Interventions to Improve Cognitive Functioning After TBI

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Traumatic injury to the brain can affect the core of what makes us
human—our cognition and emotion. The injuries are acute but may result
in chronic burdens for individuals and families as well as society. Effective
approaches to improving functioning are needed, and the benefits may
be far-reaching. We discuss some basic principles to guide current prac-
tice, as well as major directions for continuing advancement of ways to
improve functioning after injury. Interventions are more likely to be effec-
tive when we take into account multiple levels of brain functioning, from
neurons to pharmacological systems to social networks. Training of cogni-
tive functions is of special importance, and benefits may synergize with
pharmacologic and other approaches that modify biology. The combina-
tion of physical and experiential trauma deserves special consideration,
with effects on cognition, emotion, and other substrates of behavior.
Directing further research toward key frontiers that bridge neuroscience
and rehabilitation will advance the development of clinically effective
interventions.

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Interventions to Improve Cognitive Functioning After TBI

  1. 1. Interventions to Improve Cognitive Functioning After TBI 15 Anthony J.-W. Chen and Tatjana Novakovic-Agopian Abstract Traumatic injury to the brain can affect the core of what makes us human—our cognition and emotion. The injuries are acute but may result in chronic burdens for individuals and families as well as society. Effective approaches to improving functioning are needed, and the benefits may be far-reaching. We discuss some basic principles to guide current prac- tice, as well as major directions for continuing advancement of ways to improve functioning after injury. Interventions are more likely to be effec- tive when we take into account multiple levels of brain functioning, from neurons to pharmacological systems to social networks. Training of cogni- tive functions is of special importance, and benefits may synergize with pharmacologic and other approaches that modify biology. The combina- tion of physical and experiential trauma deserves special consideration, with effects on cognition, emotion, and other substrates of behavior. Directing further research toward key frontiers that bridge neuroscience and rehabilitation will advance the development of clinically effective interventions. Keywords Traumatic brain injury • Rehabilitation • Cognitive training • Cognitive neuroscience • Frontal lobes • Attention • Memory • Executive controlA.J.-W. Chen, M.D. ( )Department of Neurology, VA Northern CaliforniaHealth Care System and University of California at SanFrancisco, San Francisco, CA, USAe-mail: anthony.chen@ucsf.eduT. Novakovic-Agopian, Ph.D.Department of Neurology, University of California atSan Francisco and Martinez VAMC, San Francisco,CA, USAJ.W. Tsao (ed.), Traumatic Brain Injury: A Clinician’s Guide to Diagnosis, Management, and Rehabilitation, 273DOI 10.1007/978-0-387-87887-4_15, © Springer Science+Business Media, LLC 2012
  2. 2. 274 A.J.-W. Chen and T. Novakovic-Agopian Outline I. Introduction and Overview Brain injuries and cognition Acute injuries, chronic consequences A combined combat neurotrauma syndrome (TBI–PTSD)? II. Approaches to Intervention Overview of potential targets of therapy: overlapping layers of brain functioning Targeting the outer layers: modulators of cognition Targeting core cognitive processes Integrating behavioral and pharmacologic therapies Special considerations for TBI–PTSD and frontiers for the interactions between cognition and emotion III. Directions and Imperatives for Future Work A long-term view Challenges for implementation Bridges between neuroscience and rehabilitation A service member returning from active duty deployment to the Middle East states on a screening questionnaire that he was exposed to multiple blasts in combat. In one incident, while he was riding in a convoy, his truck was struck by a blast from a roadside improvised explosive device. A wheel was caught in the crater and the vehicle dove into a ditch. “I think my head struck the side of the truck, and I may have blacked out—I’m not sure how long.” He admits to feeling dazed and somewhat confused. This seemed to resolve within a day, and the soldier returned to full duty. However, he was exposed to several more blasts during his deployment. While he cannot recall the details of each incident clearly, he endorses feeling dazed with each episode. He complains that he has had many difficulties since returning home. He has had trouble getting organized for job applications and other tasks—“I would get started, but then I always ended up doing something else.” He complains of feeling highly distractible and easily overwhelmed, and states that his memory is like “swiss cheese.” Others describe him as irritable and easily angered. He has difficulty in sleeping, feels depressed, and avoids leaving his home.Introduction and Overview the Middle East have resulted in an increased incidence of TBI, and TBI has been called aCognitive Dysf unction from Traumatic “hallmark injury” of current combat activities. ItBrain Injury has been estimated that 59% of soldiers exposed to blasts will have some form of closed headThis individual’s experience is quite common injury (Okie 2005). Head injury is commonlyamong veterans who have served in active duty. caused by other combat and non-combat-relatedApproximately 7,000 military personnel with causes, such as motor vehicle collisions, fallingtraumatic brain injury (TBI) were admitted annu- objects, altercations, or projectile strikes toally to military and Veterans Hospitals based on a helmets. According to Walter Reed’s Brain Injury2003 report by the Defense and Veterans Brain Center, 31% of battle-injured soldiers admittedInjury Center. Recent combat-related activities in between January 2003 and April 2005 had TBIs.
  3. 3. 15 Interventions to Improve Cognitive Functioning After TBI 275The impact of these injuries may be at once basic of military life to civilian life, including adjust-and far-reaching, yet difficult to recognize. ments to school or new occupations. TBI, if recognized at all, is predominantly addressed during acute stages. Ironically, chronicFrom Acute to Chronic Cognitive cognitive problems tend to receive relatively littleDysfunction medical attention. The issue of insurance cover- age in the private sector has been raised as oneIn the moment of an instant, an injury to the barrier to care that has even been recognized bybrain can cause changes that affect a person for a public press (Burton 2007). However, anotherlifetime. Although the injuries are acute, func- fundamental factor is the need for improved guid-tional deficits that result from TBI may produce ance for treating chronic cognitive dysfunction.tremendous chronic burden on individuals, fami- Treatment needs tend to be complex and indi-lies, and health care systems. This discussion vidual, and few general guidelines have beenwill focus on problems that persist to become available to guide treatment. However, an evi-debilitating on a chronic basis. This is an impor- dence base for cognitive rehabilitation interven-tant area to address for several reasons. The tions is being progressively strengthened.intrinsic importance of problems that are persis- A long-term view is needed and major long-tent (not resolving spontaneously or not respon- term issues need to be taken into account in clini-sive to therapies) is obvious. Acquired brain cal programs (Chen and D’Esposito 2010). Theinjuries have been a leading cause of long-term far-reaching impact of these seemingly “invisible”disability in the USA, even before the current deficits is often not recognized. For example,conflicts (Thurman et al. 1999) and a leading individuals who cannot pay attention, hold infor-contributor to increasing health care costs in the mation in mind, and actively participate in learn-VA (Yu et al. 2003). Individuals with TBI are at ing activities will have reduced benefit fromrisk for being unable to live independently. other rehabilitation efforts, such as those directedSurveillance for TBI across 14 states showed that toward motor or speech functions (Prigatano andapproximately one-third of patients continue to Wong 1999). Individuals who have suffered arequire assistance with daily activities 1 year TBI may also be at increased risk for developingafter injury (Langlois et al. 2003). For patients cognitive changes later in life (Mauri et al. 2006;hospitalized for TBI, cognitive status is a major Van Den Heuvel et al. 2007; Schwartz 2009).factor in determining whether individuals aredischarged to institutions (van Baalen et al. 2008).A more dire but difficult to quantify consequence Injuries and Cognitive Symptomsis the cascade that may lead to homelessness. For less severe dysfunction, patients may have Although it is commonly understood that TBIsymptoms that are not recognized by health care can result in almost any neurologic deficit, theproviders without specific screening, but which most common and persistent deficits tend to beare significant and need to be addressed (Hux et al. in cognitive functions. Among cortical regions,2009). One specific challenge for combat-related prefrontal and mesial temporal structures areinjury is that some of the “milder” effects of brain vulnerable to contusions and hemorrhages. Theseinjury may not be immediately detected. Detection correspond to deficits in frontal executive func-may be particularly complicated as some individ- tions and declarative memory, as well as otheruals experience problems that only become appar- aspects of behavioral and emotional self-regulation.ent with a change in setting, new cognitive demands, Diffuse or multifocal axonal injury may affectloss of supportive social structure, and demands to commissural, callosal, association as well aslearn new skills or knowledge. For example, cogni- particularly vulnerable long fibers, includingtive dysfunction may become particularly debili- those carrying neuromodulators in projectionstating during transitions from the familiar structure from the brainstem to cerebral end targets and
  4. 4. 276 A.J.-W. Chen and T. Novakovic-Agopianthose that connect the prefrontal cortex (PFC) though preliminary evidence suggests that similarwith other brain regions. Some of the most com- issues occur with blasts as other forms of TBImon deficits with distributed axonal injury, even (Belanger et al. 2009). As will be discussed inin the absence of cortical lesions, are in speed of this chapter, there may be a number of contrib-processing, frontal executive functions, and utors to poor cognitive functioning, asides frommemory (Scheid et al. 2006). The nature of cog- the physical brain injury per se.nitive dysfunction with TBI and intervention Spontaneous recovery? Despite their impor-approaches for these symptoms are discussed in tance, chronic deficits in cognitive functions aregreater detail in this chapter. often poorly addressed. Patients with mild TBI, Are cognitive deficits important in mild TBI? but also patients with more severe initial injuries,The occurrence of cognitive deficits in moderate are commonly advised that recovery will simplyand severe TBI is well-recognized, but cognitive occur with time. This can be reassuring, and, for-deficits may also be a significant problem after tunately, the recovery trajectory for most patientsso-called “mild” TBI (Binder et al. 1997; Mathias who survive TBI is positive over time. Mostand Coats 1999; Cicerone and Azulay 2002; individuals with mild TBI improve to baseline.Mathias et al. 2004; Belanger et al. 2005; However, there is significant variability in theFrencham et al. 2005; Vanderploeg et al. 2005). rate and end point of recovery. A significantDelineation of cognitive dysfunction has been minority (10–20% in nonmilitary settings) reportmore problematic, however. The controversies persistent deficits that can last months and yearsand debates have been extensive. We argue that it post-injury, leaving chronic, residual disabilitiesis particularly important to define the severity of that have a wide-ranging impact on an indi-dysfunction, rather than the severity of initial vidual’s life (Binder et al. 1997; Ruff 2005).injury. It is clear that traditional labels of “mild, Additional data from tracking of military veter-moderate, or severe” are poor characterizations ans will be needed in order to understand theof individuals with TBI (Saatman et al. 2008). long-term effects of combat-related TBI, whichFurthermore, injury history is often not clear for commonly results in forms of “mild TBI.”many veterans who suffered injury(ies) in the Approaching treatment of post-TBI cognitivefield, making these labels even more imprecise. dysfunction is complicated by the frequentCurrent functional status is measurable. For the occurrence of multiple and varied symptoms. Forcurrent discussion, an emphasis is placed on example, the existence of a “post-concussive syn-considering “mild” cognitive dysfunction as a drome” (PCS) is now widely accepted, thoughpersistent problem, not “mild TBI.” In other this remains a somewhat difficult to define entitywords, we emphasize the targeting of interven- or entities even in the better studied nonmilitarytions to current functioning, not the diagnostic settings, with variable presentations, sources, andlabel for the historical acute injury. possible courses. The syndrome is characterized Although self-reported symptoms and out- by headaches, dizziness, general malaise, exces-comes from cognitive testing vary greatly, deficits sive fatigue, or noise intolerance; irritability,in control processes, including attention and emotional lability, depression, or anxiety; subjec-working memory, and also reflected in speed of tive complaints of concentration or memoryprocessing are commonly reported and may be difficulty; insomnia; reduced tolerance to alco-the most affected domains in mild TBI (Binder hol; preoccupation with these symptoms and fearet al. 1997; Mathias and Coats 1999; Cicerone of permanent brain damage. Documentation ofand Azulay 2002; Mathias et al. 2004; Belanger cognitive dysfunction on “objective” testing iset al. 2005; Frencham et al. 2005; Vanderploeg not required for diagnosis, though altered cogni-et al. 2005). Aspects of executive control may be tive functioning may accompany these symp-important factors in determining successful toms. Although these symptoms are, by definition,return to work after mild TBI (Drake et al. 2000). occurring after a concussion, this does not neces-Deficits from blast injury are still being defined, sarily mean that brain injury directly causes these
  5. 5. 15 Interventions to Improve Cognitive Functioning After TBI 277symptoms. The pathogenetic factors that lead a these epidemiological findings raise questionspersistence of symptoms are not fully understood about the interactions between TBI and PTSD.and remain controversial. It is not clear that The interactions between TBI and PTSD areimaging findings are predictive of persistence undoubtedly complex and multilayered. Traumaof symptoms. However, it is likely that psycho- may alter an individual’s brain functioning vialogical factors play an important role—this is a many routes. Direct physical injury may certainlyparticularly important consideration given the be caused by traumatic forces, leading not onlycontexts in which physical trauma and recovery to contusions, hemorrhages, and even strokesperiods occur, including the associated traumatic but also injuries to the white matter fibers thatexperiences in combat or even in medical settings. connect brain regions. However, severe distressThese factors may be important in formulating from the traumatic experience may also haveinterventions to improve functioning. immediate as well as long-term effects on brain functioning. Post-traumatic stress effects are increasingly recognized as being mediated byBeyond Post-concussive Symptoms: altered brain functions and possibly structure.A Combined Combat Neurotrauma Both physical and experiential trauma may con-Syndrome tribute to acute disruption of function as well as ongoing cascades of sequelae that layer uponIt is increasingly recognized that a large portion the initial injury. Understanding that these mech-of individuals returning from combat activities anisms of injury interact at multiple levels is ofsuffer from both TBI and post-traumatic stress great importance for understanding, diagnosing,disorder (PTSD) or at least symptoms. A 2005 and managing the effects of these injuries. Thissurvey of Iraq/Afghanistan veterans found that may have particularly important ramifications forfor the 12% of 2,235 respondents with a history the formulation of interventions, and this isof mild TBI, the strongest factor associated with discussed in detail in this chapter.persistent post-concussive symptoms was PTSD, The story told by the veteran above is likely toeven after removing overlapping symptoms raise a number of important questions in a clini-from the PTSD score (Schneiderman et al. 2008). cian’s mind, including questions of etiology,A cross-sectional survey of Army veterans, diagnosis, and diagnostics, but perhaps the most3–4 months after return from Iraq in 2006, important question is this: What can be done torevealed the highest prevalence of PTSD among improve this person’s functioning?those with a history of loss of consciousness(LOC) (Hoge et al. 2008). LOC was also associ-ated with major depression. Mild TBI (defined by Approaches to Interventiona history of traumatically induced disruption ofbrain function accompanied by LOC or alteration Synopsis of Intervening to Improveof mental status) was associated with post- Cognitive Functioningconcussive symptoms—but not after controllingfor PTSD and depression. In examining the inci- The following are key points to consider in deter-dence of PTSD, rates increase in relationship to mining interventions for improving cognitivethe occurrence of TBI, with increased incidence functioning after brain injury.of PTSD along the gradient of no TBI to altered • The most common difficulties after TBImental status to LOC (Taber and Hurley 2009). involve complex attention, learning, memory,A study by examining TBI and PTSD service organization, and other processes importantutilization of OIF veterans found that 1-year post- for goal-directed behavior.deployment, 65% of those with “mild TBI”–PTSD • Sources of dysfunction may be multifactorial.reported seeking treatment for concerns related Sources include not only deficits in specificto re-integration (Polusny et al. 2011). All of neural processes but also functional difficulties
  6. 6. 278 A.J.-W. Chen and T. Novakovic-AgopianFig. 15.1 Multiple sources of dysfunction lead to mul- formance (e.g., sleep, fatigue), pharmacologictiple tiers of intervention. Core targets of intervention influences (e.g., medications, other drugs), emotionalinclude specific neural-cognitive processes important functioning (e.g., irritability, anger, depression), andfor healthy, goal-directed functioning after brain inju- other comorbidities (e.g., chronic pain). All of these areries. However, these processes may also be affected by potential targets for interventions to improve cognitivemodulators that alter cognitive state or cognitive per- functioning in engaging cognitive processes for goal- • Some processes may be worth targeting even relevant activities, factors that modulate phys- if “deficits” are not detectable, including pro- iologic brain states, emotional factors that cesses that are “gateways” to learning and interact with cognitive functioning, pharma- change. Although a wide range of cognitive cologic and other biological modifiers, and processes may be affected by injury, a core interactions of cognition with specific envi- set of cognitive processes may be considered ronments. The interactive nature of these fac- central to enhancing the rehabilitation pro- tors is illustrated in the overlapping layers in cess itself. These include “meta-cognitive” Fig. 15.1. Any or all of the above may have to processes such as self-awareness (awareness be taken into account for a therapeutic inter- of one’s abilities, strengths, weaknesses, and vention to be effective. Each of these layers is goals, with the ability to monitor and review discussed in this chapter. one’s actions in these contexts), and func-• Interventions may be targeted to specific tions for regulating attention, learning, and cognitive processes, specific sources of dys- memory in an organized, goal-directed manner. function, supportive processes, specific mod- These processes will also be crucial for ulating or exacerbating factors, and/or an continued learning and adaption outside of integrated approach that addresses multiple clinician-guided settings. targets concurrently based on a particular • Behavioral approaches for modifying behavior therapeutic goal. include training, i.e., the guidance of learning
  7. 7. 15 Interventions to Improve Cognitive Functioning After TBI 279 through activities with specific learning and in more detail in subsequent sections. Considering goals. Training forms the most fundamental the spectrum along each axis may be helpful in core of post-injury rehabilitation, but may be determining the best approach for each patient. combined with biological approaches (e.g., pharmacotherapy). Targeting the environment vs. the patient:• A number of factors may need to be accounted Managing an individual’s environment (organi- for in synergizing therapies to optimize zation of the physical environment, work, and improvements in functioning. These include time demands, etc.) is a common approach to not only understanding the immediate effects post-injury care. This may be particularly valu- and side effects of pharmacologic agents but able during acute phases of injury or with more also the potential influences on processes of severe deficits in self-management. This approach learning and change and relationships between may sometimes be taken alone for at least two the underlying neural systems modified by reasons. There may be an interest in maximizing these agents vs. training. Different drugs, as function in a specific environment, given the well as different doses of the same drug, may least amount of time and effort. Second, there have differential effects for specific neural may be an assumption that the patient’s function- subsystems and the behaviors they subserve. ing is “static” (at least within the time allotted.)• Engagement of active participation for each indi- However, increasing evidence supports signi- vidual in treatment is a major factor in treatment ficant functional plasticity over long periods of outcome. Elements of enhancing engagement time, although the time course may not be condu- include raising awareness of one’s abilities and cive to standard practice parameters. Significant difficulties, opportunities for self-direction during expertise is available in various fields of rehabili- treatment, and active attempts at applying and tation therapy; this chapter focuses more on transferring learned skills to personally relevant patient-targeted approaches, where one of the situations and goals. These are basic, almost mun- ultimate goals is to alter the abilities of an dane considerations that become all the more individual to adapt to or manage their own important when patient have deficits affecting environment. awareness, motivation, attention, and other aspects of self-regulation. Issues of active avoidance or Targeting of ancillary health factors vs. directly negative reactions to intervention may be further targeting central neural-cognitive processes: As heightened when TBI is combined with PTSD or will be discussed, a number of ancillary factors other psychological health conditions. may be addressed that may have dramatic effects• Transfer of the gains achieved during treatment on cognitive functioning, with or without detailed to new contexts, and generalization to each consideration of deficits in central neural-cog- individual’s personal life must be taken into nitive processes or systems. It may sometimes account when considering intervention approach be advantageous to address these contributing as well as measurement of outcomes. factors first, revealing a clearer picture of the underlying status of an individual’s cognitive functioning. However, this approach alone willOverarching Considerations not resolve underlying deficits.in Intervening to Improve CognitiveFunctioning After Brain Injury Application of external tools vs. internalized skills and strategies: Within an individual’sInterventions may be considered along a number of “personal environment,” one may consider exter-major axes. Various axes may be used to characterize nal tools vs. internal tools available for a patient’sthese approaches. Each of these axes briefly high- use. The use of external tools is clearly a valuablelights particular considerations in determining opti- aspect of human functioning and has an impor-mal interventions, discussed briefly in this overview tant role in improving functioning post-injury.
  8. 8. 280 A.J.-W. Chen and T. Novakovic-AgopianTools may provide immediate benefits as external neuromodulators, such as dopamine, norepineph-“signals” or orthotics (e.g., paging systems for rine, acetylcholine, and serotonin, and the predi-alerts or reminders, Fish et al. 2008a, b), but they lection for TBI to affect the cortical terminationmay also include training to leverage external zones as well as the long projection fibers thattools to compensate for one’s deficits or augment carry these neuromodulators. Almost all of theone’s abilities (e.g., using a planner to improve major neuromodulators of the brain are producedorganizational skills). Strong evidence supports in small nuclei at the base of the brain or in thethe use of external tools for improving an indi- brain stem and project to distributed cerebralvidual’s ability to accomplish intended actions. structures. Acetylcholine from the basal forebrainAn important question for continued investiga- is projected to cortex throughout the brain.tion is the extent to which use of any of these Dopamine from the ventral tegmental area is pro-tools may improve an individual’s intrinsic abili- jected primarily to PFC. Norepinephrine from theties. This chapter emphasizes approaches that locus coeruleus is projected to cortex throughoutmay alter an individual’s neurologic functioning. the brain, as well as thalamus, cerebellum, and spinal cord. Serotonin (5-HT) is also predomi-Behavioral modification vs. biological modifica- nantly produced in brainstem and rostral nucleition: Methods for modifying biological under- (in the pons and midbrain) projections throughoutpinnings of behavior may be applied separately the brain, with prominent targets including frontalor in combination with behavioral modification. lobes and hippocampus. On the other hand, GABABiological modification approaches, considered neurons are distributed throughout the brain, inbroadly, may include not only pharmacotherapy particular as inhibitory inter-neurons. Disruptionbut also identification and targeting of factors in one or more of these systems presumably con-that influence the neural systems that support tributes to neurologic symptoms seen in TBI.cognition. These may include factors such as A number of drugs that affect neuromodulatorsleep, pain, physical activity, circadian systems, systems have been used in clinical practice fornutrition, and more. It is valuable to keep in mind years. Each pharmacotherapeutic agent is, inthat biological approaches will more likely aid in theory, targeted to particular neural systems,accomplishing therapeutic goals when applied in whether defined by particular receptor types,the context of a behavioral modification plan synthesis of or metabolism of particular neu-(e.g., goal-driven rehabilitation training), rather rotransmitters, or other drug-specific mecha-than in isolation. nisms. The delineation of the targets of a particular drug, and the relation to cognitive functioning, isIntegrating pharmacotherapy with rehabilitation: an area in need of further investigation. HelpfulCareful application of pharmacotherapy can play an and hurtful effects of drugs must be considered,important role in improving cognitive functioning and these may occur simultaneously. For example,after brain injury. Clinical evidence to support par- more detailed examination may reveal domain-ticular medications is slowly accumulating specific effects (as described in McDowell et al.(reviewed in Warden et al. 2006), and the approach 1998) or simultaneous helpful vs. detrimentalis generally empiric, with little information to guide effects on separable brain systems (i.e., “double-a clinician’s prescription of one drug or another for edged sword” effects) (Cools et al. 2001). Anany given individual. Determining the benefit of any important frontier will be to determine the phar-given medication remains dependent on trial-and- macology of each patient, potentially providingerror. Systematic trials involving step-wise dose guidance for therapy.adjustments of medications may be helpful. It is also valuable to consider separately imme- There are a number of reasons to consider neu- diate effects of pharmacologic modulation, e.g.,romodulator systems of the brain as therapeutic altering current behavior, vs. longer-term effects.targets. These include findings that TBI tends to Attending to longer-term effects raises consider-affect cognitive functions dependent on these ations of effects on learning and response to
  9. 9. 15 Interventions to Improve Cognitive Functioning After TBI 281other therapies. Drug effects may be supportive with severe TBI (Dikmen et al. 1991, 2000).for current issues, but may also be detrimental for Carbemazepine may also have cognitive sidelonger-term goals. For example, medications effects (Smith et al. 1994). Among older anti-have long been used to address problematic epileptic agents, valproate may be preferable.behavior post-injury. The immediate effects may Among newer agents, topiramate may be par-seem helpful (e.g., reducing behavioral instability), ticularly concerning for cognitive side effects.but the same medication may adversely affect Benzodiazepines and baclofen are GABAfunctioning in a cumulative manner (e.g., by agonists, and these may reduce the rate of recov-altering attention and learning during training). ery from TBI (Zafonte et al. 2004). The use of New approaches to biological modification these medications should be minimized in themay actually have no beneficial immediate context of cognitive dysfunction after TBI. Ineffects, but may help to accomplish long-term certain circumstances, spasticity may be treatedtherapeutic goals but altering the plasticity of by more localized means (e.g., intrathecalneural systems. Such approaches may include baclofen or targeted botulinum toxin).using stem cells, growth factors, small molecules, Dopamine antagonists, such as haloperidol,or other novel approaches (Zhang and Chopp have been shown to impede learning and recovery2009). However, the effectiveness of these (Stanislav 1997; Wilson et al. 2003; Meintzschelmethods for helping to accomplish therapeutic and Ziemann 2006; Hoffman et al. 2008; Klinegoals will depend on effectively augmenting the et al. 2008). These agents are commonly used forspecific changes guided by training. managing behavioral dysregulation, but should be used sparingly, and continual use should be avoided as much as possible.Factors That Modulate Cognitive In sum, it is important to repeatedly review theFunctioning and “Brain State” rationale, necessity, and dosage of each medica-on a Dynamic Basis: Important Targets tion at each clinical juncture, with a concern forof Therapy potential adverse effects on cognition and recov- ery. In general, when medications are deemedMedications necessary, cognitive functioning should be moni-Medications may have both beneficial and detri- tored while dosing is adjusted. It is often neces-mental effects on cognition. Patients may have sary to discontinue medications before reliableprescriptions for issues that arise during the many determination of sources of dysfunction can bephases from acute injury to chronic recovery. made. Indeed, cessation of medication is often asPolypharmacy is a common problem, likely due valuable as starting any medications in the reha-to factors such as multiple comorbidities with bilitation course.TBI (e.g., anxiety, PTSD, insomnia, pain) andattempts to treat some post-TBI sequelae (e.g., Alertness and Arousal Statebehavioral dysregulation, seizures, headaches). Optimal alertness may be considered a pre-A valuable first-step in clinical decision-making requisite for effectively activating and engagingis a review of medications that may contribute to other cognitive functions. The concept of alert-poor cognitive functioning. Unfortunately, numer- ness is integrally tied to the sustainment of atten-ous medications commonly used for patients with tion. The translation of alertness or arousal toTBI have adverse effects on cognition. task-related attention may lead to greater neural- Post-traumatic epilepsy, especially with com- cognitive processing (Spitzer et al. 1988). Tonicplex partial seizures, is a treatable potential con- alertness refers to the ongoing state of intrinsictributor to cognitive dysfunction. However, arousal that is intimately involved in sustainingmedications may need to be managed with atten- engagement during higher-order functions suchtion to cognitive side effects. Phenytoin has been as selective attention, working memory, andshown to impair cognitive function in patients executive control (Sturm et al. 1999; Posner
  10. 10. 282 A.J.-W. Chen and T. Novakovic-Agopian2008). Although the term “attention” is commonly Commonly used pharmacologic agents thatused in this context, it should be distinguished affect neuromodulator function include meth-from the many other meanings of attention, as ylphenidate and amphetamines as well as newerseparable neural systems appear to subserve stimulants. For example, methylphenidate hasalertness vs. other “attention” functions (Sturm been shown to alter sustained attention in patientset al. 1999; Posner 2008). Alertness may influence with TBI (Whyte et al. 1997). Modafinil is aperformance in almost all cognitive domains, newer agent that promotes alertness. Atomox-including during rehabilitation (Sohlberg et al. etine works selectively on noradrenergic systems.2000). Improving regulation of this “gateway” “Antidepressants” with noradrenergic targets andfunction may improve the “readiness” state of possible “activating” effects, such as venlafaxineindividuals for participation in rehabilitation. or duloxetine, may be helpful for some individu- Alertness and arousal need to be considered als. These agents could be considered for use asin terms of optimizing balance. Patients with agents satisfying multiple therapeutic goals, min-more severe TBI may exhibit marked deficits in imizing the total number of different medications.alertness (Whyte et al. 1995; Manly et al. 1999). Reuptake inhibitors for serotonin as well as nor-Noradrenergic systems involving inter-connected epinephrine are perhaps among the few agentsregions of brainstem and frontal cortex, in par- that may improve stability of arousal state.ticular, have been proposed to be particularly As always, the effects of medications, prescribedimportant mediators of alertness state (Aston- for other reasons, must be evaluated. A number ofJones and Cohen 2005). The importance of long medications commonly used after TBI, as well asdistance connections, both for delivering nora- for post-traumatic stress and anxiety symptoms,drenergic signals from brainstem to cortex as affect alertness. Other factors that modulate cogni-well as regulation of brainstem nuclei, may help tive state that are related to alertness are fatigue andto explain why alertness is so often dysregulated sleep. These are discussed separately, given someafter TBI. High levels of arousal may also be distinct considerations.maladaptive. This is a significant problem withTBI–PTSD, for example. Thus, therapies may Fatigueneed to focus on the concept of optimizing the Fatigue is likely the most commonly reportedregulation of alertness, rather than simply increas- symptom after TBI, reported in 21–73% ofing or decreasing arousal per se. patients with TBI (Olver et al. 1996; Hillier Approaches to regulating arousal state may et al. 1997), and is also common after otherinvolve behavioral regulation, training, and phar- types of brain injury (Staub and Bogousslavskymacologic treatments. Recent training approaches 2001; De Groot et al. 2003). Fatigue is a subjec-may provide methods for improving regulation of tive complaint. There is no standard definitionarousal and are discussed in more detail with of fatigue, but the key elements include aother training approaches. A number of pharma- requirement for increased effort to maintaincologic agents that affect alertness and arousal mental activities and difficulty sustaining goal-are already in common use. However, the effects directed efforts (Fellus and Elovic 2007). Centralof each agent can be quite individual, especially fatigue is the concern in TBI, and should begiven underlying issues with variability in alert- distinguished from peripheral fatigue, whichness state, i.e., lability, rather than a simple refers to muscular or other sources outside theuni-directional deficit. Thus, each agent needs to brain. Central fatigue is itself a major cause ofbe considered carefully based on patient goals poor functioning, adding to other physical orand treatment contexts. Multifactorial consider- cognitive deficits. Failure to sustain cognitiveations become particularly challenging when TBI effort is a major limitation for effective cogni-is combined with post-traumatic stress symp- tive functioning even when brief assessmentstoms, behavioral lability, anxiety, or depression. reveal intact abilities. Just as distractibility might
  11. 11. 15 Interventions to Improve Cognitive Functioning After TBI 283cut short an effort before a goal is completed, Similarly, improving regulation of emotions,so might fatigue. Fatigue affects functional such as anger, may also reduce fatigue.recovery, emotional well-being, cognitive func- Medications such as beta-blockers, anti-tioning, quality of life, and ability to perform dopaminergics, and anti-epileptics may all con-daily activities (Bushnik et al. 2008a, b). tribute to feelings of tiredness. Pharmacotherapy Assessment of fatigue is complicated by its with agents that improve alertness, attention, anddynamic nature. Characterization of fatigue concentration, such as methylphenidate, amanta-needs to take into account fluctuations and the dine, dextroamphetamine, atomoxetine, orcontexts in which an individual functions. A key modafinil, may improve fatigue. Activating anti-goal of the assessment is to determine potential depressants may be helpful. Systematic evidencesources or factors that exacerbate fatigue, as to support the effectiveness of any given therapythese may be targets for management. Clinical for fatigue remains limited, and studies may beassessments of fatigue are often brief and subjec- complicated by the heterogeneity of fatiguetive. Questionnaires querying subjective report sources and symptoms. This is a major frontiermay be helpful in characterizing an individual’s for development with potentially wide-reachingfatigue (reviewed elsewhere) (Borgaro et al. benefits for individuals with brain injury.2004; Fellus and Elovic 2007; Bushnik et al.2008a, b). Assessment of associated factors, Sleepsuch as sleep, depression, and pain, may be par- Sleep disturbances are a major issue after TBIticularly valuable. The development of objective (Mahmood et al. 2004; Castriotta et al. 2007;measurements, as an adjunct to subjective report, Watson et al. 2007; Zeitzer et al. 2009) andmay be helpful for identifying underlying sources insomnia is particularly common for combatof fatigue or tracking fatigue more closely when veterans, whether related to TBI, PTSD, or otherself-awareness is limited. causes (Lewis et al. 2009). Poor sleep adversely Interventions for improving post-injury fatigue affects cognitive function, particularly for frontalremain very basic and general at the current systems and memory functions (Muzur et al.time. Regular physical exercise is one of the first 2002; Yoo et al. 2007), including sustained atten-recommendations. Adherence to an exercise tion after TBI (Bloomfield et al. 2009). Chronicregimen is a major obstacle, with factors including lack of sleep may also be associated with anxietymotivation, pain, and other physical limitations. and depression (Neckelmann et al. 2007), anotherOvercoming these problems may require creative pathway by which poor sleep may worsen func-problem-solving, with expert guidance in indi- tioning after TBI. Dopamine may play a role invidualizing exercise activities. Compensatory compensating for cognitive changes after sleepstrategies to manage energy use may be helpful deprivation (Volkow et al. 2008). This againfor a person to achieve desired functional goals highlights the importance of considering multi-given limited capacity for activity. The patient ple levels of factors in determining treatmentmay require assistance identifying situations or prescription.behaviors that exacerbate fatigue that could be Sleep regulation and adequate sleep may be ofmodified. Addressing sleep disturbances is an fundamental importance for learning and recov-obvious and crucial step to improving energy ery after brain injury. As mentioned, sleep depri-levels. Sleep history, and in some cases, polysom- vation may have adverse effects on functions thatnography may help diagnose sleep disturbances. are crucial for learning, such as alertness,Reduction of distractions, thereby reducing the attention, and memory (Mahmood et al. 2004).amount of cognitive effort required to accomplish In addition, sleep, including naps, has been showntasks, may be beneficial. Improved self-regulation to benefit learning of information or skills learnedof attention and other aspects of cognitive pro- prior to sleeping (Mednick et al. 2003; Tuckercessing may help improve the efficiency (reduc- et al. 2006). Thus, thinking of sleep in both aing the work load) for accomplishing tasks. retrospective direction (sleep deprivation) and a
  12. 12. 284 A.J.-W. Chen and T. Novakovic-Agopianprospective direction (planned sleep after learning the regular sleep cycle but also potentially fromactivities) may significantly alter one’s approach hypoxia itself (Canessa and Ferini-Strambi 2011;to sleep in rehabilitation. Yaffe et al. 2011). Prescription of sleep-inducing Management of sleep as a direct, explicit target medications such as benzodiazepines may actu-of therapy is an important frontier for further ally exacerbate these issues.development. There remains a major need fordefining optimal approaches for improving sleep Painduration and quality after TBI, as well as deter- Pain is a common accompaniment of TBI.mining how best to integrate sleep into rehabili- Chronic pain, in particular, may have wide-rangingtation treatment regimens. Asides from basic effects on well-being, emotional, and social func-considerations of sleep hygiene and the effects tioning as well as cognitive functioning. Some ofof substances (e.g., caffeine, alcohol, or other the effects of pain on cognition may be mediateddrugs), more complex issues may need to be by influences on sleep, mood, and energy levels.addressed. Dysregulation in sleep cycles may For example, chronic pain may lead to irritabilityoccur from physical injury to the brain (Ayalon and poor frustration tolerance, reducing cognitiveet al. 2007), medications or even intensive effort for cognitive tasks that are challenging. Painmilitary training and experiences. Insomnia is a may also modulate cognitive functioning viamajor symptom of PTSD, and barriers to sleep increased fatigue or poor sleep. On the other hand,may include not only hyper-arousal but also treatments for chronic pain, such as with opioidactive resistance to sleep due to feelings of fear analgesics, may contribute to poor cognitive func-and nightmares. Intensive schedule regulariza- tioning. Although opioid medications may playtion may be necessary, but not sufficient, and an important role in pain management, especiallyindividualized trials combining scheduling with in settings of acute injury, other approachesefforts to augment sleep or wake signaling may be particularly valuable in the long term.(e.g., melatonin supplementation at night; sun- Multidisciplinary collaboration in an intensivelight, exercise, possibly stimulants in the morning) program may be necessary, especially given themay be valuable. multifactorial nature of chronic pain. Approaches Pharmacologic agents for inducing or pro- to pain management that include strengthening oflonging sleep all have potential side effects, and self-regulation and coping (e.g., with mindfulness-balancing becomes more complex when cogni- based training or biofeedback), as well as local-tive dysfunction, pain (and associated medica- ized interventions (e.g., transcutaneous electricaltions), substance abuse, psychopathology, and stimulation, injections), with a goal of minimizingother factors inter-mix. Furthermore, medication- systemic opiates, may be particularly valuable.induced sleep does not replace normal physio-logic sleep, and use of such drugs would ideallybe limited in time. For example, such drugs may Training to Improve Cognitivebe used during initial phases of therapy, to Functioningtemporarily address extreme sleep deprivationand associated complications of cognitive and Training of Neurologic Functionsemotional dysfunction that may impede initiation Training forms the most fundamental core ofof other therapies with longer-term benefits. In post-injury rehabilitation. Training involves specificthe long term, addressing underlying psycholog- activities that guide changes in brain functioningical issues (e.g., anxiety, PTSD) will be particu- based on specific learning goals. Within thelarly important for achieving restful sleep without training approaches, different learning goalsmedication assistance. may be defined. Identifying and treating sleep apnea is another Training may emphasize the learning andmajor priority. Sleep apnea may contribute to application of cognitive skills and/or strategies.cognitive dysfunction not only from disruption of Strategies help to organize behavior may be
  13. 13. 15 Interventions to Improve Cognitive Functioning After TBI 285helpful in improving the efficiency or effective- situations) or “functional skills” (procedures forness of accomplishing particular tasks. Strategies, accomplishing a task, such as making a sandwich).once internalized, may be thought of as providing The latter may blur the borders between poten-intrinsic “tools” available to an individual to tially separable cognitive processes, but this is eco-help accomplish particular tasks. Examples of logically relevant as real-life tasks typically requirecognitive strategies are discussed in this chapter. the integration of multiple neurologic processes.Effective application of a strategy typically results These differing approaches may help toin an immediate beneficial effect; however, the achieve different goals in rehabilitation. Forlong-term benefits depend on a number of factors. example, it is theorized that if fundamental neural-Factors to consider include to what extent the cognitive processes are improved, then thestrategies are context-specific or transferable to benefits will more likely carry over to tasks andother contexts, to what extent the individual can contexts outside the training. On the other hand,learn and remember the strategy, and to what training on specific actions (functional tasks)extent the individual will be able to prospectively may be thought of as consolidating a particularinitiate use of the strategy in the appropriate situ- task-specific skill or procedure. As such, theations. For example, it is not uncommon for an behavioral improvements may be more immedi-individual to be able to learn a strategy during ately apparent as patients improve in task perfor-therapy (e.g., a method for breaking problems mance, but the improvements may be task- orinto manageable steps), but then fail to apply this context-specific. The choice of approach maystrategy when faced with a real-world problem. depend on the nature and severity of cognitiveSuch failures of transfer may be directly related deficits. It has been argued that functionalto an individual’s cognitive deficits. approaches may be more effective for patients Available literature on treatment of combat- with severe deficits (Giles 2010).related “mild TBI” is sparse. A recent pilot study The utility of training that targets specificexamined strategy training in combat veterans neurologic processes remains controversial, andwith mild cognitive dysfunction and a history of this is an active area of research and develop-TBI (Huckans et al. 2010). Training involved a ment. Process-targeted methods have typicallyvariety of compensatory internal and external involved practice on tasks “isolated” from complexcognitive strategies, including day planner usage real-world situations. The development of trainingin a structured group-based format. Following programs that target neurologic processes andtraining, participants reported increased use of result in effective and ecologically relevant gainscompensatory cognitive strategies and day plan- remains an important frontier for further advance-ners, increased perception that these strategies ment in intervention development. Optimizationwere useful to them, increased life satisfaction, of methods for higher level cognitive functionsand decreased depressive, memory, and cognitive continues to be a challenge. Advances in neuro-symptom severity. science, informed by clinical concerns, provide a A skills-based approach may also be taken. foundation for defining, targeting, and trainingThough the distinctions between strategies and cognitive functions. In the next section, we out-skills may blur, skills may generally be considered line the foundations for process-targeted, neuro-as the integrated use of particular neurologic science-driven interventions.functions or processes for the accomplishmentof functional tasks. Skill training is generally Cognitive Neuroscience Foundations forconsidered a more gradual process, with improve- Rehabilitation Trainingments accumulating over repetitive practice. Although a wide range and variety of deficits canSkills may be further divided into the concepts of result from TBI, symptoms in two general areas“neurologic skills” (based on definable neuro- stand out as some of the most common and dis-cognitive processes, such as working memory, ruptive to patients—“executive control” andwhich are applicable to multiple specific tasks or memory. The abilities of paying attention, holding
  14. 14. 286 A.J.-W. Chen and T. Novakovic-Agopianinformation in mind, organizing, and developing example, improved goal-directed functioningefficient strategies for completing activities seem may enhance an individual’s ability to activelyto be particularly vulnerable to TBI. These pro- participate in attempts to rehabilitate motorcesses come together in the regulation and con- functions, allowing an individual to hold learn-trol of other, more basic neurologic processes ing goals in mind, selectively focusing attentionbased on goals, and are often referred to as to learning activities, and solve problems in the“executive control” functions (Hecaen and Albert numerous intervening steps between a current1978; Lezak 1995). Although problems with state and achieving a learning goal. Finally,memory are some of the most commonly reported individuals with brain injury spend a muchcomplaints after TBI, the actual deficits may be larger amount of time on their own than with aquite varied. Processes important for goal- therapist; thus, the importance of executive con-directed behavior, learning, and memory will trol and memory functions translates to an indi-receive special focus in this section. vidual’s ability to self-teach skills, remember strategies and self-adjust to residual deficits inFunctional Impacts of Cognitive Dysfunction any domain.and the Impetus to Address ThemProcesses important for goal-directed behavior, Foundations for Training: Neural Baseslearning, and memory are fundamental for of Cognitive Functions Important After TBIsuccessful independent living, and deficits may It is conceptually simple to understand how onedirectly contribute to poor outcomes. At the might train motor strength by training particularbroadest level, poor executive control leads to muscles, but how would one prescribe trainingdisorganized behavior that affects numerous for “executive control” functions? Reviews ofaspects of personal functioning. Executive con- interventions have noted a gap between theoriestrol functions are crucial for the pursuit of educa- about subsystems of executive functions andtional and occupational goals (Drake et al. 2000; intervention design and practice (Kennedy et al.Ownsworth and McKenna 2004; Doctor et al. 2008; Levine et al. 2008). A better understanding2005; Machamer et al. 2005) with TBI resulting of the nature of the specific underlying neuralin an increased rate of job turnover and reduced processes, as well as mechanisms of learning andjob status (Machamer et al. 2005). However, the recovery specific to these functions may helpeffects may be even more fundamental in the advance treatment development (Chen et al.process of recovery from brain injury. 2006; D’Esposito and Chen 2006; D’Esposito As empirically observed by rehabilitation cli- and Gazzaley 2006).nicians, if certain cognitive functions are not Neurologic deficits caused by TBI are notintact, other attempts at rehabilitation are made unique to trauma per se, but certain patterns ofmuch more difficult. Who, after all, are the most dysfunction are more common with TBI thandifficult individuals to teach? Which patients are other causes of injury. While these patterns aremost likely to be labeled as “not ready” for inten- partially explained by traditional neurologicsive rehabilitation efforts? Individuals who can- localization with focal cerebral lesions, thenot pay attention, hold information in mind, and localization approach has left many TBI sequelaeactively participate in learning activities may poorly explained. Basic abilities, such as ambula-have reduced benefit from rehabilitation training tion and speech, may be spared, and the impact ofefforts for other neurologic domains (Tatemichi deficits may only become clear when individualset al. 1994; Prigatano and Wong 1999; Ozdemir are challenged by the complexities of real-life.et al. 2001; Hyndman and Ashburn 2003; Fischer Deficits in executive control functions are gener-et al. 2004). As a frontier reaching beyond simply ally attributable to damage to prefrontal systems,triaging patients, the remediation of these func- which include not only PFC per se but alsotions may be valuable for influencing learning extensive interconnections with subcortical andand recovery in other neurologic domains. For posterior cortical structures (D’Esposito and
  15. 15. 15 Interventions to Improve Cognitive Functioning After TBI 287Chen 2006). The importance of axonal injuries neurons within local networks is also important.in TBI highlights the need to understand brain The neural representations of information appearfunctioning in terms of distributed but coordi- to be coded not in single neurons, but rather innated network processes (Chen et al. 2006). networks of neurons. For example, representa-“Diffuse axonal injury” without focal cortical tions of the myriad possible visual objects,lesions has been shown to lead to changes in including household objects, faces etc., have beenexecutive working memory processing activity shown to be encoded in a distributed architecture(Levine et al. 2008). (Haxby et al. 2001). This organizational architec- PFC is involved in multiple major networks ture allows for a much wider range of informa-(Goldman-Rakic and Friedman 1991). One major tion to be encoded with a limited number ofnetwork involves connections with posterior neurons. Otherwise, if a separate neuron wereparietal cortex as well as anterior and posterior needed for every item or variation of informationcingulate and medial temporal lobe regions stored, the number of neurons needed would far(Selemon and Goldman-Rakic 1988). Another exceed what exists in the human brain. Distributedmajor network involves cortical–subcortical injury, atrophy, or degeneration could disruptconnections between the PFC and the striatum, neural processing even in the absence of obviousglobus pallidus, substantia nigra, and mediodorsal cortical lesions. Examples of this may occur innucleus of the thalamus (Ilinisky et al. 1985). age-related degeneration (Park et al. 2004) and isAdditional interactions with other more posterior likely to occur in TBI as well.brain regions such as sensory or motor cortex are Thus, understanding the importance of net-likely important for the domain-specificity of work interactions is an important foundation forcontrol processes (Postle 2006; Ranganath 2006). understanding the functional consequences ofDeficits may also be related to damage to neuro- TBI, which might otherwise be labeled “non-modulatory pathways from the base of the brain focal.” This also has implications for the mea-to the cortex. These interactions are crucial for surement methodologies to be used to understandthe modulatory control of distributed neuronal neural mechanisms of injury, learning, and recov-activity in order to facilitate processes that are ery in rehabilitation studies. Examples of thisrelevant to internal goals while suppressing non- frontier are discussed at the end of this chapter.relevant processes (Fuster 2000; Miller andCohen 2001; Curtis and D’Esposito 2003). Cognitive Functions as Potential Targets How is goal-directed control implemented in of Therapyneural systems? At the simplest level, neural Functions for Goal-Directed Control:aspects of control involve modulation of neural Attention and Other Components Processesactivity from the “top-down” based on goals, as of “Executive Control”well as coordination and monitoring of distrib- Control over neurologic functions to accomplishuted neural networks in the brain. Without such goals may involve control over perception andcontrol, activity would be either driven by information processing, motor actions, emotionallow-level processes, such as by “stimulus- functioning, as well as other aspects of behavior.response” principles, or generally disorganized, One way to organize our conceptualization ofwith poorly coordinated activity that lacks control functions is to consider the componentsguidance by a higher level goal structure. The required for successful goal attainment. (Formodulation of neurologic processes from the additional discussion, anatomically based schema“top-down” is accomplished by at least two for subdividing frontal functions (Stuss andimportant general mechanisms: selection Alexander 2007; Levine et al. 2008) and goal(enhancement and suppression) of neural activity management steps have been reviewed by othersbased on goal-direction and active maintenance (Levine et al. 2000; Rath et al. 2003).) Deficits inof goal-relevant neural activity for the accom- any component may disrupt efficient and effec-plishment of tasks. The functional integration of tive goal attainment.
  16. 16. 288 A.J.-W. Chen and T. Novakovic-Agopian• At the outset, a goal needs to be generated initiation of planning and decision-making, and/or selected. Whether the goal is simple or and is another point at which an individual complex (e.g., make a cup of coffee vs. apply may stall. for college), inability to generate clear goals, • Once actions are initiated, goals and plans or deficiencies in evaluating and selecting a need to be maintained to accomplish each manageable goal, will obviously result in poor subgoal and the sequence of subgoals that goal attainment. build toward the main goal. Goal maintenance• This goal will then be important for guiding becomes increasingly important with goals all subsequent processes. An attentional set that require multiple steps over extended based on the selected goal needs to be estab- periods of time, as the risk of going “off track” lished, framing all upcoming information or increases (Shallice and Burgess 1991; Gouveia actions (Banich et al. 2000a, b; Luks et al. et al. 2007). This may be another form of “goal 2002). Poor establishment of the appropriate neglect” (Duncan et al. 1996). set will make it more likely that the individual • Throughout the goal attainment process, the will be distracted or take the wrong path. individual will likely be exposed to vast• Goal attainment activities need to be initiated, amounts of information (from perception or and this depends on motivation and an appro- memory)—some of this will be relevant and priate level of alertness or arousal. Apathy, some non-relevant to the goal. Positive selec- depression, low arousal (such as from fatigue) tion of goal-relevant information for deeper may lead to poor initiation. processing (with the complementary negative• Goal attainment activities including determin- selection of non-relevant information) at the ing the optimal plans to accomplish the main outset and at every stage of the goal attain- goal. Planning includes more in-depth analy- ment process will be necessary to reach the sis of the goal, and breakdown of the goal into goal, else the individual may be distracted or an appropriately sequenced series of subgoals even overwhelmed. Selected information (steps), including re-organization of potential needs to be maintained, at the exclusion of actions in relation to the main goal. These other competing information, to accomplish processes may require interactions across a each step toward the goal. The selection and hierarchy of prefrontal networks (Badre and maintenance of goal-relevant information D’Esposito 2009). involves processes often referred to as selec-• Strategy determination and related processes tive attention and working memory, functions of planning are crucial for efficient goal attain- that are integrally related (D’Esposito et al. ment, especially with more complex tasks. 1995; D’Esposito and Postle 1999; D’Esposito This higher level function is relevant for learn- et al. 1999; Bunge et al. 2001; Thompson- ing, memory, and problem-solving. Patients Schill et al. 2002; Gazzaley et al. 2005; Gilbert with frontal injuries show impairments in stra- et al. 2006; Chen et al. 2007). tegic planning and organization of informa- • Similarly, a plethora of actions is possible at tion (Baldo et al. 2004; Yochim et al. 2009). any moment in time, but only a selected few• Some goals may require more complex levels will be goal-relevant. Response selection and of planning, and maintenance of the goal inhibition refers to the ability to select during this process can be important. The between competing alternatives and to inhibit planning process can be thrown off track with inappropriate response tendencies (Bunge forgetting of the main goal or disconnection of et al. 2002a, b). planning from the goal (one form of “goal • The selection of actions also needs to be neglect”) (Duncan et al. 1996). framed by rules (e.g., do not drive across the• Translation of the imagined cognitive seque- double-yellow lines while trying to get across nces (plans) into action requires a step of the street). Making use of rules includes pro- initiation of action that is separable from the cesses for the retrieval, maintenance, selection,
  17. 17. 15 Interventions to Improve Cognitive Functioning After TBI 289 and implementation of relevant rules that function, such as dextroamphetamine, meth- guide behavior on a task (Bunge et al. 2003; ylphenidate, amantadine, are also commonly Donohue et al. 2005; Crone et al. 2006). used. However, there is less direct evidence to• In determining appropriate actions, multiple support positive clinical effects on executive considerations may need to be integrated. control functions. As a general rule, agents that Relational integration requires the ability to modulate dopaminergic function should be integrate multiple relationships, and is crucial considered to be dosed based on individual in problem-solving and reasoning (Bunge response, as dopamine modulation of function et al. 2005; Bunge and Zelazo 2006). tends to follow a “U-shaped” curve that varies in• There may be a need to transition between dose-relationship for each individual (Kimberg tasks, such as to move to the next subgoal or to et al. 1997; Cools et al. 2003, 2008). deal with an interruption and yet return back Although difficult to isolate to a specific pro- to the goal-relevant path. Direction and re- cess, the efficiency and speed with which an direction of attention, information processing, individual can process information and accom- and actions is necessary for successfully plish cognitive tasks is commonly affected by making these transitions. Patients with frontal TBI. Although the neural substrates of speed of lesions are relatively impaired on tests that processing are not well understood, one underly- require switching between tasks or attentional ing pathophysiologic factor may be damage to sets (Yochim et al. 2007). interconnecting systems in the brain, as would• Once actions are taken, the results that follow occur with axonal injury, reducing the efficiency may or may not be relevant to goal attainment. of computations that require interregional inter- Comparison of results with the original goals actions. As a general theme, first, medications and detection of disparities or errors is neces- should be reviewed for potential contribution to sary for correction of the above series of pro- slow processing. Medications, such as dopamine cesses to ultimately achieve the goal. However, antagonists, benzodiazepines, and opiates, may neglect of the goal, deficits in awareness of also contribute to slow processing. Other con- errors, as well as failure to take corrective tributors may be of concern as well, e.g., sleep actions are major impediments to successful deprivation. Practice guidelines support the use goal attainment. of the stimulant methylphenidate in the treat-• Independence in the above processes, and cogni- ment of deficits in attention and speed of infor- tive functioning in general, requires some ability mation processing following TBI (Warden et al. to generate ideas and information with minimal 2006). The evidence for methylphenidate is cuing, especially for processes that require cre- strongest for an effect on speed of cognitive pro- ativity and/or problem-solving. Aspects of gen- cessing and sustained attention/vigilance (Whyte erative ability may be impaired with brain et al. 1997, 2004). The cholinesterase inhibitor injuries (Baldo and Shimamura 1998; Baldo donepezil has also been recommended for et al. 2001, 2006). Overall, frontal systems enhancing attention in patients with moderate- appear to be broadly important for core abilities to-severe TBI in subacute and chronic periods of that allow a person to flexibly and adaptively recovery. Dextroamphetamine and amantadine solve problems across multiple contexts (Duncan may also be considered. To what extent these et al. 1995; Kane and Engle 2002). medications are indicated for “mild TBI,” such as from blasts, needs to be further tested.Pharmacotherapy: Bromocriptine has been The specific effects of each medication onrecommended for use in enhancing aspects of each of the specific component functions is notexecutive functioning (e.g., divided attention/ yet clear, and further work will be valuable forcentral executive functions) in patients with providing specific guidance on how best to com-severe TBI (McDowell et al. 1998; Warden et al. bine pharmacotherapies with any particular reha-2006). Other agents that modulate catecholamine bilitation training regimen.
  18. 18. 290 A.J.-W. Chen and T. Novakovic-AgopianLearning and Memory (e.g., Raskin 2000). For patients with severeFunctions of learning and memory are integrally deficits in declarative memory related to mesialintertwined with all of the above process of temporal injury, external aids are particularlygoal-direction. Thus, this discussion treats these valuable. Evidence to date argues againstprocesses as part of the ensemble of functions significant potential for remediation of suchneeded for goal attainment. For example, infor- memory deficits, though this has mainly beenmation, strategies, and skills need to be learned examined in the context of hypoxic injury.and remembered so that they may be applied to However, memory problems related to deficits inproblem-solving and goal attainment. Conversely, controlled aspects of encoding and retrieval,learning and memory are also dependent on many related to executive control functions, mayof the control processes discussed. Indeed, one of respond well to training, such as with strategiesthe most common subjective complaints after for selecting or organizing information forTBI is of problems with “memory.” memory. Thus, distinguishing the underlying eti- The underlying sources of these complaints ologies of memory complaints may be highlymay vary. Deficits related to declarative or epi- valuable in therapeutic decision-making.sodic memory may be related to damage to medialtemporal structures. The basal forebrain and long Pharmacotherapy: The cholinesterase inhibitortracts that connect the forebrain to other structures donepezil (5–10 mg/day) has been recommendedare also important for memory processing. The as a practice guideline to enhance aspects ofbasal forebrain, a major source of cholinergic pro- memory function for patients with moderate-to-jections throughout the brain, is particularly vul- severe TBI in subacute and chronic periods ofnerable to injury, and, furthermore, long projections recovery (Zhang et al. 2004; Warden et al. 2006).may be vulnerable to shearing injury (Salmond There is support for rivastigmine improvinget al. 2005). However, complaints of problems memory deficits as well, in a subgroup of patientswith “memory” do not necessarily equate to prob- with moderate-to-severe memory impairment atlems with these structures systems. baseline (Silver et al. 2006). In general, these Problems with memory encoding and retrieval cholinesterase inhibitors appear to be safe andmay also be related to attention and “frontal execu- well-tolerated in patients with TBI (Gualtieri andtive” functions that influence the selectivity and Evans 1988). Although the rationale for thesedepth of information processing, as well as the agents was previously focused on bolsteringability to organize information to be encoded and “memory systems,” effects on attention andstrategically retrieve information to be recalled registration of information may be particularly(Blumenfeld and Ranganath 2007). Encoding and important contributors to the amelioration ofretrieval of information from memory may be symptoms. Methylphenidate, amphetamines, andimpaired in individuals with frontal systems dys- other agents that enhance attention or executivefunction. Important aspects of encoding and control may also improve learning and memoryretrieval of information from memory appear to functioning after TBI. To what extent these medi-be mediated by the role of PFC in activating, main- cations are indicated for mild TBI, such as fromtaining, and organizing information in working blasts, needs to be further tested, and additionalmemory, as well as in re-activating and retrieving considerations of the interaction with anxiety andstored information (Ranganath et al. 2003, 2007). PTSD need to be considered.A common deficit seen is that a patient hasdifficulty on free delayed recall, but when pro- Targeting Cognitive Functions: Integrationvided with a retrieval strategy (cue) his perfor- of Component Processesmance improves. An additional set of functions is In sum, each component process provides aimportant for the “prospective” memory of upcom- potential target for intervention. This is summa-ing events or actions (Burgess et al. 2011). rized in a schematic in Fig. 15.2. Behavioral approaches to compensating for or Discussed as separate processes, the abovetraining memory have been reviewed elsewhere may seem like a confusing and complex array of
  19. 19. 15 Interventions to Improve Cognitive Functioning After TBI 291 Distractions External distractions, intervening actions, non- and relevant paths, memories, anxieties, habits, etc. Disruptions GOAL Protect and maintain goal-direction Working Learning/ Memory Decisions Action Outcome Sources of information Feedback Perception Memories Modulators Fatigue, sleep, pain, medications, etc.Fig. 15.2 Component processes in pathways to goal maintain goal-directed processes from distractions andattainment: targets for intervention. All the main pro- disruptions, which may otherwise affect any component incesses, connected in red, work together for goal attainment the pathway. As discussed separately, other potential modu-and are potential targets for interventions. An overarching lators may influence the central processes and are alsotarget for strengthening involves abilities to protect and potential targets for other forms of interventionfunctions that are difficult to understand or target. Principles for Training and ImprovingHowever, an important principle is that the Functions of Goal-Directed Controlcomponent processes need to be coordinated or Functions that subserve goal-directed behaviorfunctionally integrated in the accomplishment of are a particularly important training target forany particular goal. Goals may be conceptualized individuals with TBI. This encompasses func-as serving to functionally organize the multiple tions that have far-reaching influence on neuralneural processes necessary for accomplishing processes in almost any neurologic domain,the goal, including selecting the relevant path- crucial to navigating the challenges of learningways or processes (while excluding others), and adaptation after injury. Given the difficulty incoordinating them at any given moment in time, understanding and designing interventions toand dynamically adjusting this coordination improve goal-directed cognitive functioning, wewhile maintaining the central goal across time to have proposed some basic principles of trainingeventually accomplish the goal. Thus, not only could be incorporated into interventions to targetthe components but also their functional coordi- and maximize improvements in these functionsnation may be important targets for intervention. (D’Esposito and Chen 2006).Process-based approaches may be analogous to Many of the methods applied in clinical reha-isolating and working out the biceps muscle, bilitation are designed for the learning of strate-while functional approaches may be analogous to gies that compensate for deficits. We focus heretraining the coordination of multiple muscles to on possible approaches for remediation of goal-accomplish basketball shots. A more advanced directed control deficits, a challenging but worth-question is whether training that involves func- while goal that remains at the frontiers of clinicaltionally integrated approaches may actually serve rehabilitation. As introduced above, the extensiveas an effective, more motivating way to improve research on the neural mechanisms underlyingunderlying component processes. goal-directed control functions may provide a
  20. 20. 292 A.J.-W. Chen and T. Novakovic-Agopianuseful theoretical foundation for the development engagement of networks across multiple brainof interventions for remediation. These principles regions, not just the PFC. This is particularlymay not only bolster therapies where goal- relevant to patients with “disconnection” inju-directed cognition is the primary target of therapy ries. Therapies that target control processesbut may also be incorporated into cognitive, may be a way of promoting the “re-integration”motor, speech, or other therapies in order to of damaged brain into functional networksmaximize the targeting of frontal systems func- (Chen et al. 2006). Targeting core PFC func-tions in any of these contexts. Furthermore, tions in process-oriented training shouldincreasing the engagement of goal-directed con- increase the likelihood of generalization oftrol in these settings may maximize improve- gains to new contexts, though this may not bements across domains. sufficient without additional considerations.1. Training of process, not content: cognitive 2. Cognitive training should explicitly include a training tasks should challenge patients to goal-based approach. engage “top-down” modulatory processes The role of goal-based executive processes mediated by PFC networks. may be to functionally organize the multiple As delineated above, there are a number of neural processes necessary for accomplishing cognitive processes that could be targeted by the goal, including selecting the relevant path- training. Functional imaging studies aimed at ways or processes (while excluding others), investigating normal brain-behavior relation- coordinating them at any given moment in ships may provide a relatively new source of time, and dynamically adjusting this coordina- guidance for the type of tasks that can engage tion while maintaining the central goal across PFC networks. For example, tasks that require time to eventually accomplish the goal. In the selective processing of competing information development of a training protocol, it is impor- based on task-relevance (selective attention), tant to consider the processes required for working memory (e.g., the maintenance of accomplishment of any specific goals during information over a short period of time and training. These processes will differ depend- especially manipulation of that information), ing on the nature of the goals. For example, if performance of dual tasks, as well as goal– the goal is to make a quick decision regarding subgoal management have all been shown to a left vs. right button press based on an image engage the PFC networks (D’Esposito et al. on a computer screen in an isolated setting, 1995; Banich et al. 2000a, b; Curtis et al. 2004; then the engaged processes and the level of D’Esposito and Chen 2006). During the integration necessary will be very different performance of these tasks, it is the process- than what is engaged by a more complex task, ing demands, and not the specific contents of such as paying attention to one’s supervisor in stimuli per se, that engage PFC networks. For a noisy office in order to accomplish an example, PFC networks are engaged during extended project. Thus, the opportunity for the working memory tasks regardless of the type greatest engagement of goal-direction pro- of information (e.g., words or objects) that cesses will be provided with complex goals. must be remembered (D’Esposito et al. 1998; A goal-based approach will allow training Collette et al. 2005). Thus, training needs to of multiple goal-direction processes. Who sets target specific top-down control processes, the goals? Goal-generation involves the high- and not specific task content. This contrasts est levels of goal-directed control, requiring with training that emphasizes repetition of generation de novo, or retrieval and appraisal task content, which promotes a shift toward of potential goals that will guide behavior. automatic processing and disengagement of Training that involves an active role for the PFC-mediated control (Petersen et al. 1998). trainee in defining the goals and subgoals of Importantly, examination of the neural sub- the tasks being learned may differ in effect strates of these functions emphasizes the from when goals are “assigned.” Coordination
  21. 21. 15 Interventions to Improve Cognitive Functioning After TBI 293 of the many steps required for goal attainment improve functioning in a significant way, even may critically rely on the protection and main- if the trainee is challenged progressively. tenance of the goal. Thus, goals which require 4. Training should enhance the transfer and greater lengths of time and multiple tasks to generalization of training effects to new and accomplish will provide greater challenge to real-world contexts. maintenance of goal information. What is the A major gauge of the success of any training- personal relevance of the goals to the indi- based therapy is the extent to which benefits vidual? It is important for several reasons that actually extend beyond the training tasks and the goals of training are of significance to the context. As mentioned above, if functions of patient: this will increase motivation, encour- the core PFC networks for goal-directed age application of skills to (“real-life”) goals control are effectively improved, then gener- that are often more complex than “artificial” alization of benefits should be more likely. goals, and allow for increased practice of goal How would this be accomplished? To effec- processing in daily life. There is also the tively target core PFC functions, and not potential for increased positive feedback from simply context-specific abilities, it is arguably accomplishment of goals that are important to important to train the target processes in the trainee. Incorporation of some or all of multiple modalities and multiple settings. PFC these features would significantly affect the is multimodal association cortex, and PFC nature of the intervention and likely benefits. networks serve to integrate information from3. Cognitive training tasks should progressively multiple modalities (Schumacher et al. 1996; challenge the patient. Collette et al. 2005; Postle 2006; Zelano et al. The importance of progressive increases in 2005). Training across multiple modalities challenge is underscored by the ability of the may maximize engagement of core PFC net- brain to adapt to tasks. Even tasks that engage works leading to improved functioning across goal-directed control processes may become contexts. The above simplified process- less challenging with practice, and thus less oriented view of PFC involvement in goal- effective at encouraging learning in the tar- directed control raises a question regarding geted domain. As a patient’s level of function the importance of the context(s) in which these improves for a specific process, tasks may functions are engaged. Any training context need to be adjusted such that demands for that carries with it important cues and inherent process are increased. This is more specific structure, which may provide scaffolding for than simply increasing the general “difficulty” an injured individual. Most deficits in goal- of the task, as parameters that are adjusted directed control are only apparent in contexts should quantitatively vary the level of engage- that lack strong external cues for action, ment of specific processes, such as working requiring hierarchical organization that allows memory, multitasking (Erickson et al. 2007), top-down goal-directed signals to out-compete updating (Dahlin et al. 2008), or interference bottom-up signals encouraging engagement control (Persson and Reuter-Lorenz 2008). with the environment (Duncan et al. 1995, However, again, practicing on isolated tasks 1996). Thus, the opportunity for the greatest that are designed to engage control mecha- engagement of goal-direction processes will nisms may improve performance, but in a be provided in unstructured settings. way limited to the specific tasks practiced. Furthermore, learning a skill within a specific Extensive studies on the effects of practice of context does not guarantee that that the skill well-known cognitive control tasks have will be applied to other contexts, where scaf- documented context-specific improvements folding is no longer present. Indeed, certain (MacLeod and Dunbar 1988; MacLeod 1991). rehabilitation approaches emphasize the train- Thus, simply practicing isolated, purportedly ing of context-specific “functional” skills process-targeted tasks may not be sufficient to (such as getting dressed). This is highly

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