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 49
The ebb and flow of traumatic brain injury research JORDAN GRAFMAN1* AND ANDRES M. SALAZAR2 Department of Physical Medicine and Rehabilitation; Department of Psychiatry and Behavioral Sciences; Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Medical School and Department of Psychology, Northwestern University, Chicago, IL, USA
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Oncovir Inc., Washington, DC, USA
RECENT TRENDS IN TRAUMATIC BRAIN INJURY RESEARCH As noted throughout this volume, traumatic brain injury (TBI) is a common event, although the majority of TBIs are mild and either never arrived at an emergency room or are discharged shortly after a brief evaluation (see Ch. 1). Nevertheless, the field has increasingly recognized the broad systemic and neurologic consequences of TBI, many of which can have a major impact on TBI survivors. These range from general systemic and autonomic changes to motor, language, behavioral, and cognitive changes. Many of these sequelae are detailed in this volume. While TBI evaluation and treatment strategies, particularly for moderate and severe injuries, have been fairly stable over the last three decades, the dissatisfaction with them in the TBI community is frequently articulated (see Chs 2 and 29). Newer methods of evaluation are discussed in this volume with different intervention or outcome targets depending on the particular goals of the evaluation, whether it be to predict survival, inform neuroprotection research choices, predict acute care requirements and duration of treatment, choose therapeutic strategies for their potential use in rehabilitation in order to enhance community outcomes, or predict risk of longer-term TBI-related neurodegenerative disorders. Thanks to research in the TBI field, there is increasing knowledge about the neurobiological mechanisms underlying the response to trauma, brain repair, persistent tissue dysfunction, and plasticity (see Chs 5, 7, 22, and 42). Primarily using animal models, a very detailed picture of the complex post-trauma molecular response
to injury and damage is emerging (see Ch. 8). Such investigations have led to the development of new biomarker assays for TBI (see Ch. 16), new suggestions for various treatment options, and a new awareness of the extended time course of some of these processes. This is further discussed below. Recent US combat operations have resulted in a new cohort of patients with TBI, and the increasing use of improvised explosive devices by opposing forces has led to a new awareness that blast exposure may also result in a significant traumatic brain injury (see Chs 6, 11, 20, and 24). Although blast-induced TBI rarely occurs without another concurrent blow to the head, initial reports suggest that pure blast injury causes deficits that resemble the effects of a blunt mild TBI or concussion. Animal models indicate the unique mechanisms by which a blast exerts its force in the body, eventually impacting brain tissue and function, but animal models are limited by the nature of the experimental designs used to examine blast injury (e.g., the animal held stationary, size of brain, etc.). It is also likely that at least some combatants will have multiple exposures to blasts, putting them at higher risk for the long-term effects of repetitive brain injury (see Ch. 4). There is thus an increasing need for development of biomarkers and evaluation instruments for the early postinjury period. One likely marker appears to be the hyperphosphorylated tau protein, which is increasingly associated with mild TBI. On the other hand, while sequelae such as post-traumatic epilepsy (PTE) are highly associated with penetrating combat brain injury, there are few or no data to suggest any significant increased risk of PTE in patients surviving mild or moderate isolated blastforce TBI.
*Correspondence to: Jordan Grafman, Ph.D., Director, Brain Injury Research, Chief, Cognitive Neuroscience Laboratory, Coleman Chair of Rehabilitation Medicine, Rehabilitation Institute of Chicago, 345 East Superior Street; Suite 1796, Chicago, Illinois 60611, USA. Tel: +1-312-238-1495, E-mail: [email protected]
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The military’s interest in determining the risk for brain injury after blast exposure has also motivated researchers to look at other occupations where individuals might be exposed to blast, such as construction workers or breachers (professionals who use or train others to use explosives for military, police, or industrial purposes). Such work is ongoing and potentially could lead to new operational regulations in order to avoid even the mild effects of blast on the brain due to occupational risk.
RESEARCH STABILITY Despite many technological and methodological advances in fields that are relevant for the investigation of the effects of TBI, some of the basic tenets of TBI clinical management and research as well as the recovery slope have not changed over the last three decades. Most recovery is still within the first 3–6 months postinjury, with slower changes in the first year, and few changes occurring beyond 1–2 years without significant further rehabilitation intervention. Although individual differences based on age, preinjury abilities, education, sex, severity of injury, rehabilitation efforts, and other factors will be apparent (see Ch. 43), recovery still follows this general pattern. With some exceptions, treatment practices in the emergency room also remain stable, with most research eliminating ineffective practices rather than introducing new reliable and effective treatments (see Chs 15, 23, and 29). Despite the advent of high-resolution brain scans and related techniques (see Chs 9, 17, and 18), it may still be difficult to ascribe many of the symptoms seen after mild TBI to persistent brain damage, since simply exposing someone to a traumatic event (without any evidence of acquired brain damage) can cause short-term behavioral cognitive changes (see Chs 9 and 39). At least in some cases of suspected mild TBI, however, diffusion tensor imaging has shown structural (and presumably functional) changes in the white matter of selected tracts that may explain some of the variability in post-mild TBI outcomes (but see Ilvesma¨ki et al., 2014, for caution in interpreting DTI changes in TBI).
TIMELINE FOR INTERVENTION Many chapters in these two volumes detail the rapid advances made in identifying the molecular response to brain injury, along with the time window of opportunity for optimizing various interventions. Clearly the greatest focus has been in understanding and in stemming the secondary brain damage that occurs in the hours and days following an injury, but opportunities may also exist for primary prevention and especially for beneficial modulation of the longer term neuroplastic response.
PRIMARYAND SECONDARY NEUROPROTECTION Preinjury prevention strategies Aside from accident prevention strategies, including behavioral control of risk taking, use of helmets, seat restraints and other vehicle design features, another intriguing aspect of primary neuroprotection is the question of whether the brain and the organism in general can be subacutely preconditioned to better cope physiologically with a given injury. Recent studies in the stroke field suggest that this is indeed the case. For example, preconditioning with limb ischemia has been shown to protect from subsequent ischemic cerebral injury in animals and is now being explored in clinical trials (Hougaard et al., 2014). Likewise, early studies suggest that induction of a preinjury protective antiinflammatory state with agents such as certain Toll-like receptor (TLR) agonists (TLR 3 and 9) can provide dramatic protection from cerebral and renal ischemic injury (Packard et al., 2012; Pan et al., 2014; Wang et al., 2014). The immunomodulatory mechanisms underlying this effect are still under intense investigation and appear to involve alteration of the balance between pro- and anti-inflammatory signaling cascades immediately postinjury, but current studies suggest that the protection is limited to a few days and intervention must generally be given in anticipation of the injury. From a pragmatic point of view this currently limits its value to certain situations in which an individual is at immediate high risk for an ischemic or traumatic injury, but the potential for extending the window of effectiveness to the immediate postinjury period shows great promise, particularly with regard to certain elements of the secondary injury cascade. (See also Chs 5, 22, 28, and 47.)
Acute care and traumatic brain injury Perhaps one of the most practically important advances in TBI over the past three decades has been the realization of the particular sensitivity of the injured brain to additional secondary hypoxic/ischemic injury, and the widespread implementation of strategies for immediate postinjury resuscitation (see Ch. 23). While rapid transport of the moderate to severely injured TBI patient to a trauma center emergency room is a critical part of this paradigm, perhaps even more important is the widespread training of the lay population in the ABCs of resuscitation: “Airway, Breathing, Circulation,” to be applied immediately at the site of the accident. Much of this advance has been driven by military evacuation procedures after combat injury. For example, during the Vietnam conflict, in addition to immediate resuscitation in the field, most patients had definitive
THE EBB AND FLOW OF TRAUMATIC BRAIN INJURY RESEARCH 797 neurosurgery within a few hours of injury, a remarkable potentially useful for smaller N studies, may well be interval at that time. Helicopter evacuation pioneered in more appropriate for acute TBI trials. Similarly, the the Korean and Vietnam conflicts thus helped revoluquite variable results in outcome have persuaded many tionize care for combat head injuries and was rapidly prominent TBI clinical researchers to adopt comparative incorporated into civilian systems, many of which have effectiveness designs to tease out potentially predictive now surpassed the military experience. treatment variables (Maas et al., 2010). Given all these factors, the costs associated with demonstrating efficacy to the satisfaction of regulatory MEDICAL NEUROPROTECTION agencies have further blunted the enthusiasm of the STRATEGIES AND PITFALLS IN CLINICAL pharmaceutical industry for development of TBITRAUMATIC BRAIN INJURY RESEARCH specific neuroprotective drugs. Alternatively, advances In addition to the hypoxic/ischemic events in the immediin neuroprotective interventions for more common ate and early period post-trauma, the recognition of the and more readily studied conditions such as stroke cascade of secondary neuronal injury post-TBI and its may lead to progress in TBI. potential medical management has led to extensive research over the past several decades that is detailed TRAUMATIC BRAIN INJURY in many of the chapters in this volume. A myriad of trials REHABILITATION are either underway or have been recently conducted to A remaining weakness in TBI research, despite an extenlimit these effects, but no trial has shown dramatic and sive literature, is determination of the effectiveness of reliable effects to date. Most recently, two large definidifferent rehabilitation treatments for significantly tive trials of progesterone for severe TBI have failed to improving outcomes, including return to work, return show a benefit (Wright et al., 2014; Skolnick et al., 2014). to school, family integration, and social mobility (see The challenges associated with designing and conCh. 48 and the Handbook of Neurology, vol. 110). Rehaducting such neuroprotection trials have generated conbilitation strategies have not typically been subjected to siderable controversy over the past few decades. Issues the rigorous scrutiny for efficacy and cost-efficiency range from the heterogeneity of TBI and secondary found in many other fields of medicine. To date, there injury mechanisms, to the need for single or combination are still very few well-controlled clinical trials indicating agents with a broader multipotential spectrum of activthat current rehabilitation methods in any domain are ity, to patient selection, to tailoring of outcome meaany better than a matched control condition. Many of sures to particular interventions, etc. These issues are the reasons for the failure of acute neuroprotection trials further detailed in Chapters 22, 28, 29, 46, and 47. discussed above are also valid here. Rehabilitation itself Among the more promising recent avenues are control is often multifaceted, making it difficult to tease apart of post-traumatic neuroinflammation and modulation specific effects of selected interventions in the context of microglial activation in the acute postinjury period. of the overall rehabilitation regimen the patient receives, Similarly, a vicious cycle leading to chronic microglial although this criticism can be dealt with by introducing activation may continue to injure tissue for months clinical trials postrehabilitation, even if that limits the (and perhaps years) and may play a role in development generalization of any effects to that time period. of post-traumatic epilepsy as well as in chronic neurodeAlthough remarkable feats of engineering have recently generation. Likewise, the identification of tau protein as given hope to amputees that bionic limbs may prove both a potential culprit in the latter also opens potential thercost-effective and functionally useful in the very near apeutic avenues. future, and other advances in understanding sensorimoAt the same time, there has been considerable disaptor functions have allowed for the development of pointment with the typical acute care clinical trial devices to stimulate arm and hand movement and designs utilized by other areas of medicine and borrowed brain–machine interfaces that may help patients obtain for TBI research (see Chs 46 and 47). For example, the greater motor control, other areas of rehabilitation medtypical natural, yet variable early improvement posticine have lagged in their ability to facilitate outcomes. TBI can make it difficult to tease out therapeutic effects It is not a secret that (with the possible exception of of an intervention. Similarly, the complexities of definindividuals with prior select motor skills and roles), the ing injury severity and the marked individual differences best predictors of outcome are not sensorimotor ability in the location of an injury can overwhelm the ability of or mobility, but social and executive functions. Yet, there the treatment randomization process to control for these are very few clinical trials that have shown a positive multiple variables effectively, and may even call into functional outcome in these domains compared to conquestion the utility of the classic randomized controlled trol conditions. The exclusion of neuropsychology from trial in this situation. Thus, Bayesian statistical designs,
798 J. GRAFMAN AND A.M. SALAZAR insurance reimbursement for cognitive remediation conas possible, with longer-term predictions of outcome tributes to this dilemma, thus limiting the expertise that over several years. can be utilized in patient management. But perhaps a bigYet little has been known about the effects of an earger issue is the lack of research by cognitive neuroscienlier TBI on the aging nervous system. Meta-analytic tists in most rehabilitation programs and consequently studies have indicated, on average, a slightly higher risk the slow adoption of advances in cognitive neuroscience of developing a later life neurodegenerative disease for into rehabilitation practice. For example, there have been TBI patients compared to matched controls, but these rapid advances in many areas of executive and social effects were often small. There is also little evidence that behavior research that could help drive rehabilitation patients suffering penetrating TBI, compared to closed efforts if encouraged (see Chs 26, 31, and 37). head injury, were at any greater risk of later life neuroIn addition, there are promising and speedy advances degenerative disease (see Ch. 44). Recently, renewed in portable device technology that might allow for the interest in the later life effects of TBI has been spurred real-time use of such devices for compensatory purposes by case and nonrandomized small group reports on a in patients with persistent deficits in memory retrieval, TBI-induced encephalopathy in people primarily decision making, and socially appropriate behavior. exposed to repeated concussions due to playing profesNot only would these devices potentially create more sional sports (see Chs 4, 9, and 10). The behavioral manindependent individuals while relieving the burden on ifestations of this form of encephalopathy tended to primary caregivers, but their use beyond the immediate resemble that seen in the behavioral variant of frontotherapeutic milieu would allow useful interventions to be temporal degeneration (FTD), although the exact posiextended further into the post-TBI time period and tioning of the tau pathology in the brain noted in the community. chronic traumatic encephalopathy syndrome (CTE) is Another example of the distressing lack of interacdistinct from that seen in FTD. Even if the sampling tion between cognitive neuroscientists and rehabilitation methods in these early CTE reports were biased for professionals is the lack of studies examining whether a inclusion, they still indicate that a proportion of people systematic approach to rewarding patients during rehaexposed to repetitive concussions or in some cases a sinbilitation would provide reinforcement that is superior to gle concussion because of their employment or particithe current mostly informal and variable feedback given pation in sports will be at higher risk for developing a to patients when they achieve therapeutic goals. In genCTE. Since the precipitating event in these cases is eral, explicit, and under certain conditions, implicit repeated concussion or mild TBI, scientific investigators rewards can have a significant effect upon performance have been attempting to use biomarkers to determine that is often sustained after the removal of the rewarding whether any significant brain damage can accompany stimulus. a mild TBI and, in particular, whether the abnormal bioFinally, a cautionary point should be made. In the marker changes persist (see Ch. 16). effort to rehabilitate patients and promote certain abiliCan brain biomarkers identify those mild TBI ties, is it possible that we incur a loss in other abilities? patients most at risk for later life neurodegenerative disThere is limited brain real estate and even with network orders and who might thus be obvious targets for therareorganization, some forms of plasticity inevitably peutic intervention? Recent studies have shown “borrow” neurons from the borderland between funcdetectable albeit transient elevations of tau protein in tional brain sectors, allowing for subtle changes in the serum of concussed players, although any link to behavior – both positive and negative. Thus, when mealong-term cognitive loss is still speculative (Shahim suring for improvement in a specific behavioral funcet al., 2014). Rather than wait decades in the case of early tion, we should also be measuring behavior dependent life TBIs, it may be possible to accelerate this research by upon either the neighboring or homologous brain sectors studying people with a first concussion or mild TBI in to ensure they remain at least functionally stable in the later life, thus shortening the period between the precippresence of attempts to rehabilitate behavior dependent itating event and the average age of onset of neurodeupon the damaged region. generative disorders. Another hypothesis is that TBI, in some individuals, triggers a persistent and abnormal inflammatory reaction that exceeds the normal response LONG-TERM EFFECTS OFA TRAUMATIC to an acute TBI. This persistent inflammatory response BRAIN INJURY might lead to a breakdown in normal neural environment “housekeeping chores,” leading to the development of As we indicated above, much effort has been made to abnormal cellular structures such as overproduction of chart the recovery slope following TBI in order to help tau that can lead to a neurodegenerative disorder. clinically manage the patient, introduce interventions Detecting such a persistent response might lead, in this at the appropriate time, and provide the family, as early example, to an anti-inflammatory therapy that could
THE EBB AND FLOW OF TRAUMATIC BRAIN INJURY RESEARCH 799 help reduce later life risk for a neurodegenerative disorincreasingly recognized phenotypic changes that can der. This is only one of several possible mechanisms for be induced by therapeutic interventions. Rehabilitation how single or repetitive TBI earlier in life could lead to for TBI is, in principle, an intensive effort at promoting later life neurodegenerative disease. Even if there were neuroplasticity at both levels in order to facilitate recovonly a few TBI survivors susceptible to CTE, identifying ery of functions affected by brain damage. There is evithe causal factors could potentially also lead to a better dence that neuroplasticity is composed of several understanding of the mechanisms governing short-term features, including the reorganization of local and disneural environmental responses to TBI. tributed neural networks, with some of this remodeling Occasionally, there may also be diagnostic confusion involving specific synaptic morphology changes, at least surrounding later life decline in neurobehavioral funcin some spared brain regions. Seen in this light, proper tions after an earlier TBI if some consideration is not rehabilitation can prevent the emergence of maladaptive given to the potential additive effects of early brain dambehaviors which in turn likely have their basis in aberrant age and the typical changes in neuronal loss that accomregeneration or redirection of neural networks. pany aging (see also Ch. 43 on cognitive versus brain In the early post-TBI period, brain repair mechanisms reserve). As shown best by studies of patients who sufmay overlap with neuroplastic processes responsive to fered a penetrating brain injury in combat and who have the post-TBI rehabilitation environments people find preinjury induction cognitive test data available, a themselves in, although eventually neuroplastic prosteeper decline in functions can be documented based cesses are predominant, spurring discussion about the on several factors including preinjury cognitive ability, most effective ways and time to deliver rehabilitation. size and location of lesion, and genetic predisposition Currently it is unclear whether and how early brain repair (see below). But this decline in function is not due to a mechanisms might influence concurrent or later facilitaneurologic disease and can be distinguished in its earlier tion of neuroplastic processes (see Ch. 42). manifestation later in life from the new onset of a neuAre there new methods or technologies that might rodegenerative disease (Moretti et al., 2012). Whether facilitate recovery of function by modulating the brain’s this exacerbated neurobehavioral decline eventually trigneuroplastic inclinations? As discussed, attempts at gers other processes that lead to a “secondary” neurodeacute pharmacologic neuroprotection to date have had generative disease is at present unknown. minimal if any effects on functional outcomes (see Chs 22 and 28). However, the use of neural stem cells or certain growth or trophic factors may replenish or NEUROPLASTICITY support not only adaptive reliance on an existing netThe effect of neuroplasticity on function can generally work, but also compensatory processes, including some be conceived of as restorative or compensatory and of those that are governed by the homologous brain secmay either be relatively passive or facilitated by systemtor in the opposite hemisphere and that previously played atically applied therapeutic interventions. Neuroplastia relatively minor role in performing a selected task comcity can also have unintended negative consequences pared to the impaired function. such as the development of phantom pain. Although neuNoninvasive brain stimulation techniques such as roplasticity supports behavioral change and normal transcranial magnetic stimulation (TMS) or transcranial learning in healthy people, as well as in patients followdirect current stimulation (tDCS) also hold some proming brain damage, it is unclear whether there is an advanise in facilitating or inhibiting cortical (and some subcortage in implementing therapeutic interventions as early tical) brain sectors enough to modulate behavior, with as possible versus at later stages of recovery of function some investigators demonstrating significant and meanafter moderate to severe TBI, when the patient is more ingful improvements in mood and various behaviors that able to accommodate the demands of therapeutic persist beyond the therapeutic trial (Iyer et al., 2005; instructions and participate in the therapy. Some eviWassermann and Grafman, 2005; Huey et al., 2007; dence indicates that early intervention has some advanKoenigs et al., 2009). More widespread and larger clintage in steering the overall recovery of function effect ical trials are needed to support the routine use of non(see Ch. 42), although the often rapid, traininginvasive brain stimulation within the rehabilitation independent brain repair that typically occurs in the early environment. More invasive deep brain stimulation has postacute period makes it more difficult to evaluate the been used in comatose patients (Giacino et al., independent contribution of early rehabilitation or other 2013, 2014) and Ch. 25. interventions to recovery of function. Optimal designs for learning and retaining all kinds One useful paradigm is that of two basic interconof information have been reported in the cognitive psynected aspects to the issue of neuroplasticity: plasticity chology literature for over two decades, with some at the tissue level and plasticity at the behavioral, methods slowly being adopted by educators. These cognitive level. The two come together through the methods argue for use of massed practice for improving
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short-term retention and use of spaced practice for promoting long-term retention. Frequent testing is better at improving later test performance and long-term retention compared to rote practice. As noted before, there may be some limitations to trying such novel therapeutic designs in a rehabilitation medicine facility because of restrictive reimbursement practices for rehabilitation institutions, thus leaving such research to be implemented after discharge from a rehabilitation facility (see Ch. 48). In principle, it should be expected that these methods would have the same effect in patients who suffered a TBI as in the primarily healthy volunteers who participated in the research that led to these general findings. Finally, conducting basic cognitive neuroscience studies that lead to improved knowledge about the brain basis of many cognitive and social functions can contribute to the improved design of strategic interventions to promote positive recovery of function after a TBI. Eventually, newer technologies such as wearable devices, cell phones, and tablets can all be used for delivery of validated cognitive training paradigms under varying reallife conditions. They will also be used to complement the patient’s cognitive abilities by presenting needed information to the patient in real time in the relevant environment. There has long been concern about the effect of a brain injury on subsequent violence and aggression, including in veterans returning from combat with potential TBIs. Aside from a continuing premorbid risk for such behavior, there is evidence that location of lesion and genetic predisposition are important factors in predicting aggression and violence (Pardini et al., 2011, 2014). However, genetic predisposition is not destiny, and environmental exposure may reduce the phenotypic expression of a given gene. For example, there is evidence that having the bad version of a gene that is predictive of increased violence and aggression is of less concern if a person is raised in a healthy family environment. This effect has been linked to epigenetic modification of genetic instructions and emphasizes that all kinds of environmental exposures may mitigate the effects of certain genetic polymorphisms. Such factors as the timing and duration of exposures that could have epigenetic ramifications that could lead to a temporary or permanent effect on genetic predisposition are currently underspecified.
motivation to learn certainly contribute to premorbid abilities, it is also likely that genetic predisposition will play a key role in mediating the development of greater premorbid abilities and promoting postinjury recovery of function (see Chs 3 and 45). Key genes that will affect recovery from TBI may include some placing the person at risk for later life neurodegenerative disorders, but mostly should include those genes that help manage the repair of damaged or dysfunctional brain tissue as well as genes concerned with facilitating neuroplasticity. While some candidate modulator genes that may have the greatest predictability for outcome following a TBI have been identified, the typically smaller cohorts in these studies limit the number of genes that can be sampled adequately in any one study. There are many reasons to pursue this area of research, including the possibility of eventually developing a genetic panel for rehabilitation triage that might help dictate the intensity and frequency of rehabilitation for individual TBI patients and the design of individual tailored programs. In addition, it should be possible to conduct basic research on genetic polymorphisms that influence neuroplasticity by using fibroblast-derived neural stem cells from living TBI participants in order to examine their in vitro neuronal morphology and neural network development. This research could help identify the molecular determinants that distinguish people with good and bad outcomes after a TBI. If reliable differences could be identified, then new potential therapeutic interventions could be developed that target the relevant neuroplastic processes. Epigenetic changes are known to be induced from various kinds of environmental exposures and can potentially counteract the negative effects caused by specific genetic polymorphisms. One looming question for rehabilitation is whether patient exposure to rehabilitation therapies induces an epigenetic change or whether more extended exposure to therapy is necessary to produce a desired change such as alteration of the risk for violence discussed above. The animal research literature, although reporting on many forms of epigenetic manipulation of a gene’s instructions that eventually lead to a change in neuronal function, has yet to determine the optimal timing and duration of a potential environmental exposure to induce this desired effect or what the persistence is of the obtained epigenetic effect. Answers to these crucial questions will eventually indicate whether rehabilitation can take advantage of epigenetic prods to facilitate recovery of function and long-term outcomes following a TBI.
GENETIC PREDISPOSITION AND EPIGENETICS
CONCLUDING REMARKS
Many research studies have demonstrated the importance of cognitive predisposition or reserve upon recovery of function following brain damage (see Ch. 43). While an enriched premorbid environment and
In this concluding chapter, we have highlighted some of the limitations and promises apparent in ongoing research in traumatic brain injury. This volume has focused on the science of TBI, although we believe that
THE EBB AND FLOW OF TRAUMATIC BRAIN INJURY RESEARCH 801 two nonscientific factors will continue to play a role in entering a rehabilitation setting to participate in shortthe success of rehabilitation interventions post-TBI. and long-term research projects. Another solution is to One involves the practice of rehabilitation medicine open the rehabilitation hospital to a multidisciplinary and the other involves reimbursement strategies for medical team that could include, for example, profesrehabilitation medicine. Keeping in mind that current sionals from outside the typical fields employed by reharehabilitation practice still allows clinicians and scientists bilitation institutions. Adding sufficient time for access to potential research participants for relatively postdoctoral and other forms of research training in extended periods of time post-TBI, there are still striking the rehabilitation medicine setting would provide for limitations in the training and practice of neurophysiaimproved training for fellows who are making a committrists and on clinical neuropsychological participation ment to clinical research. Making rehabilitation outpain rehabilitation medicine that affect rehabilitation medtient facilities more research friendly could also make icine’s scientific potential. a difference in recruitment of research participants, as Among the disciplines concerned with treating and many families may not wish to make frequent visits to studying TBI, including neurology, psychiatry, neuroa downtown rehabilitation hospital to participate in surgery, cognitive neuroscience, and a few of the allied research. Rehabilitation practice could also benefit from health professions, rehabilitation medicine physicians do the routine acquisition of standard neuroimaging (to not fare as well compared to physicians from most other identify location and volume of brain damage across medical disciplines in receiving investigator-initiated groups), from genetic polymorphism profiles, and from grants from funding agencies, both in the US and in including in their patient registries the basic components Europe. In the US, many of the largest and most of the NIH Common Data Elements (Thurmond et al., respected rehabilitation institutions are independent 2010). Finally, systematic evaluation of long-term outorganizations that include a flagship inpatient hospital comes is needed for the patient, primary caregiver, along with outpatient facilities. While many of these and other social stakeholders in the rehabilitation proinstitutions have an affiliation with local universities cess, such as employers or the education system. and foundations, their principal means of income come Without such systemic changes that help integrate from insurance reimbursements for an extended course novel research avenues with routine patient care (as of treatment for their patients. With some notable excephas been accomplished in cardiac, stroke, and especially tions (e.g., bioengineering projects), time-intensive rehacancer medicine), progress in TBI will be slower and bilitation research usually has to wait for the patient to more laborious than necessary. Such changes will ultibe discharged from the acute care rehabilitation hospital mately improve the effectiveness and cost-efficiency before being initiated. Furthermore, if a scientific study of TBI management by accelerating the introduction invalidated some of the techniques that are currently into practice of new therapies based on advances in reimbursed due to having been “grandfathered” for hisgenetics, noninvasive manipulation of molecular protorical rather than scientific reasons, it could create a cesses to aid brain repair and functional plasticity, the financially unstable situation for some rehabilitation addition of complementary, supplementary, and substihospitals, potentially drastically reducing the treating tution devices to aid motor control and cognitive/social professionals reimbursable time with patients. Aside abilities, improvements in noninvasive brain stimulation from financial considerations, a closely related issue, techniques, more refined neuroimaging, and more tarcommon to much of medicine but especially to TBI, is geted drugs for TBI patient management. the often delayed introduction into practice of even Unlike many diseases, traumatic brain injury will proven improvements in care, for a variety of reasons. always be to some extent unavoidable for a certain proThus due to limitations in research training of many, portion of the human population. Whether due to combut not all, rehabilitation specialists and reimbursement bat, sports, vocational risk, accidents, or bad behavioral concerns, it may be difficult, despite the best of intenchoices, traumatic brain injury is here to stay. Preventive tions, to introduce novel clinical trials and basic research measures prior to a TBI can go a long way to modify its into an inpatient setting unable to easily accommodate effect through reduction of brain injuries (e.g., do not them. Some solutions to this situation are clear if diffidrink and drive, pretreat with medications that would cult to implement. Greater encouragement of and collabpromote brain repair in the case of an injury and would oration in research by the insurance industry and/or be otherwise safe to take), mitigation (e.g., helmets for government reimbursement agencies is one obvious bicyclists), or simply having the right predisposition approach. Another is designing space that encourages (both genetic and behavioral) that allows a person to the mingling of clinical and research staff in order to recover from, and better cope with, a traumatic brain foment new ideas about rehabilitation practice and injury. Although TBI remains common in the US popudevelop new research studies. The additional establishlation (see Ch. 1), the ebb and flow of interest in TBI is a ment of active research registries can encourage patients product of when publicity is given to the combat-related
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brain injury, sports injuries, and the potential long-term effects of a brain injury earlier in life. The fluctuating research interest in the topic is partly dependent then on increased funding that reflects the public’s awareness of, and interest in, TBI. Of great importance is whether a period of substantial research advances in TBI can result in better clinical management of patients with TBI. One positive example occurred after our experience in studying Vietnam veterans as part of phase 2 of the Vietnam Head Injury Study (VHIS). Those lessons led to the establishment of the Defense and Veterans Head Injury Program, a disease management program integrating specialized head injury care with clinical research supported jointly by the US Departments of Defense and Veterans Affairs, in collaboration with the civilian Brain Injury Association (BIA). The DVHIP was subsequently reorganized into the Defense and Veterans Brain Injury Center (DVBIC), and other, more recent offshoots of these efforts have been established. This helped catalyze an increased attention to TBI by the public in general and by other funding agencies, with a consequent flow of resources to academia for TBI research. One important lesson is that advancing research knowledge about TBI can, when paired with appropriate and assertive advocacy, elicit pragmatic changes that improve the management and treatment of TBI patients. We hope that the current swell of research into TBI has such a result. These two volumes of the Handbook of Clinical Neurology have attempted to provide important research information and insights into TBI that complement rather than supplants several excellent and more clinically oriented TBI textbooks that are currently available. As is apparent to anyone engaged in clinical or basic neuroscience research, we are advancing into a new era dominated by improving understanding of the human genome and proteome, the use of newer and smaller technologies to evaluate biological status and deliver therapeutic interventions, and more refined computational and functional models of human behavior. These combined advances should enable us to improve our efforts at diagnosing and treating TBI. But these advances will only have the desired consequences if the healthcare environment where they are most needed is ready to cooperate and accept them. We hope that will happen.
REFERENCES Giacino JT, Katz DI, Whyte J (2013). Neurorehabilitation in disorders of consciousness. Semin Neurol 33: 142–156. Giacino JT, Fins JJ, Laureys S et al. (2014). Disorders of consciousness after acquired brain injury: the state of the science. Nat Rev Neurol 10: 99–114.
Hougaard KD, Hjort N, Zeidler D et al. (2014). Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial. Stroke 45: 159–167. Huey ED, Probasco JC, Moll J et al. (2007). No effect of DC brain polarization on verbal fluency in patients with advanced frontotemporal dementia. Clin Neurophysiol 118: 1417–1418. Ilvesmaki T, Luoto TM, Hakulinen U et al. (2014). Acute mild traumatic brain injury is not associated with white matter change on diffusion tensor imaging. Brain 137: 1876–1882. Iyer MB, Mattu U, Grafman J et al. (2005). Safety and cognitive effect of frontal DC brain polarization in healthy individuals. Neurology 64: 872–875. Koenigs M, Ukueberuwa D, Campion P et al. (2009). Bilateral frontal transcranial direct current stimulation: failure to replicate classic findings in healthy subjects. Clin Neurophysiol 120: 80–84. Maas AI, Harrison-Felix CL, Menon D et al. (2010). Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Arch Phys Med Rehabil 91: 1641–1649. Moretti L, Cristofori I, Weaver SM et al. (2012). Cognitive decline in older adults with a history of traumatic brain injury. Lancet Neurol 11: 1103–1112. Packard AE, Hedges JC, Bahjat FR et al. (2012). Poly-IC preconditioning protects against cerebral and renal ischemiareperfusion injury. J Cereb Blood Flow Metab 32: 242–247. Pan LN, Zhu W, Li Y et al. (2014). Astrocytic Toll-like receptor 3 is associated with ischemic preconditioning- induced protection against brain ischemia in rodents. PLoS One 9: e99526. Pardini M, Krueger F, Hodgkinson C et al. (2011). Prefrontal cortex lesions and MAO-A modulate aggression in penetrating traumatic brain injury. Neurology 76: 1038–1045. Pardini M, Krueger F, Hodgkinson CA et al. (2014). Aggression, DRD1 polymorphism, and lesion location in penetrating traumatic brain injury. CNS Spectr 2014: 1–9. Shahim P, Tegner Y, Wilson DH et al. (2014). Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol 71: 684–692. Skolnick BE, Maas AI, Narayan RK et al. (2014). A clinical trial of progesterone for severe TBI. N Engl J Med http://dx.doi.org/10.1056/NEJMoa1411090. Thurmond VA, Hicks R, Gleason T et al. (2010). Advancing integrated research in psychological health and traumatic brain injury: common data elements. Arch Phys Med Rehabil 91: 1633–1636. Wang PF, Fang H, Chen J et al. (2014). Polyinosinicpolycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3. J Immunol 192: 4783–4794. Wassermann EM, Grafman J (2005). Recharging cognition with DC brain polarization. Trends Cogn Sci 9: 503–505. Wright DW, Yeatts SD, Silbergleit MD et al. (2014). Very early administration of progesterone for acute TBI. N Engl J Med http://dx.doi.org/10.1056/NEUMoa1404304.
Chapter 49
The ebb and flow of traumatic brain injury research JORDAN GRAFMAN1* AND ANDRES M. SALAZAR2 Department of Physical Medicine and Rehabilitation; Department of Psychiatry and Behavioral Sciences; Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Medical School and Department of Psychology, Northwestern University, Chicago, IL, USA
1
2
Oncovir Inc., Washington, DC, USA
RECENT TRENDS IN TRAUMATIC BRAIN INJURY RESEARCH As noted throughout this volume, traumatic brain injury (TBI) is a common event, although the majority of TBIs are mild and either never arrived at an emergency room or are discharged shortly after a brief evaluation (see Ch. 1). Nevertheless, the field has increasingly recognized the broad systemic and neurologic consequences of TBI, many of which can have a major impact on TBI survivors. These range from general systemic and autonomic changes to motor, language, behavioral, and cognitive changes. Many of these sequelae are detailed in this volume. While TBI evaluation and treatment strategies, particularly for moderate and severe injuries, have been fairly stable over the last three decades, the dissatisfaction with them in the TBI community is frequently articulated (see Chs 2 and 29). Newer methods of evaluation are discussed in this volume with different intervention or outcome targets depending on the particular goals of the evaluation, whether it be to predict survival, inform neuroprotection research choices, predict acute care requirements and duration of treatment, choose therapeutic strategies for their potential use in rehabilitation in order to enhance community outcomes, or predict risk of longer-term TBI-related neurodegenerative disorders. Thanks to research in the TBI field, there is increasing knowledge about the neurobiological mechanisms underlying the response to trauma, brain repair, persistent tissue dysfunction, and plasticity (see Chs 5, 7, 22, and 42). Primarily using animal models, a very detailed picture of the complex post-trauma molecular response
to injury and damage is emerging (see Ch. 8). Such investigations have led to the development of new biomarker assays for TBI (see Ch. 16), new suggestions for various treatment options, and a new awareness of the extended time course of some of these processes. This is further discussed below. Recent US combat operations have resulted in a new cohort of patients with TBI, and the increasing use of improvised explosive devices by opposing forces has led to a new awareness that blast exposure may also result in a significant traumatic brain injury (see Chs 6, 11, 20, and 24). Although blast-induced TBI rarely occurs without another concurrent blow to the head, initial reports suggest that pure blast injury causes deficits that resemble the effects of a blunt mild TBI or concussion. Animal models indicate the unique mechanisms by which a blast exerts its force in the body, eventually impacting brain tissue and function, but animal models are limited by the nature of the experimental designs used to examine blast injury (e.g., the animal held stationary, size of brain, etc.). It is also likely that at least some combatants will have multiple exposures to blasts, putting them at higher risk for the long-term effects of repetitive brain injury (see Ch. 4). There is thus an increasing need for development of biomarkers and evaluation instruments for the early postinjury period. One likely marker appears to be the hyperphosphorylated tau protein, which is increasingly associated with mild TBI. On the other hand, while sequelae such as post-traumatic epilepsy (PTE) are highly associated with penetrating combat brain injury, there are few or no data to suggest any significant increased risk of PTE in patients surviving mild or moderate isolated blastforce TBI.
*Correspondence to: Jordan Grafman, Ph.D., Director, Brain Injury Research, Chief, Cognitive Neuroscience Laboratory, Coleman Chair of Rehabilitation Medicine, Rehabilitation Institute of Chicago, 345 East Superior Street; Suite 1796, Chicago, Illinois 60611, USA. Tel: +1-312-238-1495, E-mail: [email protected]
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The military’s interest in determining the risk for brain injury after blast exposure has also motivated researchers to look at other occupations where individuals might be exposed to blast, such as construction workers or breachers (professionals who use or train others to use explosives for military, police, or industrial purposes). Such work is ongoing and potentially could lead to new operational regulations in order to avoid even the mild effects of blast on the brain due to occupational risk.
RESEARCH STABILITY Despite many technological and methodological advances in fields that are relevant for the investigation of the effects of TBI, some of the basic tenets of TBI clinical management and research as well as the recovery slope have not changed over the last three decades. Most recovery is still within the first 3–6 months postinjury, with slower changes in the first year, and few changes occurring beyond 1–2 years without significant further rehabilitation intervention. Although individual differences based on age, preinjury abilities, education, sex, severity of injury, rehabilitation efforts, and other factors will be apparent (see Ch. 43), recovery still follows this general pattern. With some exceptions, treatment practices in the emergency room also remain stable, with most research eliminating ineffective practices rather than introducing new reliable and effective treatments (see Chs 15, 23, and 29). Despite the advent of high-resolution brain scans and related techniques (see Chs 9, 17, and 18), it may still be difficult to ascribe many of the symptoms seen after mild TBI to persistent brain damage, since simply exposing someone to a traumatic event (without any evidence of acquired brain damage) can cause short-term behavioral cognitive changes (see Chs 9 and 39). At least in some cases of suspected mild TBI, however, diffusion tensor imaging has shown structural (and presumably functional) changes in the white matter of selected tracts that may explain some of the variability in post-mild TBI outcomes (but see Ilvesma¨ki et al., 2014, for caution in interpreting DTI changes in TBI).
TIMELINE FOR INTERVENTION Many chapters in these two volumes detail the rapid advances made in identifying the molecular response to brain injury, along with the time window of opportunity for optimizing various interventions. Clearly the greatest focus has been in understanding and in stemming the secondary brain damage that occurs in the hours and days following an injury, but opportunities may also exist for primary prevention and especially for beneficial modulation of the longer term neuroplastic response.
PRIMARYAND SECONDARY NEUROPROTECTION Preinjury prevention strategies Aside from accident prevention strategies, including behavioral control of risk taking, use of helmets, seat restraints and other vehicle design features, another intriguing aspect of primary neuroprotection is the question of whether the brain and the organism in general can be subacutely preconditioned to better cope physiologically with a given injury. Recent studies in the stroke field suggest that this is indeed the case. For example, preconditioning with limb ischemia has been shown to protect from subsequent ischemic cerebral injury in animals and is now being explored in clinical trials (Hougaard et al., 2014). Likewise, early studies suggest that induction of a preinjury protective antiinflammatory state with agents such as certain Toll-like receptor (TLR) agonists (TLR 3 and 9) can provide dramatic protection from cerebral and renal ischemic injury (Packard et al., 2012; Pan et al., 2014; Wang et al., 2014). The immunomodulatory mechanisms underlying this effect are still under intense investigation and appear to involve alteration of the balance between pro- and anti-inflammatory signaling cascades immediately postinjury, but current studies suggest that the protection is limited to a few days and intervention must generally be given in anticipation of the injury. From a pragmatic point of view this currently limits its value to certain situations in which an individual is at immediate high risk for an ischemic or traumatic injury, but the potential for extending the window of effectiveness to the immediate postinjury period shows great promise, particularly with regard to certain elements of the secondary injury cascade. (See also Chs 5, 22, 28, and 47.)
Acute care and traumatic brain injury Perhaps one of the most practically important advances in TBI over the past three decades has been the realization of the particular sensitivity of the injured brain to additional secondary hypoxic/ischemic injury, and the widespread implementation of strategies for immediate postinjury resuscitation (see Ch. 23). While rapid transport of the moderate to severely injured TBI patient to a trauma center emergency room is a critical part of this paradigm, perhaps even more important is the widespread training of the lay population in the ABCs of resuscitation: “Airway, Breathing, Circulation,” to be applied immediately at the site of the accident. Much of this advance has been driven by military evacuation procedures after combat injury. For example, during the Vietnam conflict, in addition to immediate resuscitation in the field, most patients had definitive
THE EBB AND FLOW OF TRAUMATIC BRAIN INJURY RESEARCH 797 neurosurgery within a few hours of injury, a remarkable potentially useful for smaller N studies, may well be interval at that time. Helicopter evacuation pioneered in more appropriate for acute TBI trials. Similarly, the the Korean and Vietnam conflicts thus helped revoluquite variable results in outcome have persuaded many tionize care for combat head injuries and was rapidly prominent TBI clinical researchers to adopt comparative incorporated into civilian systems, many of which have effectiveness designs to tease out potentially predictive now surpassed the military experience. treatment variables (Maas et al., 2010). Given all these factors, the costs associated with demonstrating efficacy to the satisfaction of regulatory MEDICAL NEUROPROTECTION agencies have further blunted the enthusiasm of the STRATEGIES AND PITFALLS IN CLINICAL pharmaceutical industry for development of TBITRAUMATIC BRAIN INJURY RESEARCH specific neuroprotective drugs. Alternatively, advances In addition to the hypoxic/ischemic events in the immediin neuroprotective interventions for more common ate and early period post-trauma, the recognition of the and more readily studied conditions such as stroke cascade of secondary neuronal injury post-TBI and its may lead to progress in TBI. potential medical management has led to extensive research over the past several decades that is detailed TRAUMATIC BRAIN INJURY in many of the chapters in this volume. A myriad of trials REHABILITATION are either underway or have been recently conducted to A remaining weakness in TBI research, despite an extenlimit these effects, but no trial has shown dramatic and sive literature, is determination of the effectiveness of reliable effects to date. Most recently, two large definidifferent rehabilitation treatments for significantly tive trials of progesterone for severe TBI have failed to improving outcomes, including return to work, return show a benefit (Wright et al., 2014; Skolnick et al., 2014). to school, family integration, and social mobility (see The challenges associated with designing and conCh. 48 and the Handbook of Neurology, vol. 110). Rehaducting such neuroprotection trials have generated conbilitation strategies have not typically been subjected to siderable controversy over the past few decades. Issues the rigorous scrutiny for efficacy and cost-efficiency range from the heterogeneity of TBI and secondary found in many other fields of medicine. To date, there injury mechanisms, to the need for single or combination are still very few well-controlled clinical trials indicating agents with a broader multipotential spectrum of activthat current rehabilitation methods in any domain are ity, to patient selection, to tailoring of outcome meaany better than a matched control condition. Many of sures to particular interventions, etc. These issues are the reasons for the failure of acute neuroprotection trials further detailed in Chapters 22, 28, 29, 46, and 47. discussed above are also valid here. Rehabilitation itself Among the more promising recent avenues are control is often multifaceted, making it difficult to tease apart of post-traumatic neuroinflammation and modulation specific effects of selected interventions in the context of microglial activation in the acute postinjury period. of the overall rehabilitation regimen the patient receives, Similarly, a vicious cycle leading to chronic microglial although this criticism can be dealt with by introducing activation may continue to injure tissue for months clinical trials postrehabilitation, even if that limits the (and perhaps years) and may play a role in development generalization of any effects to that time period. of post-traumatic epilepsy as well as in chronic neurodeAlthough remarkable feats of engineering have recently generation. Likewise, the identification of tau protein as given hope to amputees that bionic limbs may prove both a potential culprit in the latter also opens potential thercost-effective and functionally useful in the very near apeutic avenues. future, and other advances in understanding sensorimoAt the same time, there has been considerable disaptor functions have allowed for the development of pointment with the typical acute care clinical trial devices to stimulate arm and hand movement and designs utilized by other areas of medicine and borrowed brain–machine interfaces that may help patients obtain for TBI research (see Chs 46 and 47). For example, the greater motor control, other areas of rehabilitation medtypical natural, yet variable early improvement posticine have lagged in their ability to facilitate outcomes. TBI can make it difficult to tease out therapeutic effects It is not a secret that (with the possible exception of of an intervention. Similarly, the complexities of definindividuals with prior select motor skills and roles), the ing injury severity and the marked individual differences best predictors of outcome are not sensorimotor ability in the location of an injury can overwhelm the ability of or mobility, but social and executive functions. Yet, there the treatment randomization process to control for these are very few clinical trials that have shown a positive multiple variables effectively, and may even call into functional outcome in these domains compared to conquestion the utility of the classic randomized controlled trol conditions. The exclusion of neuropsychology from trial in this situation. Thus, Bayesian statistical designs,
798 J. GRAFMAN AND A.M. SALAZAR insurance reimbursement for cognitive remediation conas possible, with longer-term predictions of outcome tributes to this dilemma, thus limiting the expertise that over several years. can be utilized in patient management. But perhaps a bigYet little has been known about the effects of an earger issue is the lack of research by cognitive neuroscienlier TBI on the aging nervous system. Meta-analytic tists in most rehabilitation programs and consequently studies have indicated, on average, a slightly higher risk the slow adoption of advances in cognitive neuroscience of developing a later life neurodegenerative disease for into rehabilitation practice. For example, there have been TBI patients compared to matched controls, but these rapid advances in many areas of executive and social effects were often small. There is also little evidence that behavior research that could help drive rehabilitation patients suffering penetrating TBI, compared to closed efforts if encouraged (see Chs 26, 31, and 37). head injury, were at any greater risk of later life neuroIn addition, there are promising and speedy advances degenerative disease (see Ch. 44). Recently, renewed in portable device technology that might allow for the interest in the later life effects of TBI has been spurred real-time use of such devices for compensatory purposes by case and nonrandomized small group reports on a in patients with persistent deficits in memory retrieval, TBI-induced encephalopathy in people primarily decision making, and socially appropriate behavior. exposed to repeated concussions due to playing profesNot only would these devices potentially create more sional sports (see Chs 4, 9, and 10). The behavioral manindependent individuals while relieving the burden on ifestations of this form of encephalopathy tended to primary caregivers, but their use beyond the immediate resemble that seen in the behavioral variant of frontotherapeutic milieu would allow useful interventions to be temporal degeneration (FTD), although the exact posiextended further into the post-TBI time period and tioning of the tau pathology in the brain noted in the community. chronic traumatic encephalopathy syndrome (CTE) is Another example of the distressing lack of interacdistinct from that seen in FTD. Even if the sampling tion between cognitive neuroscientists and rehabilitation methods in these early CTE reports were biased for professionals is the lack of studies examining whether a inclusion, they still indicate that a proportion of people systematic approach to rewarding patients during rehaexposed to repetitive concussions or in some cases a sinbilitation would provide reinforcement that is superior to gle concussion because of their employment or particithe current mostly informal and variable feedback given pation in sports will be at higher risk for developing a to patients when they achieve therapeutic goals. In genCTE. Since the precipitating event in these cases is eral, explicit, and under certain conditions, implicit repeated concussion or mild TBI, scientific investigators rewards can have a significant effect upon performance have been attempting to use biomarkers to determine that is often sustained after the removal of the rewarding whether any significant brain damage can accompany stimulus. a mild TBI and, in particular, whether the abnormal bioFinally, a cautionary point should be made. In the marker changes persist (see Ch. 16). effort to rehabilitate patients and promote certain abiliCan brain biomarkers identify those mild TBI ties, is it possible that we incur a loss in other abilities? patients most at risk for later life neurodegenerative disThere is limited brain real estate and even with network orders and who might thus be obvious targets for therareorganization, some forms of plasticity inevitably peutic intervention? Recent studies have shown “borrow” neurons from the borderland between funcdetectable albeit transient elevations of tau protein in tional brain sectors, allowing for subtle changes in the serum of concussed players, although any link to behavior – both positive and negative. Thus, when mealong-term cognitive loss is still speculative (Shahim suring for improvement in a specific behavioral funcet al., 2014). Rather than wait decades in the case of early tion, we should also be measuring behavior dependent life TBIs, it may be possible to accelerate this research by upon either the neighboring or homologous brain sectors studying people with a first concussion or mild TBI in to ensure they remain at least functionally stable in the later life, thus shortening the period between the precippresence of attempts to rehabilitate behavior dependent itating event and the average age of onset of neurodeupon the damaged region. generative disorders. Another hypothesis is that TBI, in some individuals, triggers a persistent and abnormal inflammatory reaction that exceeds the normal response LONG-TERM EFFECTS OFA TRAUMATIC to an acute TBI. This persistent inflammatory response BRAIN INJURY might lead to a breakdown in normal neural environment “housekeeping chores,” leading to the development of As we indicated above, much effort has been made to abnormal cellular structures such as overproduction of chart the recovery slope following TBI in order to help tau that can lead to a neurodegenerative disorder. clinically manage the patient, introduce interventions Detecting such a persistent response might lead, in this at the appropriate time, and provide the family, as early example, to an anti-inflammatory therapy that could
THE EBB AND FLOW OF TRAUMATIC BRAIN INJURY RESEARCH 799 help reduce later life risk for a neurodegenerative disorincreasingly recognized phenotypic changes that can der. This is only one of several possible mechanisms for be induced by therapeutic interventions. Rehabilitation how single or repetitive TBI earlier in life could lead to for TBI is, in principle, an intensive effort at promoting later life neurodegenerative disease. Even if there were neuroplasticity at both levels in order to facilitate recovonly a few TBI survivors susceptible to CTE, identifying ery of functions affected by brain damage. There is evithe causal factors could potentially also lead to a better dence that neuroplasticity is composed of several understanding of the mechanisms governing short-term features, including the reorganization of local and disneural environmental responses to TBI. tributed neural networks, with some of this remodeling Occasionally, there may also be diagnostic confusion involving specific synaptic morphology changes, at least surrounding later life decline in neurobehavioral funcin some spared brain regions. Seen in this light, proper tions after an earlier TBI if some consideration is not rehabilitation can prevent the emergence of maladaptive given to the potential additive effects of early brain dambehaviors which in turn likely have their basis in aberrant age and the typical changes in neuronal loss that accomregeneration or redirection of neural networks. pany aging (see also Ch. 43 on cognitive versus brain In the early post-TBI period, brain repair mechanisms reserve). As shown best by studies of patients who sufmay overlap with neuroplastic processes responsive to fered a penetrating brain injury in combat and who have the post-TBI rehabilitation environments people find preinjury induction cognitive test data available, a themselves in, although eventually neuroplastic prosteeper decline in functions can be documented based cesses are predominant, spurring discussion about the on several factors including preinjury cognitive ability, most effective ways and time to deliver rehabilitation. size and location of lesion, and genetic predisposition Currently it is unclear whether and how early brain repair (see below). But this decline in function is not due to a mechanisms might influence concurrent or later facilitaneurologic disease and can be distinguished in its earlier tion of neuroplastic processes (see Ch. 42). manifestation later in life from the new onset of a neuAre there new methods or technologies that might rodegenerative disease (Moretti et al., 2012). Whether facilitate recovery of function by modulating the brain’s this exacerbated neurobehavioral decline eventually trigneuroplastic inclinations? As discussed, attempts at gers other processes that lead to a “secondary” neurodeacute pharmacologic neuroprotection to date have had generative disease is at present unknown. minimal if any effects on functional outcomes (see Chs 22 and 28). However, the use of neural stem cells or certain growth or trophic factors may replenish or NEUROPLASTICITY support not only adaptive reliance on an existing netThe effect of neuroplasticity on function can generally work, but also compensatory processes, including some be conceived of as restorative or compensatory and of those that are governed by the homologous brain secmay either be relatively passive or facilitated by systemtor in the opposite hemisphere and that previously played atically applied therapeutic interventions. Neuroplastia relatively minor role in performing a selected task comcity can also have unintended negative consequences pared to the impaired function. such as the development of phantom pain. Although neuNoninvasive brain stimulation techniques such as roplasticity supports behavioral change and normal transcranial magnetic stimulation (TMS) or transcranial learning in healthy people, as well as in patients followdirect current stimulation (tDCS) also hold some proming brain damage, it is unclear whether there is an advanise in facilitating or inhibiting cortical (and some subcortage in implementing therapeutic interventions as early tical) brain sectors enough to modulate behavior, with as possible versus at later stages of recovery of function some investigators demonstrating significant and meanafter moderate to severe TBI, when the patient is more ingful improvements in mood and various behaviors that able to accommodate the demands of therapeutic persist beyond the therapeutic trial (Iyer et al., 2005; instructions and participate in the therapy. Some eviWassermann and Grafman, 2005; Huey et al., 2007; dence indicates that early intervention has some advanKoenigs et al., 2009). More widespread and larger clintage in steering the overall recovery of function effect ical trials are needed to support the routine use of non(see Ch. 42), although the often rapid, traininginvasive brain stimulation within the rehabilitation independent brain repair that typically occurs in the early environment. More invasive deep brain stimulation has postacute period makes it more difficult to evaluate the been used in comatose patients (Giacino et al., independent contribution of early rehabilitation or other 2013, 2014) and Ch. 25. interventions to recovery of function. Optimal designs for learning and retaining all kinds One useful paradigm is that of two basic interconof information have been reported in the cognitive psynected aspects to the issue of neuroplasticity: plasticity chology literature for over two decades, with some at the tissue level and plasticity at the behavioral, methods slowly being adopted by educators. These cognitive level. The two come together through the methods argue for use of massed practice for improving
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short-term retention and use of spaced practice for promoting long-term retention. Frequent testing is better at improving later test performance and long-term retention compared to rote practice. As noted before, there may be some limitations to trying such novel therapeutic designs in a rehabilitation medicine facility because of restrictive reimbursement practices for rehabilitation institutions, thus leaving such research to be implemented after discharge from a rehabilitation facility (see Ch. 48). In principle, it should be expected that these methods would have the same effect in patients who suffered a TBI as in the primarily healthy volunteers who participated in the research that led to these general findings. Finally, conducting basic cognitive neuroscience studies that lead to improved knowledge about the brain basis of many cognitive and social functions can contribute to the improved design of strategic interventions to promote positive recovery of function after a TBI. Eventually, newer technologies such as wearable devices, cell phones, and tablets can all be used for delivery of validated cognitive training paradigms under varying reallife conditions. They will also be used to complement the patient’s cognitive abilities by presenting needed information to the patient in real time in the relevant environment. There has long been concern about the effect of a brain injury on subsequent violence and aggression, including in veterans returning from combat with potential TBIs. Aside from a continuing premorbid risk for such behavior, there is evidence that location of lesion and genetic predisposition are important factors in predicting aggression and violence (Pardini et al., 2011, 2014). However, genetic predisposition is not destiny, and environmental exposure may reduce the phenotypic expression of a given gene. For example, there is evidence that having the bad version of a gene that is predictive of increased violence and aggression is of less concern if a person is raised in a healthy family environment. This effect has been linked to epigenetic modification of genetic instructions and emphasizes that all kinds of environmental exposures may mitigate the effects of certain genetic polymorphisms. Such factors as the timing and duration of exposures that could have epigenetic ramifications that could lead to a temporary or permanent effect on genetic predisposition are currently underspecified.
motivation to learn certainly contribute to premorbid abilities, it is also likely that genetic predisposition will play a key role in mediating the development of greater premorbid abilities and promoting postinjury recovery of function (see Chs 3 and 45). Key genes that will affect recovery from TBI may include some placing the person at risk for later life neurodegenerative disorders, but mostly should include those genes that help manage the repair of damaged or dysfunctional brain tissue as well as genes concerned with facilitating neuroplasticity. While some candidate modulator genes that may have the greatest predictability for outcome following a TBI have been identified, the typically smaller cohorts in these studies limit the number of genes that can be sampled adequately in any one study. There are many reasons to pursue this area of research, including the possibility of eventually developing a genetic panel for rehabilitation triage that might help dictate the intensity and frequency of rehabilitation for individual TBI patients and the design of individual tailored programs. In addition, it should be possible to conduct basic research on genetic polymorphisms that influence neuroplasticity by using fibroblast-derived neural stem cells from living TBI participants in order to examine their in vitro neuronal morphology and neural network development. This research could help identify the molecular determinants that distinguish people with good and bad outcomes after a TBI. If reliable differences could be identified, then new potential therapeutic interventions could be developed that target the relevant neuroplastic processes. Epigenetic changes are known to be induced from various kinds of environmental exposures and can potentially counteract the negative effects caused by specific genetic polymorphisms. One looming question for rehabilitation is whether patient exposure to rehabilitation therapies induces an epigenetic change or whether more extended exposure to therapy is necessary to produce a desired change such as alteration of the risk for violence discussed above. The animal research literature, although reporting on many forms of epigenetic manipulation of a gene’s instructions that eventually lead to a change in neuronal function, has yet to determine the optimal timing and duration of a potential environmental exposure to induce this desired effect or what the persistence is of the obtained epigenetic effect. Answers to these crucial questions will eventually indicate whether rehabilitation can take advantage of epigenetic prods to facilitate recovery of function and long-term outcomes following a TBI.
GENETIC PREDISPOSITION AND EPIGENETICS
CONCLUDING REMARKS
Many research studies have demonstrated the importance of cognitive predisposition or reserve upon recovery of function following brain damage (see Ch. 43). While an enriched premorbid environment and
In this concluding chapter, we have highlighted some of the limitations and promises apparent in ongoing research in traumatic brain injury. This volume has focused on the science of TBI, although we believe that
THE EBB AND FLOW OF TRAUMATIC BRAIN INJURY RESEARCH 801 two nonscientific factors will continue to play a role in entering a rehabilitation setting to participate in shortthe success of rehabilitation interventions post-TBI. and long-term research projects. Another solution is to One involves the practice of rehabilitation medicine open the rehabilitation hospital to a multidisciplinary and the other involves reimbursement strategies for medical team that could include, for example, profesrehabilitation medicine. Keeping in mind that current sionals from outside the typical fields employed by reharehabilitation practice still allows clinicians and scientists bilitation institutions. Adding sufficient time for access to potential research participants for relatively postdoctoral and other forms of research training in extended periods of time post-TBI, there are still striking the rehabilitation medicine setting would provide for limitations in the training and practice of neurophysiaimproved training for fellows who are making a committrists and on clinical neuropsychological participation ment to clinical research. Making rehabilitation outpain rehabilitation medicine that affect rehabilitation medtient facilities more research friendly could also make icine’s scientific potential. a difference in recruitment of research participants, as Among the disciplines concerned with treating and many families may not wish to make frequent visits to studying TBI, including neurology, psychiatry, neuroa downtown rehabilitation hospital to participate in surgery, cognitive neuroscience, and a few of the allied research. Rehabilitation practice could also benefit from health professions, rehabilitation medicine physicians do the routine acquisition of standard neuroimaging (to not fare as well compared to physicians from most other identify location and volume of brain damage across medical disciplines in receiving investigator-initiated groups), from genetic polymorphism profiles, and from grants from funding agencies, both in the US and in including in their patient registries the basic components Europe. In the US, many of the largest and most of the NIH Common Data Elements (Thurmond et al., respected rehabilitation institutions are independent 2010). Finally, systematic evaluation of long-term outorganizations that include a flagship inpatient hospital comes is needed for the patient, primary caregiver, along with outpatient facilities. While many of these and other social stakeholders in the rehabilitation proinstitutions have an affiliation with local universities cess, such as employers or the education system. and foundations, their principal means of income come Without such systemic changes that help integrate from insurance reimbursements for an extended course novel research avenues with routine patient care (as of treatment for their patients. With some notable excephas been accomplished in cardiac, stroke, and especially tions (e.g., bioengineering projects), time-intensive rehacancer medicine), progress in TBI will be slower and bilitation research usually has to wait for the patient to more laborious than necessary. Such changes will ultibe discharged from the acute care rehabilitation hospital mately improve the effectiveness and cost-efficiency before being initiated. Furthermore, if a scientific study of TBI management by accelerating the introduction invalidated some of the techniques that are currently into practice of new therapies based on advances in reimbursed due to having been “grandfathered” for hisgenetics, noninvasive manipulation of molecular protorical rather than scientific reasons, it could create a cesses to aid brain repair and functional plasticity, the financially unstable situation for some rehabilitation addition of complementary, supplementary, and substihospitals, potentially drastically reducing the treating tution devices to aid motor control and cognitive/social professionals reimbursable time with patients. Aside abilities, improvements in noninvasive brain stimulation from financial considerations, a closely related issue, techniques, more refined neuroimaging, and more tarcommon to much of medicine but especially to TBI, is geted drugs for TBI patient management. the often delayed introduction into practice of even Unlike many diseases, traumatic brain injury will proven improvements in care, for a variety of reasons. always be to some extent unavoidable for a certain proThus due to limitations in research training of many, portion of the human population. Whether due to combut not all, rehabilitation specialists and reimbursement bat, sports, vocational risk, accidents, or bad behavioral concerns, it may be difficult, despite the best of intenchoices, traumatic brain injury is here to stay. Preventive tions, to introduce novel clinical trials and basic research measures prior to a TBI can go a long way to modify its into an inpatient setting unable to easily accommodate effect through reduction of brain injuries (e.g., do not them. Some solutions to this situation are clear if diffidrink and drive, pretreat with medications that would cult to implement. Greater encouragement of and collabpromote brain repair in the case of an injury and would oration in research by the insurance industry and/or be otherwise safe to take), mitigation (e.g., helmets for government reimbursement agencies is one obvious bicyclists), or simply having the right predisposition approach. Another is designing space that encourages (both genetic and behavioral) that allows a person to the mingling of clinical and research staff in order to recover from, and better cope with, a traumatic brain foment new ideas about rehabilitation practice and injury. Although TBI remains common in the US popudevelop new research studies. The additional establishlation (see Ch. 1), the ebb and flow of interest in TBI is a ment of active research registries can encourage patients product of when publicity is given to the combat-related
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brain injury, sports injuries, and the potential long-term effects of a brain injury earlier in life. The fluctuating research interest in the topic is partly dependent then on increased funding that reflects the public’s awareness of, and interest in, TBI. Of great importance is whether a period of substantial research advances in TBI can result in better clinical management of patients with TBI. One positive example occurred after our experience in studying Vietnam veterans as part of phase 2 of the Vietnam Head Injury Study (VHIS). Those lessons led to the establishment of the Defense and Veterans Head Injury Program, a disease management program integrating specialized head injury care with clinical research supported jointly by the US Departments of Defense and Veterans Affairs, in collaboration with the civilian Brain Injury Association (BIA). The DVHIP was subsequently reorganized into the Defense and Veterans Brain Injury Center (DVBIC), and other, more recent offshoots of these efforts have been established. This helped catalyze an increased attention to TBI by the public in general and by other funding agencies, with a consequent flow of resources to academia for TBI research. One important lesson is that advancing research knowledge about TBI can, when paired with appropriate and assertive advocacy, elicit pragmatic changes that improve the management and treatment of TBI patients. We hope that the current swell of research into TBI has such a result. These two volumes of the Handbook of Clinical Neurology have attempted to provide important research information and insights into TBI that complement rather than supplants several excellent and more clinically oriented TBI textbooks that are currently available. As is apparent to anyone engaged in clinical or basic neuroscience research, we are advancing into a new era dominated by improving understanding of the human genome and proteome, the use of newer and smaller technologies to evaluate biological status and deliver therapeutic interventions, and more refined computational and functional models of human behavior. These combined advances should enable us to improve our efforts at diagnosing and treating TBI. But these advances will only have the desired consequences if the healthcare environment where they are most needed is ready to cooperate and accept them. We hope that will happen.
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