high levels of drinking. Taken together, it is not surprising that problem drinking after TBI is associated with significantly poorer outcomes. For instance, alcohol misuse after TBI is associated with poorer rehabilitation compliance and outcomes (Corrigan, 1995). Patients who drink to excess after TBI are more likely to meet the diagnostic criteria for mood disorders than are patients who abstain or drink in moderation following injury (Jorge et al., 2005). Alcohol was the most common reason cited for TBI patients to be terminated from jobs obtained through a vocational employment program after both 12 and 30 months of work (Ellerd and Moore, 1992). In terms of organic health outcomes, the rates of post-traumatic seizures are much greater in patients who drink after injury and abstinence from drinking is a common medical instruction for individuals at increased risk for seizures (Vaaramo et al., 2014b). Perhaps most critically, drinking after TBI greatly increases the chances of subsequent TBIs that can produce devastating neurological disability (Vaaramo et al., 2014a). These negative consequences, along with the large amount of epidemiological data indicating that a substantial subset of patients resume problem drinking, has been recognized as a problem by the rehabilitation community. There has been an effort to include substance abuse treatment in the overall TBI rehabilitation program (Bogner et al., 1997; Corrigan and Cole, 2008). However, relatively little work has been done on assessing the costs of continued substance abuse in brain injury patients, and most studies in this field have used intoxication at the time of injury as a proxy for substance abuse rather than directly assessing alcohol abuse after TBI (Alfonso-Loeches et al., 2010; Bombardier et al., 2003; Chen et al., 2012; Dikmen et al., 1993). This short-cut may be due, at least in part, to the difficulty with loss to follow up in this population (Corrigan et al., 1997). In any case, the evidence that alcohol abuse has negative consequences in the general population is overwhelming and therefore targeting the already compromised TBI population is likely of paramount importance.

4. Animal models of posttraumatic drinking As discussed above, clinical and epidemiological studies of the relationship between TBI and alcohol abuse are complicated by the high incidence of prior alcohol abuse in TBI populations, the marked heterogeneity in TBI type, severity and age at injury, and are obscured by the difficulty in tracking alcohol abusing TBI patients longitudinally. Therefore animal studies that can hold these variables constant could provide powerful insight into the underlying biology, although clearly animal models that minimize heterogeneity of injuries also reduce the translatability of findings to clinical populations. There are several common techniques for inducing traumatic brain injury in rodents. Although a full discussion of the methodology is beyond the scope of this paper and these details are reviewed extensively in (Cernak, 2005; Morganti-Kossmann et al., 2010; Xiong et al., 2013) they will be very briefly described here. Lateral or midline fluid percussion injury, is induced by propelling pressurized fluid against the surface of the dura, this model can produce graded injuries depending on the pressure of the fluid and models mild-moderate head injury without skull fracture. Similarly, cortical contusion injuries are produced by opening a small window in the skull and propelling an impactor device directly against the exposed dura and into the brain parenchyma. These injuries can also be graded by the depth and velocity of the impact and result in injuries that produce a focal lesion and diffuse damage. Closed head injuries can be induced by impact acceleration models where

a weight or other device is propelled against the closed skull to model concussive injuries. Finally, blast injuries, intended to model injury induced by explosives or other combat-related stimuli are induced with small explosive devices or rapid changes in air pressure (Cernak, 2005). Several recent experimental studies have reported that TBI alters spontaneous drinking behavior in rodents. Lowing et al. (2014) performed relatively mild closed TBIs using an electromagnetic impactor in adult male mice. They reported that, at least at an acute time point (14–21 days post-injury), TBI mice exhibited reduced intake in the drinking in the dark paradigm compared to sham-injured animals. Further, their injury paradigm increased the sedative effects of intraperitoneal alcohol without apparently altering ethanol metabolism. Finally, injured mice did not exhibit the increase in phosphorylation of DARPP-32, induced by ethanol that was evident in sham-injured mice. The authors speculated that this reduction in ethanol consumption and increase in ethanol sensitivity could serve as a model of the acute reduction in alcohol intake that has been reported in many epidemiological studies (Lowing et al., 2014; Ponsford et al., 2007). In contrast, Mayeux et al. (2015) reported that lateral fluid percussion injury in adult male rats increased operant alcohol intake. Interestingly, the amount of the increase in drinking behavior was strongly correlated with operant alcohol performance prior to the injury, such that rats that drank greater amounts prior to injury exhibited the greatest increase in drinking behavior following TBI. In contrast, rats that drank less at baseline exhibited smaller increases in drinking behavior (Mayeux et al., 2015). Similarly, blast-induced TBI had minimal effect on drinking behavior in Sprague-Dawley rats, a strain that exhibits low baseline alcohol preference (Khanna et al., 1990). Blast TBI did not increase voluntary alcohol administration during a limited access exposure paradigm or after alcohol deprivation. However, a median split analysis indicated that among high drinking rats blast injury increased alcohol intake during a short exposure trial (Lim et al., 2015). These studies together suggest that TBI can differentially exacerbate drinking behavior in individuals with other risk factors for problem drinking. We recently reported that mice injured during juvenile development (approximately 21 days) exhibited significantly greater spontaneous alcohol intake, in adulthood, than did animals injured as adults or sham-injured mice. Further, the increase in drinking behavior only occurred in female mice. Importantly, alterations in alcohol consumption following TBI could be mediated by alterations in sensory responses to alcohol, changes in the kinetics of alcohol metabolism, or alterations in the rewarding properties of alcohol itself. In order to determine the specific mechanism of increased drinking behavior following TBI we performed several additional studies. For instance, loss-of-righting reflex assays indicated that injury did not alter the sensitivity or kinetics of responses to intraperitoneal alcohol. Further, deficits in sensory perception of alcohol did not appear to underlie this increased alcohol intake, as there were no effects of injury on intake of bitter or sweet tastants. Critically, conditioned place preference testing revealed that intraperitoneal alcohol was only rewarding to injured females and not sham-injured females or males (Weil et al., 2015). We next sought to determine whether a proxy for sustained rehabilitation, environmental enrichment, would reduce the increase in drinking behavior following TBI. Notably, environmental enrichment, immediately following the injury and sustained through adulthood abolished the increase in drinking behavior following adolescent TBI. Additionally, enrichment reduced the axonal degeneration and normalized brain derived neurotrophic factor gene expression associated with TBI. In terms of the sex difference in posttraumatic drinking the translational relevance remain unspecified. There has been rela-


tively little investigation into sex differences in the sequelae of childhood TBI in general, or post-traumatic drinking behavior in particular (Witt, 2007). However, there are mounting epidemiological findings that TBI incidence may be increasing, and that women often suffer worse outcomes (Farace and Alves, 2000). Further, women are particularly vulnerable to the medical consequences of heavy drinking, including liver disease, infertility, and mortality (Ashley et al., 1977). Clearly, epidemiological and outcome studies to determine the interactions among sex, age of injury and pre-injury drinking behavior are imperative and will be critical to both understanding this phenomenon and tailoring interventions to specific populations. Taken together, these data indicate that TBI significantly alters the neural circuitry associated with the rewarding properties of alcohol and that it does so in a sex- and age-dependent manner (Weil et al., 2015). These data also provide hope that sustained interventions with these patients have the capacity to reduce overall functional deficits and minimize the risk of developing substance abuse disorders (Weil et al., 2015). On the whole, these animal studies indicate that various aspects of the drinking behavior associated with TBIs, including age and sex differences, biphasic alteration in alcohol intake and the effect of prior drinking, can be effectively modeled in animals. Further, these animal models provide the basis to assess the underlying neurobiological mechanisms that may mediate the increase in drinking after brain injury. 5. Potential mechanisms As discussed above, TBIs tend to result in an acute reduction in drinking followed gradually by a return to pre-injury baseline or higher, as well as much greater rates of problem drinking in patients injured during development or in combat zones. This section of this paper will evaluate and discuss several non-mutually exclusive potential mechanisms for problem drinking after TBI that range from psychosocial to neurochemical. These include self-medication strategies for the mitigation of negative affective state, peer pressure and a desire to relate to social groups via substance use, cortico-limbic dysfunction that makes processing of the potential costs of heavy drinking difficult, changes in drinking mediated by heightened inflammatory responses in the brain, and dysfunction in neurotransmitter signaling (i.e., mesolimbic dopamine system). It is highly likely that the individual substance abuse phenotype that is expressed is the result of a combination of these factors. 5.1. Neuropsychological basis The incentive motivation theory of alcohol suggests that the decision to drink is made in order to attain specific desired outcomes. This theory specifically predicts that individuals believe that drinking behavior will produce either an enhancement of positive or a reduction in negative affect. Increasing positive affect can occur via direct internal effects of alcohol on mood or indirectly via social-based rewards. Similarly, alcohol may reduce negative affect by direct chemical effects on neural substrates mediating mood (or reducing withdrawal symptoms) and indirectly by reducing social anxiety or peer pressure. Additionally, negative consequences (relationship issues, hangover, legal problems, cost etc.,) of drinking are weighed against the perceived benefits and can predict whether individuals will choose to drink. Critically, the specific motivations to drink can predict the pattern of drinking behavior. For instance, individuals who drink for social enhancement tend to drink moderately and are less likely to overuse alcohol than are those who use it for reducing negative affect (Carey and Correia, 1997). TBIs have the potential to influence many different

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aspects of this motivational equation including increasing negative mood and anxiety, reducing social cohesion, and impairing the ability of injured patients to process the potential negative consequences of excessive drinking (Bjork and Grant, 2009; Godfrey et al., 1996; Osborn et al., 2014; Rapoport et al., 2005). 5.2. Self medication One prominent component of the incentive motivation theory that may partially explain the potential increases in drinking behavior after TBI is that drinking occurs as a form of selfmedication and is used to reduce negative affective states, anxiety or other psychiatric symptoms (Bolton et al., 2009; Quitkin et al., 1972). Additionally, there are now powerful links between TBI and the development of posttraumatic stress disorder (PTSD). Three domains of symptoms, re-experiencing, emotional numbing/withdrawal and hyperarousal characterize PTSD (American Psychiatric Association, 2013). The link between TBI and PTSD are both direct and indirect. For instance, a single traumatic event can cause both a brain injury and PTSD. Additionally, because corticolimbic damage (and thus dysfunction in emotional regulation, threat appraisal and endocrine physiology) is an extremely common result of TBI, patients who have suffered a brain injury may be less able to experience subsequent traumatic events without developing PTSD symptoms (Bryant, 2001, 2008; Ford and Russo, 2006; Stein and McAllister, 2009). Among combat veterans nearly 75% of patients who met the diagnostic criteria for PTSD also met the criteria for alcohol abuse or dependence. In the general population, lifetime substance use disorders prevalence range from 8.1 to 24.7% depending on the criteria used. However, in PTSD patients substance abuse rates range from 21.6 to 43% (Breslau et al., 1991; Breslau et al., 1997; Kessler et al., 1995). PTSD rates in the general population are around 8.4% but up to 42.6% among patients in inpatient substance abuse treatment (Cottler et al., 1992; Dansky et al., 1995). Even absent clinical PTSD symptoms, TBI is associated with both mood and anxiety disorders. Additionally, particularly for patients who suffer more severe injuries, there is a significant period of adjustment to living with serious cognitive or physical disabilities that may increase drinking (Bishop, 2005; Smedema and Ebener, 2010). This relationship may be distinct from any direct neurochemical changes mediated by the TBI because there is often increased drinking in patients who have suffered a spinal cord injury which, presumably, has less direct effects on the central alcohol circuitry, but may be more related to the challenge of adapting to a new disability (Elliot et al., 2002; Tate et al., 2004). Further, the period after serious injury is often associated with reduced contact with peer groups and thus drinking may serve as a way to become reintegrated into social settings (Block et al., 2001). It should be pointed out however, that to the best of our knowledge, there is no direct evidence that TBI patients report self-medication with alcohol to mitigate negative affective states. 5.3. Cognitive deficits The flip side of the incentive motivation theory of drinking is that the negative consequences of drinking are weighed against the potential benefits. However, both TBI and alcoholism can impair the neural substrates necessary for processing such costs and thus increase the likelihood of drinking (Graham and Cardon, 2008). Decision-making is very often impaired in TBI patients (Kolitz et al., 2003; Yody et al., 2000). Patients with prefrontal damage perform suboptimally on a gambling task and seem unable to act on explicit information regarding future consequences (Bechara et al., 1994). Further, impulsivity, which is a common outcome of TBI, is a strong predictor of problem alcohol use and is higher among dependent drinkers (Vuchinich and Simpson, 1998; Wood and McHugh,

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2013). In a delayed discounting task, where participants can choose between smaller reinforcers immediately or larger rewards following a delay, both TBI patients and uninjured controls will discount the larger reward with longer delays. However, the slope of the delay curve in TBI patients is steeper and produces sub-optimal rewards indicating that these individuals perform more impulsively (Wood and McHugh, 2013). A general intolerance to delayed consequences has also been reported in other contexts (Newcombe et al., 2011). Clearly these are indirect markers of vulnerability to substance abuse in TBI patients and direct examination of this relationship is warranted, still, many of the cognitive deficits associated with TBI closely resemble those of patients dependent on drugs (Bjork and Grant, 2009; Reynolds, 2006). 5.4. Neuroinflammation TBIs produce persistent inflammatory events in the nervous system that can be detected as cerebral edema, gliosis, proinflammatory cytokine expression, and in some cases infiltration of peripheral leukocytes. Importantly there is a strong and growing body of literature that has defined a bidirectional relationship between alcohol intake and inflammation, wherein alcohol is proinflammatory in the brain and inflammatory states drive alcohol consumption (Crews et al., 2011). Therefore the inflammatory events associated with TBI could serve to drive alcohol intake (Fig. 1). The pathophysiology of TBI is complex and varies across injury type and severity. However, inflammation is a consistent and often sustained feature of TBI (Holmin and Mathiesen, 1999; Johnson et al., 2013; Nagamoto-Combs et al., 2007). TBI is characterized by disruption in the blood brain barrier, mechanical damage to cellular and organelle membranes, uncontrolled release of glutamate and in severe cases hemorrhage or ischemia due to disruptions in the cerebral vasculature (Kelley et al., 2007; Schmidt et al., 2005). Further, these primary mechanical injuries can be followed by cell death and the resultant oxidative and nitrosative stress, spilling of cytoplasmic contents into the extracellular environment and the presence of cellular debris (Cederberg and Siesjö, 2010). These events are all strongly inflammatory causing both the activation of local microglial and astrocyte populations and in some cases the invasion of peripheral leukocytes into the injured tissue (Loane and Byrnes, 2010). Similarly, brains of chronic alcoholic patients exhibit a characteristic pattern indicative of ongoing inflammation. For instance, there are increases in activated microglia and elevated protein content of the chemokine macrophage chemoattractant protein 1 (MCP-1; also known as CCL-2) in the ventral tegmental area, amygdala, hippocampus, and substantia nigra in post mortem brain samples of alcoholic patients (He and Crews, 2008). MCP1 is a protein that can attract and alter the activational state of microglia. MCP-1 concentrations also rise in serum, liver and whole brain homogenates following alcohol exposure in rodent brains (Qin et al., 2008). Other post-mortem studies have also reported increases in the expression of the transcription factor nuclear factor kappa B (Nf␬B) and some of the downstream targets of this signaling cascade in the prefrontal cortex of alcoholic patients (Okvist et al., 2007). In experimental animals, cell culture, and tissue slices, alcohol has repeatedly been shown to directly induce inflammatory responses including activating microglia, inducing cytokine gene expression and driving Nf␬B-dependent transcription (Ward et al., 1996). For instance, binge drinking increases the expression of the proinflammatory mediators TNF and MCP-1 while reducing expression of the anti-inflammatory cytokine IL-10 in whole mouse brain (Qin et al., 2008). Importantly, in the context of brain injury, alcohol amplifies inflammatory responses to other pathogen-associated

molecular patterns. For instance, alcohol increases the expression of proinflammatory cytokines following an injection of lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls that activates the immune system (Qin et al., 2008). The specific mechanisms underlying alcohol-induced activation of inflammatory responses remain under investigation but certainly include alcohol transactivation of toll-like receptors and modulation of proinflammatory gene expression in the cerebral cortex and in cultured microglia (Alfonso-Loeches et al., 2010; Fernandez-Lizarbe et al., 2013). Although neuroinflammation is both a cause and consequence of alcohol use disorders, these data provide strong evidence that alcohol can directly induce neuroinflammation. In traumatically injured brains, where there is already ongoing inflammation, chronic (10 day) exposure to inhaled alcohol exacerbates neurological dysfunction and greatly enhances gliosis and expression of the proinflammatory mediator HMGB1 in the injured cerebral cortex (Teng et al., 2015). Thus in the acute phase after TBI alcohol serves to potentiate inflammation and impair neurological function. Inversely, alcohol intake is increased by inflammatory events. Administration of LPS produces a long lasting increase in alcohol self administration (Blednov et al., 2011). In contrast, minocycline a semisynthetic antibiotic that also reduces microglial activation and proinflammatory gene expression, reduces spontaneous alcohol intake (Agrawal et al., 2011). Transgenic mice lacking genes that promote inflammation such as IL-6, CD-14 or cathepsin S exhibited reduced drinking behavior (Blednov et al., 2012). Similarly, in humans, polymorphisms that promote inflammatory states are more common in patients with alcohol use disorders. For instance polymorphisms in the Nf␬B, TNF␣, interleukin-10 (IL-10) and IL-1 antagonist genes were independently associated with alcohol use disorders (Edenberg et al., 2008; Marcos et al., 2008; Pastor et al., 2000). Thus, both chronic alcohol intake and TBI promote neuroinflammatory events in the CNS. Therefore alcohol intake following TBI may be part of a feed-forward mechanism wherein inflammatory events from the TBI promote alcohol intake, and alcohol intake further reinforces and amplifies the inflammatory state of the nervous system. 5.5. Dopaminergic dysfunction There is substantial evidence that TBIs dysregulate the midbrain dopaminergic systems and that this dysfunction contributes to the chronic cognitive and behavioral sequelae associated with TBI (Bales et al., 2009). Additionally, hypofunction of the dopamine system is a major risk factor for the development of substance and alcohol use disorders (Koob, 1992; Koob and Volkow, 2010; Nestler, 2005). The evidence of dopaminergic dysfunction following TBI comes from multiple studies where dopamine receptor agonists or other dopaminergic drugs have improved cognitive, behavioral and motor function after injury in both experimental animals and the clinical literature (Bales et al., 2009). The behavioral and cognitive sequelae of TBI, including deficits in reasoning, attention, memory and executive control, can be attributed in large part to damage or reduced function of the prefrontal cortex and striatum (Stuss, 2011; Witt et al., 2010), brain regions that are rich in dopamine receptors and dependent on dopamine signaling for optimal function (Robbins and Arnsten, 2009). There is relatively little clinical evidence for TBI-mediated impairments in dopamine physiology. Single photon emission tomography imaging in TBI patients (ranging from mild to severe) revealed reductions in striatal binding of both D2 receptors and dopamine transporters despite the absence of actual lesions to the striatum (Donnemiller et al., 2000). Further, injury severity


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Fig. 1. Potential interactions among brain injury, inflammation and post-traumatic drinking. TBI is characterized by damage to the blood brain barrier, mechanical damage to cellular and organelle membranes, uncontrolled release of excitatory amino acids and in severe cases hemorrhage or ischemia. These events are all strongly inflammatory thus activating local microglial and astrocyte populations and drawing other inflammatory cells into the brain. Alcohol is also potently neuroinflammatory and directly induces inflammatory responses including activating microglia, inducing cytokine gene expression and driving NF␬B-dependent transcription. Critically, alcohol intake is increased by inflammation. Inflammation produces a long lasting increase in alcohol self-administration that is associated with reductions in spontaneous firing of ventral tegmental dopaminergic neurons in vitro, suggesting impairments in reward processes. Although the specific neuroanatomical network that mediates this phenomenon remains unspecified, it likely includes known components of the alcohol reward system, including the dorsal and ventral striatum, ventral tegmental area, amygdala, and prefrontal cortex. Thus, neuroinflammation is both a cause and consequence of alcohol use disorders and TBI may establish a vicious cycle of greater alcohol intake, driven in part by inflammation, leading to increased inflammatory responses in the brain and more drinking.

did not predict the magnitude of alterations in dopamine receptor or transporter binding in the striatum indicating that this deficit is a common feature of TBI (Donnemiller et al., 2000). Finally, expression of the dopamine degrading enzyme catechol-omethyltransferase (COMT) is chronically elevated following TBI in adults (Redell and Dash, 2007) and children (Kurowski et al., 2015). Despite the lack of strong evidence for dopaminergic dysfunction in human patients three drugs that either directly agonize dopamine receptors or increase synaptic dopamine, bromocriptine (McDowell et al., 1998), methylphenidate (Gualtieri and Evans, 1988) and amantadine hydrochloride (Sawyer et al., 2008), have shown clinical efficacy in reducing striatocortical symptoms of TBI and are part of the standard of care for TBI patients (Neurobehavioral et al., 2006). Both methylphenidate and amantadine administered after cortical contusion injury improved performance on the Morris water maze task in rats (Dixon et al., 1999; Kline et al., 2000). These studies and many others (reviewed in (Bales et al., 2009)) strongly suggested that dopaminergic activity following TBI was either significantly dysregulated or insufficient to properly manage cognition following TBI (Bales et al., 2009). In contrast, a wealth of experimental animal studies have demonstrated that there are both rapid and sustained alterations in dopamine physiology after TBI. First, dopaminergic neurons in the midbrain are both killed by lateral fluid percussion injuries and rendered more vulnerable to damage from environmental toxins (Hutson et al., 2011). Dopamine concentrations in the cortex and striatum rise sharply after both fluid percussion and cortical impact and remain elevated for around the first 24 h post injury (Massucci et al., 2004; McIntosh et al., 1994). Other studies have reported increases in tyrosine hydroxylase expression and activity for up to two weeks post-injury that were associated with increased

infra- and prelimbic dopamine concentrations (Kobori et al., 2006). Additionally, the dopamine transporter protein (DAT) is down regulated for at least 2–4 weeks after experimental TBI (Shimada et al., 2014; Wagner et al., 2005). Under normal circumstances, a reduction in DAT expression should increase synaptic dopamine availability but no differences in dopamine reuptake are detectable following TBI (Wagner et al., 2005). These initial increases in dopamine after injury appear to be compensatory and rapidly give way to an extended period of striatocortical hypodopaminergia (Wagner et al., 2005). For instance, by two weeks after injury there is a reduction in electrically-, methylphenidate-, and potassiumevoked dopamine concentrations in the striatum (Bales et al., 2009; Shin et al., 2011; Wagner et al., 2005; Wagner et al., 2009). Interestingly this deficit can be reversed by prolonged treatment with the dopamine transporter inhibitor methylphenidate suggesting that the clinical benefit of these compounds may be related to a restoration in basal dopaminergic efflux (Bales et al., 2009). Additionally, the possibility exists that the initial increase in dopamine concentrations that occur following TBI may be responsible for long-term downregulation of dopamine signaling (Huger and Patrick, 1979; Massucci et al., 2004; McIntosh et al., 1994). Rats exposed to a binge-like level of alcohol in adolescence, but not in adulthood, exhibit life-long alterations in dopaminergic signaling (Philpot et al., 2009; Zandy et al., 2015). Exposure to binge-like blood alcohol concentrations during adolescence greatly increases dopamine efflux during intoxication. However, when those mice that were exposed to binge-like levels of alcohol during adolescence reach adulthood, they exhibit blunted dopaminergic signaling and responses to alcohol and also drank at much higher levels (Pascual et al., 2009; Philpot et al., 2009). Therefore, the possibility exists that the persistent increases in drinking behavior

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following injury during adolescence are mediated by the increased dopamine concentrations that occur immediately following TBI, thus permanently altering dopaminergic activity in adulthood, requires additional study. Importantly, it is highly artificial to consider the dopaminergic and inflammatory responses to TBI independently. Rather, there is extensive evidence that proinflammatory cytokines produced by activated immune cells can alter mood states at least in part by modulating dopamine signaling (Felger and Miller, 2012; Raison and Miller, 2011) and inversely that impaired dopamine release could potentially induce inflammation (Guillot and Miller, 2009). For instance, the rate limiting step in dopamine synthesis is the conversion of tyrosine into L-DOPA by the enzyme tyrosine hydroxylase (Cunnington and Channon, 2010). This enzymatic reaction requires the enzyme co-factor tetrahydrobiopterin (BH4), which is highly sensitive to oxidative modification and is also a cofactor in the activity of the inducible nitric oxide synthase enzyme, which is highly expressed in activated glia after TBI (Cunnington and Channon, 2010; Ono et al., 2010; Wada et al., 1998). Thus, inflammation can result in a reduction in available dopamine precursors by shunting BH4 into the production of nitric oxide. Further, inflammatory cytokines inhibit the activity of the vesicular monoamine transporter (VMAT), responsible for loading dopamine into synaptic vesicles (Kazumori et al., 2004). Dopaminergic neurons are highly vulnerable to damage mediated by auto-oxidation of dopamine and the production of neurotoxic quinone molecules (Gaki and Papavassiliou, 2014; Hastings and Zigmond, 1997; Jenner and Olanow, 1996). Thus, inflammatory events that reduce the activity of VMAT result in increases in intracellular dopamine that can lead to oxidative damage to dopaminergic cells (Guillot and Miller, 2009) while simultaneously reducing the dopamine available for synaptic communication (Felger and Miller, 2012). Traumatic brain injury is an event that both sensitizes central immune responses and directly reduces dopaminergic tone (Witcher et al., 2015). Additionally, inflammatory events are generally anti-dopaminergic and hypodopamine states are proinflammatory (Felger and Miller, 2012). Finally, this state of affairs is apparently conducive to increased alcohol use, which is also proinflammatory and can modulate dopaminergic function and impairments in mood state and cognitive function (Bales et al., 2009). Thus, interventions that target either dopaminergic dysfunction or neuroinflammation in the injured brain may have several overlapping benefits including improving cognitive function and mood, and reducing the likelihood of problem drinking. The concept of treating substance abuse disorders with anti-inflammatory therapies is gaining support but conceivably could be even more efficacious in the TBI population (Coller and Hutchinson, 2012; Hutchinson et al., 2012).

6. Conclusion and future directions TBI is tightly linked to alcohol abuse given the powerful relationship between intoxication and brain injuries. As such there has been a large and sustained effort in the TBI community to understand how alcohol abuse (1) affects the likelihood of experiencing a brain injury, and (2) contributes to cognitive and functional recovery from TBI. The purpose of this review was to shed light on a gap in our understanding the inverse relationship: how a TBI affects the likelihood of alcohol abuse (if not other drugs of abuse) following the injury. Taken together there are several sets of conclusions that we can draw. First, alcohol abuse drops off after injury and in a fairly large percentage of patients remains relatively low. However, there is another population of patients that will either resume alcohol abuse after injury or will develop a new alcohol use disorder at least in part because of the TBI. Although there is some evidence

for increased alcohol abuse in survivors of adult TBI, the effects are relatively modest and probably partially obscured by the high rates of prior alcohol abuse among in the population. In sharp contrast, injuries that occur during childhood and adolescence appear to greatly increase the likelihood of alcohol abuse. Given the negative consequences of post-injury alcohol abuse on both rehabilitation outcomes and overall quality of life, it is of paramount importance that these individuals be identified and targeted for clinical intervention as early as possible. The specific psychological and biological mechanisms that underlie post-traumatic drinking are not entirely clear. The existing animal and human data suggest that increased drinking behavior results from a combination of self-medication of negative affective states, impaired decision making, social pressures and alterations in neurochemical signaling that are likely mediated, at least in part, by ongoing neuroinflammation. There remains much basic and clinical research needed to define the proximate causes and determinants of problem drinking. Further, there are suggestive data that interventions can reduce the likelihood of alcohol abuse in this population, as indicated by the lack of enhanced drinking behavior and improved dopaminergic function in animals housed in enriched environments after injury (Wagner et al., 2005; Weil et al., 2015). It is not clear, whether similar interventions will be effective in reducing posttraumatic drinking in humans although sustained rehabilitation is effective at improving outcomes in other domains (Gordon et al., 2006). In any case, a better understanding of the relationships among these biopsychosocial phenomena is going to have important implications for the prevention and treatment of alcohol abuse following brain injury and has the potential to significantly improve outcomes in this population. References Adams, R.S., Larson, M.J., Corrigan, J.D., Horgan, C.M., Williams, T.V., 2012. Frequent binge drinking after combat-acquired traumatic brain injury among active duty military personnel with a past year combat deployment. J. Head Trauma Rehabil. 27, 349–360. Adams, R.S., Larson, M.J., Corrigan, J.D., Ritter, G.A., Horgan, C.M., Bray, R.M., Williams, T.V., 2016. Combat-acquired traumatic brain injury, posttraumatic stress disorder, and their relative associations with postdeployment binge drinking. J. Head Trauma Rehabil. 31 (1), 13–22. Agrawal, R.G., Hewetson, A., George, C.M., Syapin, P.J., Bergeson, S.E., 2011. Minocycline reduces ethanol drinking. Brain Behav. Immun. 25 (Suppl. 1), S165–S169. Alfonso-Loeches, S., Pascual-Lucas, M., Blanco, A.M., Sanchez-Vera, I., Guerri, C., 2010. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J. Neurosci. 30, 8285–8295. American Psychiatric Association, 2013. Diagnostic and statistical manual of mental disorders: DSM-5, 5th ed., American Psychiatric Publishing, Arlington Va. Anderson, V., Catroppa, C., Morse, S., Haritou, F., Rosenfeld, J., 2005. Functional plasticity or vulnerability after early brain injury? Pediatrics 116, 1374–1382. Ashley, M.J., Olin, J.S., le Riche, W.H., Kornaczewski, A., Schmidt, W., Rankin, J.G., 1977. Morbidity in alcoholics. Evidence for accelerated development of physical disease in women. Arch. Intern. Med. 137, 883–887. Baguley, I.J., Felmingham, K.L., Lahz, S., Gordon, E., Lazzaro, I., Schotte, D.E., 1997. Alcohol abuse and traumatic brain injury: effect on event-related potentials. Arch. Phys. Med. Rehabil. 78, 1248–1253. Bales, J.W., Wagner, A.K., Kline, A.E., Dixon, C.E., 2009. Persistent cognitive dysfunction after traumatic brain injury: a dopamine hypothesis. Neurosci. Biobehav. Rev. 33, 981–1003. Bechara, A., Damasio, A.R., Damasio, H., Anderson, S.W., 1994. Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50, 7–15. Bishop, M., 2005. Quality of life and psychosocial adaptation to chronic illness and disability: preliminary analysis of a conceptual and theoretical synthesis. Rehabil. Couns. Bull. 48, 219–231. Bjork, J.M., Grant, S.J., 2009. Does traumatic brain injury increase risk for substance abuse? J. Neurotrauma 26, 1077–1082. Blednov, Y.A., Benavidez, J.M., Geil, C., Perra, S., Morikawa, H., Harris, R.A., 2011. Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav. Immun. 25 (Suppl. 1), S92–S105. Blednov, Y.A., Ponomarev, I., Geil, C., Bergeson, S., Koob, G.F., Harris, R.A., 2012. Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict. Biol. 17, 108–120.

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