Your SlideShare is downloading. ×
Interventions to Improve Cognitive Functioning After TBI
Upcoming SlideShare
Loading in...5

Thanks for flagging this SlideShare!

Oops! An error has occurred.


Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Interventions to Improve Cognitive Functioning After TBI


Published on

Traumatic injury to the brain can affect the core of what makes us …

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

Published in: Health & Medicine

  • Be the first to comment

No Downloads
Total Views
On Slideshare
From Embeds
Number of Embeds
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

No notes for slide


  • 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. 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. 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. 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. 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. 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. 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 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. 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. 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. 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. 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. 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. 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. 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 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 Interventions to Improve Cognitive Functioning After TBI 287Chen 2006). The importance of axonal injuries neurons within local networks is also 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. 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. 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. 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. 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. 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. 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
  • 22. 294 A.J.-W. Chen and T. Novakovic-Agopian valuable as a clinical approach for patients abilities such as goal-directed control func- who have severe limitations in cognition, but tions (Arnsten and Goldman-Rakic 1998; this is also the antithesis of training underlying Gold and Shadlen 2001; Jazayeri 2008). Thus, abilities to accomplish adaptive behavior. To training that improves regulation of brain potentially remediate goal-directed control states may also improve cognitive function functions, training would ideally occur in as following brain injury. A full understanding of many contexts as possible. the regulation of brain states that is translat-5. Meta-cognitive strategy training may provide able to treatment considerations still needs to a form of goal-directed control function be developed; however, certain aspects of state remediation. regulation are understood to be important for Meta-cognitive strategies are proposed to cognitive functioning. play an important role in achieving generaliz- It is clear that brain states established by able improvements in goal-directed function- alertness and arousal, attentional sets, emo- ing. One hallmark of prefrontal networks tional states, and motivation can affect cogni- dysfunction is difficulty in structuring cogni- tive functioning. For example, a state of tion and behavior by employing strategies to hyper-arousal may lead to rapid shifts of atten- efficiently and effectively accomplish goals. tion (distractibility) while low arousal may Increasing clinical evidence supports the prop- lead to poor activation and maintenance of osition that training-based therapies targeting attention. Patients with TBI–PTSD may show problem-solving, involving the use of meta- severe hyper-arousal, while patients with more cognitive strategies, may improve functioning severe TBI may exhibit marked deficits in in individuals with brain injury (Cicerone et al. alertness (Manly et al. 1999; Sturm et al. 1999; 2005; Kennedy et al. 2008). Several interven- Posner 2008). Interventions that improve the tions have been developed and implemented regulation of arousal state may improve goal- with such an approach (D’Zurilla and directed functioning. External cues may help Goldfried 1971; Kabat-Zinn 1990; VonCramon (Manly et al. 2002; Fish et al. 2008a, b), but et al. 1991; Cicerone 2002; Rath et al. 2003; training to improve self-regulation, from Robertson et al. 2005; Nezu et al. 2007). For mindfulness exercises to more recent develop- example, in goal management training (Levine ments with computer-assisted techniques, may et al. 2000), patients are trained to clearly also be helpful (Degutis and Van Vleet 2010; define a goal, learn the steps required to Van Vleet et al. 2011). Mindfulness-based achieve it, and then regularly check their prog- training approaches may train regulation of ress. Engagement of PFC appears to play an arousal state, reduce the load of non-relevant important role in the successful application of cognitive or emotional processing on limited strategies (Newman et al. 2003; Miotto et al. neuro-cognitive resources, and improve an 2006). Thus, meta-cognitive strategy training individual’s ability to re-direct attention to may enhance PFC-mediated control processes, goal-relevant processes (Posner et al. 2006; rather than simply being compensatory. The Jha et al. 2007; Slagter et al. 2007; Novakovic- neural mechanisms underlying successful Agopian et al. 2011). It is often presumed that improvement with meta-cognitive strategy individuals with goal-directed control func- training will be worth further investigation. tion deficits due to brain injuries would not be6. Training of goal-directed control of brain good candidates for such training, given states. difficulty with attention regulation. We have Goal-directed control may also be improved found that cognitive training that incorporates via improved regulation of brain states. At a principles of mindfulness can improve atten- neural level, modulation of brain states alters tion, working memory, and goal-directed signal and noise properties of information functioning for individuals with brain injury processing systems in the brain that support (Novakovic-Agopian et al. 2011).
  • 23. 15 Interventions to Improve Cognitive Functioning After TBI 295 It is worth noting that improvements in tional self-regulation may also improve state regulation may improve implicitly during emotional self-regulation, and vice versa. any training intervention. For example, it is Thus, in order to improve an individual’s likely that trainees develop self-regulatory ability to learn, change, and adapt in the pro- skills during intensive training when tasks are cess of goal attainment, it will often be neces- challenging (cognitively or physically), requir- sary to address both cognitive and emotional ing the ability to regulate one’s cognitive and self-regulation. These issues are discussed in emotional states (Paulus et al. 2009). Thus, more detail in the next section, with a focus on even tasks that are described as task-based the combination of TBI and PTSD, perhaps (e.g., computer games) may result in improve- the “hallmark” syndrome of recent combat ments in functioning that are due to improve- activities. ments in state regulation.7. Interactions of emotion and cognition. Special consideration needs to be made for Cognition, Emotion, and Combined the importance of emotion regulation for TBI–PTSD: Frontiers for Treatment optimal cognitive functioning. Poor emotional control can significantly affect cognition and Interactions of TBI–PTSD goal attainment. Emotional and cognitive Either TBI or PTSD alone may alter cognitive, control are directly tied together in that the emotional, and behavioral functioning. The co- underlying neural systems interact significantly occurrence of TBI and PTSD raises the question in achieving self-regulatory control necessary of how the two entities interact, and whether the for goal-directed behavior. combination of physical and experiential trauma Dysregulation of emotion can occur at results in consequences not simply explained by multiple levels. An individual experiencing additive effects of TBI or PTSD alone. feelings of anxiety, irritability, and/or distress PTSD and mild TBI may have independent and will be less able to effectively complete tasks additive roles (Vanderploeg et al. 2009), but may that require overcoming challenges and solving also interact at multiple levels, including at the gen- problems, especially unexpected ones. Even esis of injury, the maintenance of symptoms, various further, she may negatively “over-react” to aspects of cognitive-emotional functioning, and challenging situations, and the emotional at the level of neural mechanisms. Features of each reaction may impede the clear cognition may interact to worsen functioning and/or make needed for effective goal attainment. It is also treatment more difficult. Approaching TBI–PTSD likely that reduced cognitive control would will require a multifactorial approach that add- contribute to poorer emotional control. resses multiple, interacting layers of functioning. Individuals with TBI, with reduced self- Furthermore, potential special features of the regulatory control, may have more difficulty combination may need to be addressed. Defining in managing and altering negative and/or certain core targets of intervention, such as pro- traumatic associations and the “triggered” cesses of self-regulatory control important for both emotions. For example, an inability to filter TBI and PTSD, may provide a gateway to enhance out information and demands that are not the success of other aspects of therapy. Special directly related to a current goal (additional considerations are discussed in more depth in each “cognitive noise”) may lead to increased feel- section below. ings of being overwhelmed. Indeed, given the known limitations of neural processing Interactions Between Cognitive and resources, it seems logical that an increase in Emotional Functioning with TBI–PTSD “load,” whether from cognitive or emotional Although TBI can result in dysfunction in almost sources, would lead to less efficient overall any neurologic domain, the most common and functioning. Interventions that improve atten- persistent deficits tend to be in the control of
  • 24. 296 A.J.-W. Chen and T. Novakovic-Agopiancognitive-emotional functions. Indeed, injured information and environmental stimuli (Vasterlingindividuals may be able to engage basic func- et al. 1998).tions, but the disrupted regulation of these func- A number of studies have documented impair-tions leads to variability, lability, inconsistency. ment in learning and remembering new informa-As a classic example, some individuals with TBI tion in PTSD patients. With respect to learningdisplay emotional lability, in one instant coopera- new information, impairments in PTSD havetive and friendly, in the next instant irritable and been noted on both verbal and visual memoryangry. This may be due to cognitive factors, such tasks but are more pronounced on verbal memoryas misinterpreting or overreacting to environ- tasks (Brewin et al. 2007). PTSD-related deficitsmental stimuli, as well as issues in the control of have been observed at different stages of memoryemotions or behavioral expression. This charac- processing, including the initial registration ofterization overlaps greatly with PTSD. Effective new information and, somewhat less commonly,regulation of emotion is crucial for optimal in retaining the newly learned information overcognitive functioning. Dysfunction in emotional time (Vasterling and Brewin 2005; Verfaellie andcontrol, leading to frustration, irritability, anger, Vasterling 2009).or even apathy, may significantly alter cognitiveperformance. Could TBI Contribute to the Development In another example, individuals may com- and Sustainment of PTSD Symptoms?monly complain of reduced ability to pay atten- There are clearly commonalities in terms of thetion and hold information in mind, affecting external events that generate physical and experi-many aspects of life functioning. However, atten- ential trauma. Could TBI contribute to the develop-tional processes may be disrupted by “noise” ment and sustainment of PTSD symptoms? Thefrom both “external” and “internal” sources. For occurrence of TBI could actually increase the riskexample, it may be difficult to concentrate on a of development of PTSD. Repeated exposure tosingle conversation when other conversations experiences involving fear, horror, or helpless-are being heard in a crowded room, or it may be ness in situations of threat to life or well-being isdifficult to focus on a lecture during class when common in combat. In the post-deployment healthemotion-laden thoughts are also distracting from assessment and re-assessment of 88,000 soldiers,processing that goal-relevant stream of informa- 53% witnessed someone wounded or killed, 49%tion. Should these symptoms be attributed to TBI felt in danger of being killed, up to 42% requiredor PTSD? Or is that the wrong question? mental health treatment, PTSD reported in up to 25% (Milliken et al. 2007). There is an increasedThe Occurrence of PTSD May Add risk of PTSD with personal physical injury. Into the Cognitive Dysfunction Associated particular, there is an increased rate of PTSD forwith TBI those with TBI (RR 1.8) (van Reekum et al.The addition of PTSD to TBI may contribute to 2000). In examining the incidence of PTSD, ratescognitive difficulties. The most common cogni- increase in relationship to the occurrence of TBI,tive deficits associated with PTSD involve atten- with increased incidence of PTSD along the gra-tion, executive functions, and memory (Vasterling dient of no TBI to altered mental status to LOCand Brewin 2005). Attention and executive func- (Taber and Hurley 2009). All of these numberstions deficits commonly found in PTSD include argue that some aspect of TBI contributes to theworking memory difficulties (Brandes et al. 2002; development or sustainment of PTSD symptoms.Gilbertson et al. 2001), problems in sustaining From the initial instant of injury mechanism,attention over time (Vasterling et al. 2002), physical and experiential injuries are intertwined.response inhibition (Leskin and White 2007; However, there are likely additional interactionsVasterling et al. 1998), and impaired ability to that contribute to symptom maintenance acrossgate, monitor, and regulate the flow of incoming time.
  • 25. 15 Interventions to Improve Cognitive Functioning After TBI 297Cognitive Dysfunction May Impede respond differently to standard treatmentsTreatment for Emotional Problems, and compared to those with only TBI or PTSD.Emotional Dysregulation May Impede Cognitive limitations may make it necessary toTreatment of Cognitive Dysfunction modify cognitive-behavioral therapies, and emo-Severe emotional control dysfunction, including tion regulation and impulse control problemsanxiety, hyper-vigilance, and avoidance, may may complicate the use of exposure techniques.become significant barriers to treatment of Physical pain, which frequently occurs aftercognitive issues. On the other hand, cognitive TBI, may limit the extent to which patients candeficits, especially those affecting aspects of engage in PTSD treatments that involve in-attention, learning, and memory, may become person exposure to anxiety producing situationsbarriers to effective treatment of emotional (Bryant and Hopwood 2006; Nampiaparampilissues. Existing interventions designed for TBI 2008). Conversely, the emotional dysregulation,rehabilitation or PTSD alone may need to be avoidance, and potential for triggering maymodified in order to maximize effectiveness. The impede engagement in cognitive rehabilitationmodifications may require crossing the boundar- therapies. Reduction of PTSD and managementies between traditional disciplines, creating a of severe TBI may be facilitated by teachingsignificant challenge in care systems designed to patients more adaptive coping strategies (Bryantaddress single diagnoses. et al. 2000).Modifications to Existing Treatments Interventions for TBI–PTSDIn current practice, most interventions are Recognizing complexities with regards to TBIdirected toward a diagnosis of PTSD or TBI, but diagnosis and attribution of symptoms, a recentnot both. Treating PTSD, in the context of TBI, VA directive stated the following: “The assess-may differ from treating PTSD alone. For indi- ment of an individual with persistent concussion/viduals in the chronic phase of the disorder, the mild TBI-related symptoms should be directed toPTSD treatments with the strongest evidence the specific nature of the symptoms regardless ofare cognitive-behavioral psychotherapies (Cahill their etiology. The management of an individualet al. 2009) such as cognitive processing therapy, who has sustained a documented concussion/as well as prolonged exposure (Monson et al. mild TBI and has persistent cognitive and behav-2006; Schnurr et al. 2007). Preliminary data also ioral symptoms after 1 month should not differsuggest that these therapies will be helpful for based on the specific underlying etiology of theirOEF/OIF veterans. A small, ongoing trial of pro- symptoms (i.e., concussion vs. pain, concussionlonged exposure among OEF/OIF veterans has vs. stress disorder).”shown a 50% reduction in PTSD symptoms To date, there are no empirically validatedfollowing treatment (Rauch et al. 2009). There therapies to treat comorbid PTSD and some evidence supporting the effectiveness Therapeutic formulations may also need toof CBT for treatment of acute stress disorder address associated issues with substance usefollowing mild TBI and CBT combined with disorders, pain, and the other issues discussed inneurorehabilitation for targeting general anxiety this chapter. Combined approaches for co-treatingsymptomatology in people with mild-to-moderate the variety of emotional/behavioral and cognitiveTBI (Soo and Tate 2007). sequelae may need to involve mental health/ Modification of these approaches for individ- PTSD specialists and TBI rehabilitation special-uals with cognitive dysfunction remains an ists (Vanderploeg et al. 2009).important frontier for intervention development. Vanderploeg et al. discuss the need to inter-Current experience suggests that PTSD in indi- vene early after military post-deployment withviduals who also sustain a TBI may be a more social and emotional adjustment interventions,complicated, and the chronicity of symptoms including the development of mindfulness-basedmay be extended. Patients with TBI–PTSD may relaxation and stress management skills, improved
  • 26. 298 A.J.-W. Chen and T. Novakovic-Agopiansleep hygiene, and education regarding substance functional neural network circuitry, and neuro-use/abuse and alternative coping supports pharmacology. Neurologic abnormalities associ-(Vanderploeg et al. 2009). They further suggest ated with TBI may complicate abnormalitiesthat early symptom-based adjustment and stress associated with PTSD. Limbic structures, includ-management interventions may minimize the ing the amygdala, are thought to be integral todevelopment or prolongation of PTSD and addi- emotions (e.g., anxiety) involved in the feartionally may serve to reduce residual symptoms response. As a “modulator” on the limbic system,associated with TBI. Current findings also sug- the medial PFC is thought to play a significantgest that PTSD treatment likely should be priori- inhibitory role, allowing higher-order cognitivetized after combat or other types of injury, functions to moderate less volitional limbic-basedregardless of TBI status, to decrease symptom fear responses. Because TBI may involve damagecomplaints and enhance outcomes. to prefrontal circuits, the additional loss of inhib- itory control of the limbic system related to theTargeting Core Self-Regulatory Control TBI may play a role in exacerbating and main-Functions Involved in TBI–PTSD taining PTSD symptoms.These considerations argue strongly that treat- Investigations that focus on neural mecha-ments that effectively improve cognitive and nisms of learning and plasticity in particular willemotional self-regulatory functions may be be valuable for better understanding the patho-particularly valuable in treating the combined genesis of symptoms and dysfunction as well asneurotrauma syndrome. The issues from TBI– providing foundations for treatment approaches.PTSD include disruption of core cognitive and Neural level considerations suggest that certainemotional regulation mechanisms that are treatment approaches used for TBI or PTSD mayessential for goal-directed functioning in life. need to be modified in order to maximizeInterventions that strengthen the goal-directed beneficial effects and reduce potential for unex-control functions, such as the selection of rele- pected harm in individuals with the combinedvant information along with inhibition of dis- syndrome. This applies to pharmacologic andtracting information, may be particularly helpful. other biological approaches, as well as behavioralDorsolateral PFC and ventromedical PFC inter- approaches.act in the regulation of emotions, with modula- On a broader level, all of the above interac-tion of amygdala (Phelps et al. 2004). These tions argue for a re-consideration of a combinedinteracting circuits are likely to be important for combat neurotrauma syndrome as an entitycognitive and emotional self-regulation training distinct from TBI or PTSD, with features thatsuch as mindfulness-based attention regulation. are not simply the addition of the two. DefinitionThis forms an important foundation for further of this syndrome has implications for guidingdevelopment of interventions for TBI–PTSD. future research, defining new research questions as well as requiring new approaches and method-Neural Bases of TBI–PTSD and Frontiers in ologies. Regardless of whether we can define aIntervention Development definitive syndrome and its etiology, it is clearTreating individuals with TBI–PTSD symptom- that the combinations of symptoms that veteransatically, regardless of diagnosis, is important experience after combat do need to be addressedinitial approach. However, it is possible that with available tools immediately. Addressingintervention approaches may be refined as more these symptoms will require a multifactorialis learned about the underlying biology of the approach that takes into account contributorydisorders. Consideration of potential interrela- environmental, personal, social, emotional, andtionships between traumatic and experiential cognitive factors as well as changes in underlyinginjury at neural levels generates important neural systems. In particular, a much greaterhypotheses for guiding research and interven- emphasis on cognitive, emotional, and behavioraltion development. Direct interactions may be self-regulation may be needed, even in individ-understood based on structural neuroanatomy, uals with so-called “mild” TBI.
  • 27. 15 Interventions to Improve Cognitive Functioning After TBI 299Tested Theory-Driven Cognitive that progressively engage spatial working memory,Interventions for Attention, Working Klingberg and colleagues have shown improve-Memory, and Other Control Processes ments in working memory functioning as well as transfer to higher level cognitive functions thatA variety of innovations have been developed for presumably rely on working memory (Klingbergtargeting aspects of cognitive functioning. 2010; Westerberg et al. 2007). In healthy sub-Individualization is a key tenet for optimizing jects, improvements correlated with increases inrehabilitation. Thus, each therapist may provide activation in PFC and parietal regions, as well asa different intervention for each patient, and changes in dopamine receptor binding (Olesensystematically studying such interventions is et al. 2004; McNab et al. 2009). Other recentchallenging. A small number of structured inter- studies, testing computer-based tasks withvention protocols have been directly studied. health individuals, have generated excitement byIncreasing evidence supports the proposition demonstrating improvements in aspects ofthat training-based therapies have utility for goal-directed control and even general fluidrehabilitation in the chronic phase of TBI, includ- intelligence (Erickson et al. 2007; Dahlin et training for attention, working memory, 2008; Jaeggi et al. 2008; Persson and Reuter-problem-solving, and other strategic aspects of Lorenz 2008). To what extent process-targeted,goal management. computer-based approaches may be helpful for Even within the domain of attention, there may individuals with brain injury, with improve-be many varieties of approaches to training. ments that generalize to real-world functioningSelected handful of theory-driven interventions will be worth further investigation.are highlighted here. A new paradigmatic example Approaches that train the use of meta-cognitiveis attention process training, originally formulated strategies have demonstrated utility for individ-by Sohlberg and Mateer (Sohlberg and Mateer uals with brain injury. Noting that many individu-1987; Sohlberg et al. 2000). Versions of APT train als with brain injury have difficulties with specifica hierarchy of attention processes using guided aspects of goal management, including makingexercises. This method, along with other clinically absent-minded slips, going off track, and havingbased approaches, has been reviewed in multiple difficulty completing multi-step tasks, goal man-reviews and meta-analyses (Cicerone et al. 2000, agement training emphasizes the cessation of2005; Kennedy et al. 2008; Levine et al. 2008; ongoing activity, and a meta-cognitive strategyRohling et al. 2009), and there is significant evi- for breaking down goals into manageable sub-dence to support their use for patients with brain steps. This approach attempts to ameliorateinjury. This and other approaches that target deficits related to goal neglect, and studies testingspecific processes, including a number using training protocols have shown that learning ofcomputer-based tasks, have been demonstrated these strategies may improve goal managementto improve functioning on targeted measures. for individuals with brain injury, as well asHowever, the transfer and generalization of gains healthy older adults (Levine et al. 2000, 2007).from task practice have turned out to be an impor- Another intervention that combines attentiontant barrier (D’Esposito and Gazzaley 2006). This and problem-solving as targets of therapy in araises important questions regarding the nature of group-based training protocol was recentlytransfer beyond practiced tasks, and the devel- described by Evans (2001, 2005). Initial groupopment of approaches to enhance generalization sessions address attentional difficulties, andremains an important goal. later sessions introduce and practice the use of Some recent approaches have shown promise problem-solving strategies. Participants are encour-in not only improving the targeted processes but aged to adopt a systematic approach to solvingalso showing transfer of benefits to other tasks problems and to manage and monitor goalthat were not included in training. In a series of achievement through periodic mental checking.studies utilizing computer-based practice of tasks In a study by Miotto et al. (2009), participants
  • 28. 300 A.J.-W. Chen and T. Novakovic-Agopianwith chronic frontal lesions showed improvement measurements. It would be ideal for interventionson a measure of functional performance with and measurements to be drawn from a unifiedmultiple tasks, and on caregiver ratings of execu- neuroscience framework, opening the potentialtive functioning, though not on neuropsycholog- for well-integrated studies to test the mechanismsical tests, after the implementation of training that support improvements in cognition. This isrelative to control conditions. the essence of a rehabilitation neuroscience We are all constantly faced with sources of approach.information that either contain too much infor- Two general and complementary directionsmation or are ambiguous with respect to one’s for development are worth pointing out. First,goals. The ability to synthesize core meaning any approach should be designed to enhancefrom incoming information (i.e., “get the gist”) is neural mechanisms of control. The foundations inimportant for goal-directed behavior in everyday cognitive neuroscience discussed earlier may, and relies on the integration of a number of Second, cognitive training must lead to improve-cognitive processes. Chapman and colleagues ment in function in activities of everyday living.have developed protocols to train gist-based Patients are most in need of functional improve-strategic reasoning, guiding individuals through ments for navigating the complexities and ambi-steps that engage attention (repeating and filtering guities of daily life in low-structure settings ofthe information), working memory (integration the real-world. Computer-based “brain trainingof information), and higher level elaborative games” have staged a resurgence in interestreasoning (expanding, extracting). Training has recently, and provide a timely example for con-been shown to improve the ability to extract gist, sidering whether the offered cognitive trainingas well as other aspects of learning and reasoning approaches maximize generalization of improve-for children, as well as adults with brain injury ments. In general, there has been little evidence(Vas et al. 2011). Performance on tests of atten- to support transfer and generalization of benefitstion and working memory also improved. This from practice on basic tasks, such as computerraises the interesting possibility that training in games, to improved functioning in real-lifehigher level integrative abilities may improve situations (D’Esposito and Gazzaley 2006).more basic functions. However, computer, Internet, and other technol- ogies may provide valuable tools to augment training, if applied appropriately in interventionsBridges to Improved Interventions that are well-informed by neuroscience and best clinical practice. We provide one exampleDefining neurologic processes as specific thera- of a rehabilitation neuroscience study that uti-peutic targets facilitates the “vertical integration” lizes a theory-driven intervention to test hypo-of developments in neuroscience and rehabilita- theses regarding functional, behavioral, andtive therapies. Of particular interest in this dis- neural changes.cussion are studies that “close the loop,” testingnot only the behavioral and clinical effects of Targeting the Selection Gatewaythese interventions but also hypothesized neural The regulation of information processing in themechanisms. The nature of plasticity within pre- brain deserves special emphasis. Selective pro-frontal networks remains one of the frontiers of cessing of goal-relevant information, a centralneuroscience (Miller and Cohen 2001) as well as component of executive control, is a crucial gate-rehabilitation. On the one hand, defining mecha- way that filters what information gains access tonisms of neural plasticity may provide potential more in-depth processing (Baddeley 2001; Vogeltargets for treatment. On the other hand, rehabili- et al. 2005; Cowan and Morey 2006; Repovs andtation interventions may provide powerful tools Baddeley 2006; Awh and Vogel 2008). The integ-to probe mechanisms of plasticity, especially rity of information processing, whether fromwhen matched with appropriate neurophysiologic perception or through other steps to action,
  • 29. 15 Interventions to Improve Cognitive Functioning After TBI 301requires mechanisms of selection, maintenance, been applied to patients with brain injury as welland protection from disruption during working as other populations (D’Zurilla and Goldfriedmemory, learning, decision-making, and/or 1971; VonCramon et al. 1991; Levine et al. 2000,problem-solving. The protection of information pro- 2007; Rath et al. 2003; Nezu et al. 2007) withcessing from distractions anywhere along this special emphasis on mindfulness-based attentionpathway is crucial to efficient and effective goal regulation strategies applied to daily life situa-attainment, especially when extended time or tions and complex, project-based functionalmultiple steps are required. tasks. An overarching hypothesis was that train- The general principles proposed earlier in ing that improves goal-directed control overthis chapter for optimally training control functions neural processing would benefit all subsequentwould ideally be applied with this specific stages of goal-based processing, helping by“selection” gateway as a target. In one example making damaged, poorly integrated collectionsof a rehabilitation neuroscience study, our of neurons into more efficient, better integratedparticular interest was in examining neural- functional networks for the performance of rele-behavioral changes with an intervention that vant tasks, and ultimately, goal attainment intargets goal-oriented attention regulation real-life contexts.(Novakovic-Agopian et al. 2011). Participants It may be argued that the ecologically validwith chronic brain injury and executive dys- measurement of executive control functioningfunction completed a training intervention for requires observation and quantification of per-goal-oriented attentional self-regulation that formance with real-life, functional tasks in a low-takes into account the links connecting atten- structure environment. We therefore assessedtion, working memory, and goal-based direction training-related changes in participant function-of behavior in daily life. In contrast to training ing on measures of performance in “real-life”via practice on isolated tasks, this training pro- low-structure settings. Following training, par-tocol involved application of attention regula- ticipants showed improvements in accom-tion skills and strategies to participant-defined plishing tasks, confirming generalization ofgoals in real-life, ecologically valid settings. training effects to complex, real-life settings. In Two conceptual lines converged to delineate testing whether functional improvements mighttarget processes for intervention. First, pathways be related to improvements in the targeted cogni-from perception to action require mechanisms for tive functions, we also assessed domain-specificthe selection of information for in-depth process- changes utilizing neuropsychological, as well as the maintenance and protection of Participants who completed a course of goal-this information from disruption during working oriented attentional self-regulation trainingmemory and subsequent learning, decision- improved on neuropsychological measures ofmaking, and/or problem-solving. Second, many complex attention and executive functions,patients with brain injuries show an overall “life including working memory, mental flexibility,disorganization,” with poor ability to manage inhibition, and sustained attention. Long-termand attain goals, even when they may be able to follow-up is particularly helpful in determiningdescribe their intentions at the outset. Duncan what aspects of an intervention have enduringand others have described this phenomenon as benefits. In a follow-up conducted 6 months-“goal neglect” (Duncan et al. 1995, 1996). We to-2 years post-training, 87% of participantsreasoned that selective maintenance of goal- indicated continuing to use at least one trainedrelated information is important for guiding strategy in their daily life.sequences of steps (subgoals) required to accom- Understanding the neural bases of cognition,plish the goal. Therefore, intervening on these including the mechanisms by which improve-processes may help to ameliorate symptoms of ments occur, may provide guidance for the devel-goal neglect. The experimental training protocol opment of treatments to enhance functioningwas based on training interventions that have (Chen et al. 2006; D’Esposito and Chen 2006;
  • 30. 302 A.J.-W. Chen and T. Novakovic-AgopianKennedy et al. 2008; Levine et al. 2008). would lead to changes in tuning of neural repre-Intervening via rehabilitation provides an oppor- sentations such that the balance of representationtunity to probe such mechanisms. Functional neu- would favor goal-relevant information. Ourroimaging studies examining changes associated findings with training were consistent with thiswith various forms of training in neurologically prediction. Modulation of neural processing inintact individuals have shown different patterns of extrastriate cortex was significantly enhanced byresults, primarily in terms of increases or decreases attention regulation regional brain activation, and the significance As discussed above, the lateral PFC has beenof these results remains unclear (Kelly and strongly implicated as a source of attentionalGaravan 2005; Kelly et al. 2006; Hillary 2008). It control signals that could bias neural processingis also unclear from functional neuroimaging in extrastriate cortex (Desimone 1998; Millerstudies of patients with acquired brain injuries as and Cohen 2001; Miller and D’Esposito 2005).to what neural changes support improved recov- The pattern of findings within lateral PFC showedery of cognitive function (Rosen et al. 2000; that changes in function depended on the base-Corbetta et al. 2005; Chen et al. 2008; Sanchez- line state of any given individual. One particu-Carrion et al. 2008). Information regarding neural larly important but challenging question formechanisms of improvement in executive control further investigation is to understand the indi-functions is particularly sparse. Even the extent to vidual variability in mechanisms by which dif-which the neural systems that underlie executive ferent individuals may achieve improvement incontrol are plastic, if at all, has remained an open functioning after brain injury.question. Only a handful of fMRI studies to date A training study with veterans with chronichave examined cognitive rehabilitation following TBI, some of whom have co-morbid PTSD andbrain injury (Laatsch et al. 2004; Strangman et al. depression, is currently ongoing. This study, as2009) and even fewer have examined the effects well as future studies with veterans with PTSD,of rehabilitation interventions on executive con- will help test not only whether goal-directed cogni-trol functions (Kim et al. 2009). We attempted to tive functioning may be improved, but also to whatidentify neural mechanisms that underlie improve- extent emotional functioning may be improvedments in attention and executive control with the with training in attentional self-regulation. We areabove described rehabilitation training. also working on methods that leverage the advan- We hypothesized that training in attention tages of computer game-based formats to augmentregulation improves cognitive performance by training. The intervention protocols are designedenhancing goal-based modulatory control of based on the principles discussed in this chapter,neural processing. Functional MRI methods bridging the neuroscience and clinical rehabilita-adapted for testing the effects of intervention for tion of goal-directed control functions.patients with varied injury pathology were usedto index modulatory control of neural processing(Chen et al. 2011). Another important paradigm Directions and Imperatives for Futureshift is supported by measurements that “read the Workinformation” coded in brain networks, rather thansimply quantifying activity levels. Information is A Long-Term View on Brain Injuryrepresented in the brain through the coordinated Sequelaeactivity of distributed networks. Methods fordecoding neural information representations may Functional de fi cits from TBI may produceprovide valuable tools for gauging the functional tremendous chronic burden on individuals, fami-integration of these networks, particularly impor- lies, and health care systems. The far-reachingtant in individuals who have suffered brain injury impact of these seemingly “invisible” deficits isand potentially a “disintegration” of brain networks. often not recognized. Beyond the immediateWe hypothesized that attention regulation training effects of injury on cognition, or even the effects
  • 31. 15 Interventions to Improve Cognitive Functioning After TBI 303on engagement in rehabilitation, school, or work, ing systems of care. How integrated is the overallthere may be ramifications across the lifespan approach to the patient? The organization of care(Chen and D’Esposito 2010). Individuals who needs to be considered given the complex nature ofhave suffered a TBI may be at increased risk for cognitive dysfunction after brain injury, and thedeveloping cognitive changes later in life. For approaches that are needed to improve functioning.example, individuals who have suffered moderate The effective integration of any or all of the neural-or severe TBI may be at 2.3 and 4.5 times cognitive processes and modulators illustrated inincreased risk of developing Alzheimer’s disease Fig. 15.1 is a particularly important determinant of(Plassman et al. 2000). Risk may be increased for overall cognitive functioning. Interventionthose with certain apolipoprotein E genotypes approaches may need to target not only separate(Van Den Heuvel et al. 2007). processes but also the effective integration of these What are the mechanisms by which TBI may processes. Thus, at a systems level, expert carecontribute to worsened cognitive functioning with may require the integration of expertise that isaging? Does TBI simply change an individual’s typically divided across many disciplines.cognitive baseline, thereby reducing the threshold Care may need to be re-organized to moreat which detectable dementia later in life would efficiently and effectively address the multipleoccur? This effect could be mediated by a rela- issues faced by individuals with brain injuries.tively simple mechanism that is related to the This may involve team members addressing andconcept of “cognitive reserve” (Kesler et al. 2003; reinforcing common themes and issues thatNithianantharajah and Hannan 2009). If an indi- cross psychological and emotional functioning,vidual’s baseline functioning is “knocked down” psychiatric health, social work, case manage-a notch after a TBI, leaving a reduced reserve, ment, pharmacotherapy, vocational or educa-then that person is more likely to fall below some tional assistance, family interactions, and more.“threshold” during the aging process. Taking into account interactions between Could TBI actually alter the course and rate of emotions and cognition is particularly relevantage-related cognitive decline? It is possible that given the frequent co-occurrence of TBI andthere could be a more dynamic “cumulative” post-traumatic stress symptoms. Specific themeseffect of TBI across time. One must consider the or approaches may be implemented by multipledynamic nature of brain functioning, where team members, increasing the chances of accom-development and learning vs. degradation and plishing a therapeutic goal. Individual practitio-forgetting are constantly countering each other ners may need to expand their range of expertise,to determine an individual’s current level of func- for example, incorporating strategies that bridgetioning. After a brain injury, an individual may cognitive rehabilitation with mental health,not learn as quickly or as effectively as without pain management, and substance abuse. Giventhe injury. Even small, possibly undetectable the combined issues of potentially reduced“deficits” in cognitive functioning may have a awareness, vulnerability to confusion, and poten-magnified effect over the course of aging, as the tial difficulty mentally integrating multipleeffects of poor learning accumulate over time. approaches, it would be ideal to take an inte-This has significant implications for the develop- grated, patient-centered approach.ment of interventions that address long-term Certain issues in the implementation and deliv-brain health after brain injury. ery for military veterans deserve special consider- ation. Treatment implementation and delivery methods need to be adapted to take into accountTranslation to Intervention issues related to geographic distribution of veterans,Implementation and Delivery the “culture” of military as well as communityin Systems of Care settings for post-military life, a high level of comorbidity with PTSD and other mental healthThe considerations discussed in this chapter sug- conditions, individual goals after military servicegest important changes in the organization of exist- (e.g., educational or occupational), and more.
  • 32. 304 A.J.-W. Chen and T. Novakovic-Agopian The wide geographic distribution of veterans Conclusionscreates challenges for treatment delivery andimplementation. For example, one of the largest The effects of TBI on cognition are complexcatchment areas for veterans returning from the and have challenged clinicians throughout history,combat in the Middle East spans thousands of as well as deterred neuroscientists from pursuingsquare miles of Northern California, Nevada, studies in this “messy” area of inquiry. The com-and Hawaii, from oceans to mountains and desert plexity is compounded by combinations of physi-as well as cities. The majority of veterans are not cal and experiential injury, as well as otherwithin easy travel distance to specialty medical comorbidities. Much work will need to be donecenters. This limits the applicability of intensive to better define effective therapies for cognitiveon-site therapies, and raises challenges to dysfunction caused by brain injuries. Researchachieving integrated, interdisciplinary care. and development along several key directionsFurthermore, many of the cognitive, emotional, will be crucial.or behavioral problems that occur with TBI, Building a strong theoretical and scientificeven without deficits in other physical functions, foundation will be valuable for guiding the devel-have not been standard indications for inpatient opment of new therapies. Understanding theor residential treatment. Expansion of inpatient brain systems that underlie the cognitive changesor in-residence programs may be necessary. associated with brain injury should help in the Telemedicine approaches may extend thera- delineation of targets in the rehabilitation of anpeutic range, and new tools for augmenting individual with TBI. In particular, this knowledgetherapeutic interventions at a distance will be will open the way for therapies that target bio-valuable. The development of telemedicine logical systems and synergistically augment theimplementation for treatments for complex beneficial specific effects of training.issues such as cognitive dysfunction is still in Pharmacotherapy and other biologicalits infancy. Computer-assisted therapy tools modification therapies may be integrated intomay help bridge the distances, though issues of rehabilitation to help augment learning byengagement, compliance, and monitoring need changing specific brain systems or altering theto be taken into account to maximize treatment plasticity of the brain in a more general way.effectiveness. For example, the development of Much work needs to be done to define thecomputer-assisted cognitive training regimens specific effects of drugs at multiple levels ofthat are remotely administered, yet supervised nervous system function, in order to best defineby expert therapists via telecommunication combined behavioral-pharmacotherapeutic pre-technologies, may help. scriptions. Mechanisms of plasticity to be har- Another important barrier is the divide nessed may range from changes in intracellularbetween “medical care” and community. An signaling, cellular proliferation, alterations ofimportant goal of many younger veterans is dendritic or axonal structures, and more, butsuccessful re-integration into civilian communi- these changes, occurring in isolation, will notties, with goals involving family, education, and/ necessarily be beneficial. Ultimately, for anyor new occupations. Care traditionally centered neuronal changes to beneficially affect neuro-within medical facilities will need to better con- logical functioning, they must lead to functionalnect with each individual’s community setting. changes in neuronal networks. Training providesTelecommunication technologies (e.g., video a crucial set of methods to guide or sculpt plastic-interactions from therapist to a patient’s house) ity to achieve functionally integrated networksand formulation of therapy programs that cross and improvements in behavioral functioning.the borders between medical center and home, Approaches that bridge the basic neuroscienceschool, or work may be valuable. of neural-cognitive functioning with the practical
  • 33. 15 Interventions to Improve Cognitive Functioning After TBI 305realities of clinical rehabilitation will be valuable intervention development, expanding the horizonsin intervention development. It will be particu- for improving cognitive functioning for individu-larly important to consider the relationships als who have suffered brain injury.between multiple levels of individual function-ing, from neurons to neural networks all the way Acknowledgment Special thanks to Katelyn Begany forup to social networks, each providing comple- assistance with editing.mentary targets for therapy. Improved measures of the effects and mecha-nisms of interventions are sorely needed. The Referenceslack of adequate measurements has limited inter-vention development. Measurement development Arnsten AF, Goldman-Rakic PS. Noise stress impairsneeds to progress in at least two directions. First, prefrontal cortical cognitive function in monkeys:biomarkers of the neural processes that mediate evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry. 1998;55(4):362–8.cognitive functions affected by brain injuries Aston-Jones G, Cohen JD. An integrative theory of locuswould be valuable for determining mechanisms. coeruleus-norepinephrine function: adaptive gain andCognitive neuroscience can serve as a founda- optimal performance. Annu Rev Neurosci. 2005;28:tion for development of these biomarkers. 403–50. Awh E, Vogel EK. The bouncer in the brain. Nat Neurosci.Measurements informative of cognitive pro- 2008;11(1):5–6.cesses, especially higher-order cognitive func- Ayalon L, Borodkin K, et al. Circadian rhythm sleeptioning, are also needed. These measurements disorders following mild traumatic brain injury.of neural-cognitive processes will be crucial for Neurology. 2007;68(14):1136–40. Baddeley AD. Is working memory still working? Amelucidating mechanisms of the benefits (or lack Psychol. 2001;56(11):851–64.thereof) for any intervention. Just as importantly, Badre D, D’Esposito M. Is the rostro-caudal axis of themeasurements that reflect cognitive functioning frontal lobe hierarchical? Nat Rev ecologically relevant, real-life contexts are 2009;10(9):659–69. Baldo JV, Shimamura AP. Letter and category fluency inneeded. Most tests of cognitive functioning, patients with frontal lobe lesions. Neuropsychology.including neuropsychological tests and most 1998;12(2):259–67.cognitive neuroscience measures, are designed to Baldo JV, Shimamura AP, et al. Verbal and design fluencyisolate the processes of interest. This is analogous in patients with frontal lobe lesions. J Int Neuropsychol Soc. 2001;7(5):586– judging how accurate a basketball player will Baldo JV, Delis DC, et al. Is it bigger than a breadbox?be at shooting foul shots by measuring isolated Performance of patients with prefrontal lesions on abiceps strength. On the other hand, the few func- new executive function test. Arch Clin Neuropsychol.tional assessment measures available are not 2004;19(3):407–19. Baldo JV, Schwartz S, et al. Role of frontal versus tempo-linked in any clear way to the underlying neural- ral cortex in verbal fluency as revealed by voxel-basedcognitive component processes affected by lesion symptom mapping. J Int Neuropsychol Soc.TBI. The development of ecologically relevant, 2006;12(6):896–900.neuroscience-driven interventions will benefit Banich MT, Milham MP, et al. fMri studies of Stroop tasks reveal unique roles of anterior and posteriorgreatly from measurements that bridge neural- brain systems in attentional selection. J Cogn Neurosci.cognitive processes to real-world behavior. 2000a;12(6):988–1000. Taking a long-term view on TBI in the context Banich MT, Milham MP, et al. Prefrontal regions play aof the lifespan may lead to a major paradigm predominant role in imposing an attentional ‘set’: evidence from fMRI. Brain Res Cogn Brain Res.shift for the field. We will need to consider the 2000b;10(1–2):1–9.enhancement of ongoing learning, recovery, and/ Belanger HG, Curtiss G, et al. Factors moderating neurop-or maintenance as a long-term goal of post-injury sychological outcomes following mild traumatic brain“brain health.” Keeping in mind the benefits of injury: a meta-analysis. J Int Neuropsychol Soc. 2005;11(3):215–27.bridging across levels of human functioning, Belanger HG, Kretzmer T, et al. Cognitive sequelae ofacross disciplines, and across the lifespan will blast-related versus other mechanisms of brain trauma.significantly alter the emphasis of research and J Int Neuropsychol Soc. 2009;15(1):1–8.
  • 34. 306 A.J.-W. Chen and T. Novakovic-AgopianBinder LM, Rohling ML, et al. A review of mild head Bushnik T, Englander J, et al. Patterns of fatigue and its trauma. Part I: meta-analytic review of neuropsycho- correlates over the first 2 years after traumatic brain logical studies. J Clin Exp Neuropsychol. 1997;19(3): injury. J Head Trauma Rehabil. 2008b;23(1):25–32. 421–31. Cahill S, Rothbaum B, et al. Cognitive-behavioral therapyBloomfield IL, Espie CA, et al. Do sleep difficulties for adults. In: Foa EB, Keane TM, Friedman MJ, exacerbate deficits in sustained attention following Cohen JA, editors. Effective treatments for PTSD: traumatic brain injury? J Int Neuropsychol Soc. practice guidelines for the international society for 2009;16(1):17–25. traumatic stress studies. New York: Guilford Press;Blumenfeld RS, Ranganath C. Prefrontal cortex and long- 2009. p. 139–222. term memory encoding: an integrative review of Canessa N, Ferini-Strambi L. Sleep-disordered breathing findings from neuropsychology and neuroimaging. and cognitive decline in older adults. JAMA. Neuroscientist. 2007;13(3):280–91. 2011;306(6):654–5.Borgaro SR, Gierok S, et al. Fatigue after brain injury: Castriotta RJ, Wilde MC, et al. Prevalence and initial reliability study of the BNI Fatigue Scale. Brain consequences of sleep disorders in traumatic brain Inj. 2004;18(7):685–90. injury. J Clin Sleep Med. 2007;3(4):349–56.Brandes D, Ben-Schachar G, et al. PTSD symptoms and Chen AJ-W, D’Esposito M. Traumatic brain injury: cognitive performance in recent trauma survivors. from bench to beside to society. Neuron. 2010;66(1): Psychiatry Res. 2002;110(3):231–8. 11–4.Brewin CR, Kleiner JS, et al. Memory for emotionally Chen AJ-W, Abrams GM, et al. Functional re-integration neutral information in posttraumatic stress disorder: of prefrontal neural networks for enhancing recovery a meta-analytic investigation. J Abnorm Psychol. after brain injury. J Head Trauma Rehabil. 2006;21(2): 2007;116(3):448–63. 107–18.Bryant R, Hopwood S. Commentary on “Trauma to the Chen AJ-W, Britton M, et al. Sharpening of neural repre- Psyche and Soma”. Cogn Behav Pract. 2006;13(1): sentations: a mechanism of top-down control over 17–23. information processing by selective attention. NewBryant RA, Marosszeky JE, et al. Coping style and post- York City: Cognitive Neuroscience Society; 2007. traumatic stress disorder following severe traumatic Chen JK, Johnston KM, et al. Recovery from mild head brain injury. Brain Inj. 2000;14(2):175–80. injury in sports: evidence from serial functionalBunge SA, Zelazo PD. A brain-based account of the magnetic resonance imaging studies in male athletes. development of rule use in childhood. Curr Dir Psychol Clin J Sport Med. 2008;18(3):241–7. Sci. 2006;15(3):118–21. Chen AJW, Novakovic-Agopian T, et al. Training of goal-Bunge SA, Ochsner KN, et al. Prefrontal regions involved directed attention regulation enhances control over in keeping information in and out of mind. Brain. neural processing for individuals with brain injury. 2001;124(Pt 10):2074–86. Brain. 2011.Bunge SA, Dudukovic NM, et al. Immature frontal lobe Cicerone KD. Remediation of “working attention” in mild contributions to cognitive control in children: evidence traumatic brain injury. Brain Inj. 2002;16(3):185–95. from fMRI. Neuron. 2002a;33(2):301–11. Cicerone KD, Azulay J. Diagnostic utility of attentionBunge SA, Hazeltine E, et al. Dissociable contributions of measures in postconcussion syndrome. Clin Neuro- prefrontal and parietal cortices to response selection. psychol. 2002;16(3):280–9. Neuroimage. 2002b;17(3):1562–71. Cicerone KD, Dahlberg C, et al. Evidence-based cogni-Bunge SA, Kahn I, et al. Neural circuits subserving the tive rehabilitation: recommendations for clinical retrieval and maintenance of abstract rules. J Neuro- practice. Arch Phys Med Rehabil. 2000;81(12): physiol. 2003;90(5):3419–28. 1596–615.Bunge SA, Wendelken C, et al. Analogical reasoning and Cicerone KD, Dahlberg C, et al. Evidence-based cogni- prefrontal cortex: evidence for separable retrieval and tive rehabilitation: updated review of the literature integration mechanisms. Cereb Cortex. 2005;15(3): from 1998 through 2002. Arch Phys Med Rehabil. 239–49. 2005;86(8):1681–92.Burgess PW, Gonen-Yaacovi G, et al. Functional neu- Collette F, Van der Linden M, et al. Exploring the unity roimaging studies of prospective memory: what have and diversity of the neural substrates of executive we learnt so far? Neuropsychologia. 2011;49(8): functioning. Hum Brain Mapp. 2005;25(4):409–23. 2246–57. Cools R, Barker RA, et al. Enhanced or impaired cogni-Burton, T. Why some patients get no help after brain tive function in Parkinson’s disease as a function of injury. Wall St j. January 8, 2007. http://online.wsj. dopaminergic medication and task demands. Cereb com/article/SB116822903868669978.html. Cortex. 2001;11(12):1136–43.Bushnik T, Englander J, et al. The experience of fatigue in Cools R, Barker RA, et al. l-Dopa medication remediates the first 2 years after moderate-to-severe traumatic cognitive inflexibility, but increases impulsivity in brain injury: a preliminary report. J Head Trauma patients with Parkinson’s disease. Neuropsychologia. Rehabil. 2008a;23(1):17–24. 2003;41(11):1431–41.
  • 35. 15 Interventions to Improve Cognitive Functioning After TBI 307Cools R, Gibbs SE, et al. Working memory capacity pre- Dikmen SS, Machamer JE, et al. Neuropsychological dicts dopamine synthesis capacity in the human effects of valproate in traumatic brain injury: a random- striatum. J Neurosci. 2008;28(5):1208–12. ized trial. Neurology. 2000;54(4):895–902.Corbetta M, Kincade MJ, et al. Neural basis and recovery Doctor JN, Castro J, et al. Workers’ risk of unemployment of spatial attention deficits in spatial neglect. Nat after traumatic brain injury: a normed comparison. Neurosci. 2005;8(11):1603–10. J Int Neuropsychol Soc. 2005;11(6):747–52.Cowan N, Morey CC. Visual working memory depends Donohue SE, Wendelken C, et al. Retrieving rules for on attentional filtering. Trends Cogn Sci. 2006;10(4): behavior from long-term memory. Neuroimage. 139–41. 2005;26(4):1140–9.Crone EA, Donohue SE, et al. Brain regions mediating Drake AI, Gray N, et al. Factors predicting return to work flexible rule use during development. J Neurosci. following mild traumatic brain injury: a discriminant 2006;26(43):11239–47. analysis. J Head Trauma Rehabil. 2000;15(5):1103–12.Curtis CE, D’Esposito M. Persistent activity in the pre- Duncan J, Burgess P, et al. Fluid intelligence after frontal cortex during working memory. Trends Cogn frontal lobe lesions. Neuropsychologia. 1995;33(3): Sci. 2003;7(9):415–23. 261–8.Curtis CE, Rao VY, et al. Maintenance of spatial and Duncan J, Emslie H, et al. Intelligence and the frontal motor codes during oculomotor delayed response lobe: the organization of goal-directed behavior. tasks. J Neurosci. 2004;24(16):3944–52. Cognit Psychol. 1996;30(3):257–303.D’Esposito M, Gazzaley A. Neurorehabilitation and exec- Erickson KI, Colcombe SJ, et al. Training-induced func- utive function. In: Selzer ME, Cohen L, Gage FH, tional activation changes in dual-task processing: an Clarke S, Duncan PW, editors. Neural rehabilitation FMRI study. Cereb Cortex. 2007;17(1):192–204. and repair. Cambridge, UK: Cambridge University Evans J. Rehabilitation of the dysexecutive syndrome. In: Press; 2006 p. 475–87. Wood R, McMillan T, editors. NeurobehaviouralD’Esposito M, Postle BR. The dependence of span and disability and social handicap. London: Psychology delayed-response performance on prefrontal cortex. Press; 2001. p. 209–27. Neuropsychologia. 1999;37(11):1303–15. Evans J. Can executive impairments be effectively treated?D’Esposito M, Detre JA, et al. The neural basis of the In: Effectiveness of rehabilitation for cognitive deficits. central executive system of working memory. Nature. New York, Oxford University Press; 2005. p. 247–57. 1995;378(6554):279–81. Fellus JL, Elovic EP. Fatigue: assessment and treatment.D’Esposito M, Aguirre GK, et al. Functional MRI studies In: Zasler ND, Katz DI, Zafonte R, editors. Brain of spatial and non-spatial working memory. Cogn injury medicine. New York: Demos Medical Brain Res. 1998;7:1–13. Publishing; 2007.D’Esposito M, Postle BR, et al. Maintenance versus Fischer S, Gauggel S, et al. Awareness of activity limita- manipulation of information held in working memory: tions, goal setting and rehabilitation outcome in patients an event-related fMRI study. Brain Cogn. 1999;41(1): with brain injuries. Brain Inj. 2004;18(6):547–62. 66–86. Fish J, Manly T, et al. Compensatory strategies forD’Esposito M, Chen AJW. Neural mechanisms of pre- acquired disorders of memory and planning: differen- frontal cortical function: implications for cognitive tial effects of a paging system for patients with brain rehabilitation. In: Moller A, Chapman SB, Lomber injury of traumatic versus cerebrovascular aetiology. SG, editors. Reprogramming the human brain: prog- J Neurol Neurosurg Psychiatry. 2008a;79(8):930–5. ress in brain research. Elsevier; 2006. 157. Fish J, Manly T, et al. Long-term compensatory treatmentD’Zurilla TJ, Goldfried M. Problem solving and behavior of organizational deficits in a patient with bilateral modification. J Abnorm Psychol. 1971;78:107–26. frontal lobe damage. J Int Neuropsychol Soc. 2008b;Dahlin E, Neely AS, et al. Transfer of learning after updat- 14(1):154–63. ing training mediated by the striatum. Science. Frencham KA, Fox AM, et al. Neuropsychological 2008;320(5882):1510–2. studies of mild traumatic brain injury: a meta-analyticDe Groot MH, Phillips SJ, et al. Fatigue associated with review of research since 1995. J Clin Exp Neuropsychol. stroke and other neurologic conditions: implications 2005;27(3):334–51. for stroke rehabilitation. Arch Phys Med Rehabil. Fuster JM. Executive frontal functions. Exp Brain Res. 2003;84(11):1714–20. 2000;133(1):66–70.Degutis JM, Van Vleet TM. Tonic and phasic alertness Gazzaley A, Cooney JW, et al. Top-down enhancement training: a novel behavioral therapy to improve spatial and suppression of the magnitude and speed of neural and non-spatial attention in patients with hemispatial activity. J Cogn Neurosci. 2005;17(3):507–17. neglect. Front Hum Neurosci. 2010;4:60. Gilbert SJ, Spengler S, et al. Functional specializationDesimone R. Visual attention mediated by biased compe- within rostral prefrontal cortex (area 10): a meta- tition in extrastriate visual cortex. Philos Trans R Soc analysis. J Cogn Neurosci. 2006;18(6):932–48. Lond B Biol Sci. 1998;353(1373):1245–55. Gilbertson MW, Gurvits TV, et al. Multivariate assess-Dikmen SS, Temkin NR, et al. Neurobehavioral effects of ment of explicit memory function in combat veterans phenytoin prophylaxis of posttraumatic seizures. with posttraumatic stress disorder. J Trauma Stress. JAMA. 1991;265(10):1271–7. 2001;14(2):413–32.
  • 36. 308 A.J.-W. Chen and T. Novakovic-AgopianGiles GM. Cognitive versus functional approaches to Kabat-Zinn J. Full catastrophe living. New York, NY: rehabilitation after traumatic brain injury: commen- Delacorte Press; 1990. tary on a randomized controlled trial. Am J Occup Kane MJ, Engle RW. The role of prefrontal cortex in Ther. 2010;64(1):182–5. working-memory capacity, executive attention, andGold JI, Shadlen MN. Neural computations that underlie general fluid intelligence: an individual-differences decisions about sensory stimuli. Trends Cogn Sci. perspective. Psychon Bull Rev. 2002;9(4):637–71. 2001;5(1):10–6. Kelly AM, Garavan H. Human functional neuroimagingGoldman-Rakic PS, Friedman HR. The circuitry of work- of brain changes associated with practice. Cereb ing memory revealed by anatomy and metabolic imag- Cortex. 2005;15(8):1089–102. ing. In: Levin H, Eisenberg H, Benton A, editors. Kelly C, Foxe JJ, et al. Patterns of normal human brain Frontal lobe function and dysfunction. New York: plasticity after practice and their implications for Oxford University Press; 1991. p. 72–91. neurorehabilitation. Arch Phys Med Rehabil.Gouveia PA, Brucki SM, et al. Disorders in planning and 2006;87(12 Suppl 2):S20–9. strategy application in frontal lobe lesion patients. Kennedy MR, Coelho C, et al. Intervention for executive Brain Cogn. 2007;63(3):240–6. functions after traumatic brain injury: a systematicGualtieri CT, Evans RW. Stimulant treatment for the neu- review, meta-analysis and clinical recommendations. robehavioural sequelae of traumatic brain injury. Brain Neuropsychol Rehabil. 2008;18(3):257–99. Inj. 1988;2(4):273–90. Kesler SR, Adams HF, et al. Premorbid intellectual func-Haxby JV, Gobbini MI, et al. Distributed and overlapping tioning, education, and brain size in traumatic brain representations of faces and objects in ventral tempo- injury: an investigation of the cognitive reserve ral cortex. Science. 2001;293(5539):2425–30. hypothesis. Appl Neuropsychol. 2003;10(3):153–62.Hecaen H, Albert ML. Human neuropsychology. New Kim YH, Yoo WK, et al. Plasticity of the attentional net- York: Wiley; 1978. work after brain injury and cognitive rehabilitation.Hillary FG. Neuroimaging of working memory dysfunc- Neurorehabil Neural Repair. 2009;23(5):468–77. tion and the dilemma with brain reorganization Kimberg DY, D’Esposito M, et al. Effects of bromocrip- hypotheses. J Int Neuropsychol Soc. 2008;14(4): tine on human subjects depend on working memory 526–34. capacity. Neuroreport. 1997;8(16):3581–5.Hillier SL, Sharpe MH, et al. Outcomes 5 years post- Kline AE, Hoffman AN, et al. Chronic administration of traumatic brain injury (with further reference to antipsychotics impede behavioral recovery after neurophysical impairment and disability). Brain Inj. experimental traumatic brain injury. Neurosci Lett. 1997;11(9):661–75. 2008;448(3):263–7.Hoffman AN, Cheng JP, et al. Administration of halo- Klingberg T. Training and plasticity of working memory. peridol and risperidone after neurobehavioral testing Trends Cogn Sci. 2010;14(7):317–24. hinders the recovery of traumatic brain injury-induced Laatsch LK, Thulborn KR, et al. Investigating the neuro- deficits. Life Sci. 2008;83(17–18):602–7. biological basis of cognitive rehabilitation therapyHoge CW, McGurk D, et al. Mild traumatic brain injury in with fMRI. Brain Inj. 2004;18(10):957–74. U.S. Soldiers returning from Iraq. N Engl J Med. Langlois JA, Kegler SR, et al. Traumatic brain injury- 2008;358(5):453–63. related hospital discharges. Results from a 14-stateHuckans M, Pavawalla S, et al. A pilot study examining surveillance system, 1997. MMWR Surveill Summ. effects of group-based Cognitive Strategy Training 2003;52(4):1–20. treatment on self-reported cognitive problems, psychi- Leskin LP, White PM. Attentional networks reveal execu- atric symptoms, functioning, and compensatory strategy tive function deficits in posttraumatic stress disorder. use in OIF/OEF combat veterans with persistent mild Neuropsychology. 2007;21(3):275–84. cognitive disorder and history of traumatic brain Levine B, Robertson IH, et al. Rehabilitation of executive injury. J Rehabil Res Dev. 2010;47(1):43–60. functioning: an experimental-clinical validation ofHux K, Schneider T, et al. Screening for traumatic brain goal management training. J Int Neuropsychol Soc. injury. Brain Inj. 2009;23(1):8–14. 2000;6(3):299–312.Hyndman D, Ashburn A. People with stroke living in the Levine B, Stuss DT, et al. Cognitive rehabilitation in the community: attention deficits, balance, ADL ability elderly: effects on strategic behavior in relation to goal and falls. Disabil Rehabil. 2003;25(15):817–22. management. J Int Neuropsychol Soc. 2007;13(1):Ilinisky IA, Jouandet ML, et al. Organization of the 143–52. nigrothalamocortical system in the rhesus monkey. Levine B, Turner G, et al. (2008). Cognitive rehabilitation J Comp Neurol. 1985;236:315–30. of executive dysfunction In : Cognitive Neurore-Jaeggi SM, Buschkuehl M, et al. Improving fluid intelli- habilitation: Evidence & Applications (2nd Edition). gence with training on working memory. Proc Natl D. T. Stuss, G. Winocur and I. H. Robertson Editors. Acad Sci USA. 2008;105(19):6829–33. Cambridge Unuversity Press; pp 464–87.Jazayeri M. Probabilistic sensory recoding. Curr Opin Lewis V, Creamer M, et al. Is poor sleep in veterans a Neurobiol. 2008;18(4):431–7. function of post-traumatic stress disorder? Mil Med.Jha AP, Krompinger J, et al. Mindfulness training modifies 2009;174(9):948–51. subsystems of attention. Cogn Affect Behav Neurosci. Lezak MD. Neuropsychological assessment. New York: 2007;7(2):109–19. Oxford University Press; 1995.
  • 37. 15 Interventions to Improve Cognitive Functioning After TBI 309Luks TL, Simpson GV, et al. Evidence for anterior cingu- Miotto E, Evans J, et al. Rehabilitation of executive dys- late cortex involvement in monitoring preparatory function: a controlled trial of an attention and problem attentional set. Neuroimage. 2002;17(2):792–802. solving treatment group. Neuropsychol Rehabil.Machamer J, Temkin N, et al. Stability of employment 2009;19:517–40. after traumatic brain injury. J Int Neuropsychol Soc. Monson C, Schnurr P, et al. Cognitive processing therapy 2005;11(7):807–16. for veterans with military-related posttraumatic stressMacLeod CM. Half a century of research on the Stroop disorder. J Consult Clin Psychol. 2006;74(5): effect: an integrative review. Psychol Bull. 898–907. 1991;109(2):163–203. Muzur A, Pace-Schott EF, et al. The prefrontal cortex inMacLeod CM, Dunbar K. Training and Stroop-like inter- sleep. Trends Cogn Sci. 2002;6(11):475–81. ference: evidence for a continuum of automaticity. J Nampiaparampil D. Prevalence of chronic pain after trau- Exp Psychol Learn Mem Cogn. 1988;14(1):126–35. matic brain injury: a systematic review. JAMA.Mahmood O, Rapport LJ, et al. Neuropsychological per- 2008;300(6):711–9. formance and sleep disturbance following traumatic Neckelmann D, Mykletun A, et al. Chronic insomnia as a brain injury. J Head Trauma Rehabil. risk factor for developing anxiety and depression. 2004;19(5):378–90. Sleep. 2007;30(7):873–80.Manly T, Robertson IH, et al. The absent mind: further Newman SD, Carpenter PA, et al. Frontal and parietal investigations of sustained attention to response. participation in problem solving in the Tower of Neuropsychologia. 1999;37(6):661–70. London: fMRI and computational modeling of plan-Manly T, Hawkins K, et al. Rehabilitation of executive ning and high-level perception. Neuropsychologia. function: facilitation of effective goal management on 2003;41(12):1668–82. complex tasks using periodic auditory alerts. Nezu AM, Nezu CM, et al. Solving life’s problems. New Neuropsychologia. 2002;40:271–81. York: Springer Publishing Company; 2007.Mathias JL, Coats JL. Emotional and cognitive sequelae Nithianantharajah J, Hannan AJ. The neurobiology of to mild traumatic brain injury. J Clin Exp Neuro- brain and cognitive reserve: mental and physical psychol. 1999;21(2):200–15. activity as modulators of brain disorders. ProgMathias JL, Beall JA, et al. Neuropsychological and infor- Neurobiol. 2009;89(4):369–82. mation processing deficits following mild traumatic Novakovic-Agopian T, Chen A, et al. Rehabilitation of brain injury. J Int Neuropsychol Soc. 2004;10(2): executive functioning with training in attention 286–97. regulation applied to individually defined goals: aMauri M, Sinforiani E, et al. Interaction between pilot study bridging theory, assessment and treatment. Apolipoprotein epsilon 4 and traumatic brain injury in J Head Trauma Rehabil. 2011;26(5):325–38. patients with Alzheimer’s disease and Mild Cognitive Okie S. Traumatic brain injury in the war zone. N Engl Impairment. Funct Neurol. 2006;21(4):223–8. J Med. 2005;352(20):2043–7.McDowell S, Whyte J, et al. Differential effect of a dop- Olesen PJ, Westerberg H, et al. Increased prefrontal and aminergic agonist on prefrontal function in traumatic parietal activity after training of working memory. Nat brain injury patients. Brain. 1998;121(Pt 6):1155–64. Neurosci. 2004;7(1):75–9.McNab F, Varrone A, et al. Changes in cortical dopamine Olver JH, Ponsford JL, et al. Outcome following trau- D1 receptor binding associated with cognitive train- matic brain injury: a comparison between 2 and 5 years ing. Science. 2009;323(5915):800–2. after injury. Brain Inj. 1996;10(11):841–8.Mednick S, Nakayama K, et al. Sleep-dependent learning: Ownsworth T, McKenna K. Investigation of factors related a nap is as good as a night. Nat Neurosci. 2003;6(7): to employment outcome following traumatic brain 697–8. injury: a critical review and conceptual model. DisabilMeintzschel F, Ziemann U. Modification of practice- Rehabil. 2004;26(13):765–83. dependent plasticity in human motor cortex by neuro- Ozdemir F, Birtane M, et al. Cognitive evaluation and modulators. Cereb Cortex. 2006;16(8):1106–15. functional outcome after stroke. Am J Phys MedMiller EK, Cohen JD. An integrative theory of prefrontal Rehabil. 2001;80(6):410–5. cortex function. Annu Rev Neurosci. 2001;24: Park DC, Polk TA, et al. Aging reduces neural specializa- 167–202. tion in ventral visual cortex. Proc Natl Acad Sci USA.Miller BT, D’Esposito M. Searching for “the top” in 2004;101(35):13091–5. top-down control. Neuron. 2005;48(4):535–8. Paulus MP, Potterat EG, et al. A neuroscience approach toMilliken CS, Auchterlonie JL, et al. Longitudinal assess- optimizing brain resources for human performance in ment of mental health problems among active and extreme environments. Neurosci Biobehav Rev. reserve component soldiers returning from the Iraq 2009;33(7):1080–8. war. JAMA. 2007;298(18):2141–8. Persson J, Reuter-Lorenz PA. Gaining control: trainingMiotto EC, Savage CR, et al. Bilateral activation of the executive function and far transfer of the ability to prefrontal cortex after strategic semantic cognitive resolve interference. Psychol Sci. 2008;19(9):881–8. training. Hum Brain Mapp. 2006;27(4):288–95.
  • 38. 310 A.J.-W. Chen and T. Novakovic-AgopianPetersen SE, van Mier H, et al. The effects of practice on Saatman KE, Duhaime AC, et al. Classification of trau- the functional anatomy of task performance. Proc Natl matic brain injury for targeted therapies. J Neurotrauma. Acad Sci USA. 1998;95(3):853–60. 2008;25(7):719–38.Phelps EA, Delgado MR, et al. Extinction learning in Salmond CH, Chatfield DA, et al. Cognitive sequelae of humans: role of the amygdala and vmPFC. Neuron. head injury: involvement of basal forebrain and asso- 2004;43(6):897–905. ciated structures. Brain. 2005;128(Pt 1):189–200.Plassman BL, Havlik RJ, et al. Documented head injury in Sanchez-Carrion R, Fernandez-Espejo D, et al. A longitu- early adulthood and risk of Alzheimer’s disease and dinal fMRI study of working memory in severe TBI other dementias. Neurology. 2000;55(8):1158–66. patients with diffuse axonal injury. Neuroimage.Polusny MA, Kehle SM, et al. Longitudinal effects of 2008;43(3):421–9. mild traumatic brain injury and posttraumatic stress Scheid R, Walther K, et al. Cognitive sequelae of diffuse disorder comorbidity on postdeployment outcomes in axonal injury. Arch Neurol. 2006;63(3):418–24. national guard soldiers deployed to Iraq. Arch Gen Schneiderman AI, Braver ER, et al. Understanding seque- Psychiatry. 2011;68(1):79–89. lae of injury mechanisms and mild traumatic brainPosner MI. Measuring alertness. Ann N Y Acad Sci. injury incurred during the conflicts in Iraq and 2008;1129:193–9. Afghanistan: persistent postconcussive symptoms andPosner MI, Sheese BE, et al. Analyzing and shaping posttraumatic stress disorder. Am J Epidemiol. human attentional networks. Neural Netw. 2006;19(9): 2008;167(12):1446–52. 1422–9. Schnurr P, Friedman M, et al. Cognitive behavioralPostle BR. Working memory as an emergent property of therapy for posttraumatic stress disorder in women: a the mind and brain. Neurosci. 2006;139:23–38. randomized controlled trial. JAMA. 2007;297(8):Prigatano GP, Wong JL. Cognitive and affective improve- 820–30. ment in brain dysfunctional patients who achieve Schumacher EH, Lauber E, et al. PET evidence for an inpatient rehabilitation goals. Arch Phys Med Rehabil. amodal verbal working memory system. Neuroimage. 1999;80(1):77–84. 1996;3:79–88.Ranganath C. Working memory for visual objects: comple- Schwartz A. New sign of brain damage in N.F.L. New mentary roles of inferior temporal, medial temporal, and York: New York Times; 2009. prefrontal cortex. Neuroscience. 2006;139(1):277–89. Selemon RD, Goldman-Rakic PS. Common corticalRanganath C, Johnson MK, et al. Prefrontal activity asso- and subcortical targets of the dorsolateral prefrontal ciated with working memory and episodic long-term and posterior parietal cortices in the rhesus monkey: memory. Neuropsychologia. 2003;41(3):378–89. evidence for a distributed neural network servingRanganath C, Heller AS, et al. Dissociable correlates of spatially guided behavior. J Neurosci. 1988;8: two classes of retrieval processing in prefrontal cortex. 4049–68. Neuroimage. 2007;35(4):1663–73. Shallice T, Burgess PW. Deficits in strategy applicationRaskin SA. Memory. In: Raskin SA, Mateer C, editors. following frontal lobe damage in man. Brain. Neuropsychological management of mild traumatic 1991;114:727–41. brain injury. Oxford: Oxford University Press; 2000. Silver JM, Koumaras B, et al. Effects of rivastigmine onRath J, Simon D, et al. Group treatment of problem-solving cognitive function in patients with traumatic brain deficits in outpatients with traumatic brain injury: a injury. Neurology. 2006;67(5):748–55. randomised outcome study. Neuropsychol Rehabil. Slagter HA, Lutz A, et al. Mental training affects distri- 2003;13(4):461–88. bution of limited brain resources. PLoS Biol.Rauch S, Defever E, et al. Prolonged exposurefor PTSD 2007;5(6):e138. in a Veterans Health Administration PTSD clinic. Smith Jr KR, Goulding PM, et al. Neurobehavioral effects J Trauma Stress. 2009;22(1):60–4. of phenytoin and carbamazepine in patients recoveringRepovs G, Baddeley A. The multi-component model of from brain trauma: a comparative study. Arch Neurol. working memory: explorations in experimental cogni- 1994;51(7):653–60. tive psychology. Neuroscience. 2006;139(1):5–21. Sohlberg MM, Mateer CA. Effectiveness of an attention-Robertson IH. Goal management training: a clinical manual. training program. J Clin Exp Neuropsychol. 1987;9(2): Cambridge: PsyConsult. 1996. 117–30.Rohling ML, Faust ME, et al. Effectiveness of cognitive reha- Sohlberg MM, McLaughlin KA, et al. Evaluation of atten- bilitation following acquired brain injury: a meta-analytic tion process training and brain injury education in re-examination of Cicerone et al’.s (2000, 2005) system- persons with acquired brain injury. J Clin Exp atic reviews. Neuropsychology. 2009;23(1):20–39. Neuropsychol. 2000;22(5):656–76.Rosen HJ, Petersen SE, et al. Neural correlates of recov- Soo C, Tate R. Psychological treatment for anxiety in ery from aphasia after damage to left inferior frontal people with traumatic brain injury. Cochrane Database cortex. Neurology. 2000;55(12):1883–94. Syst Rev. 2007(3): CD005239.Ruff R. Two decades of advances in understanding of Spitzer H, Desimone R, et al. Increased attention enhances mild traumatic brain injury. J Head Trauma Rehabil. both behavioral and neuronal performance. Science. 2005;20(1):5–18. 1988;240(4850):338–40.
  • 39. 15 Interventions to Improve Cognitive Functioning After TBI 311Stanislav SW. Cognitive effects of antipsychotic agents in Vasterling JJ, Duke LM, et al. Attention, learning, and persons with traumatic brain injury. Brain Inj. memory performances and intellectual resources in 1997;11(5):335–41. Vietnam veterans: PTSD and no disorder comparisons.Staub F, Bogousslavsky J. Fatigue after stroke: a major but Neuropsychology. 2002;16(1):5–14. neglected issue. Cerebrovasc Dis. 2001;12(2):75–81. Verfaellie M, Vasterling JJ. Memory in PTSD: a neu-Strangman GE, Goldstein R, et al. Neurophysiological rocognitive approach. In: Shiromani P, Keane TM, alterations during strategy-based verbal learning in LeDoux J, editors. Neurobiology of PTSD. Totowa, traumatic brain injury. Neurorehabil Neural Repair. NJ: Humana Press; 2009. p. 105–32. 2009;226–236. Vogel EK, McCollough AW, et al. Neural measures revealSturm W, de Simone A, et al. Functional anatomy of individual differences in controlling access to working intrinsic alertness: evidence for a fronto-parietal- memory. Nature. 2005;438(7067):500–3. thalamic-brainstem network in the right hemisphere. Volkow ND, Wang GJ, et al. Sleep deprivation decreases Neuropsychologia. 1999;37(7):797–805. binding of [11C]raclopride to dopamine D2/D3 recep-Stuss DT, Alexander MP. Is there a dysexecutive syn- tors in the human brain. J Neurosci. 2008;28(34): drome? Philos Trans R Soc Lond B Biol Sci. 8454–61. 2007;362(1481):901–15. VonCramon D, Matthes-Von Cramon G, et al. Problem-Taber KH, Hurley RA. PTSD and combat-related injuries: solving deficits in brain-injured patients: a therapeutic functional neuroanatomy. J Neuropsychiatry Clin approach. Neuropsychol Rehabil. 1991;1:45–64. Neurosci. 2009;21(1):1p. preceding 1, 1–4. Warden DL, Gordon B, et al. Guidelines for the pharma-Tatemichi TK, Paik M, et al. Dementia after stroke is a cologic treatment of neurobehavioral sequelae of predictor of long-term survival. Stroke. 1994;25(10): traumatic brain injury. J Neurotrauma. 2006;23(10): 1915–9. 1468–501.Thompson-Schill SL, Jonides J, et al. Effects of frontal Watson NF, Dikmen S, et al. Hypersomnia following lobe damage on interference effects in working mem- traumatic brain injury. J Clin Sleep Med. 2007;3(4): ory. Cogn Affect Behav Neurosci. 2002;2(2):109–20. 363–8.Thurman D, Alverson C, et al. Traumatic brain injury in Westerberg H, Jacobaeus H, et al. Computerized working the United States: a public health perspective. J Head memory training after stroke – a pilot study. Brain Inj. Trauma Rehabil. 1999;14(6):602–15. 2007;21(1):21–9.Tucker MA, Hirota Y, et al. A daytime nap containing Whyte J, Polansky M, et al. Sustained arousal and atten- solely non-REM sleep enhances declarative but not tion after traumatic brain injury. Neuropsychologia. procedural memory. Neurobiol Learn Mem. 1995;33(7):797–813. 2006;86(2):241–7. Whyte J, Hart T, et al. Effects of methylphenidate onvan Baalen B, Odding E, et al. Cognitive status at dis- attentional function after traumatic brain injury. A ran- charge from the hospital determines discharge destina- domized, placebo-controlled trial. Am J Phys Med tion in traumatic brain injury patients. Brain Inj. Rehabil. 1997;76(6):440–50. 2008;22(1):25–32. Whyte J, Hart T, et al. Effects of methylphenidate onVan Den Heuvel C, Thornton E, et al. Traumatic brain attention deficits after traumatic brain injury: a multi- injury and Alzheimer’s disease: a review. Prog Brain dimensional, randomized, controlled trial. Am J Phys Res. 2007;161:303–16. Med Rehabil. 2004;83(6):401–20.van Reekum R, Cohen T, et al. Can traumatic brain injury Wilson MS, Gibson CJ, et al. Haloperidol, but not olan- cause psychiatric disorders? J Neuropsychiatry Clin zapine, impairs cognitive performance after traumatic Neurosci. 2000;12(3):316–27. brain injury in rats. Am J Phys Med Rehabil.Van Vleet TM, Hoang-Duc AK, et al. Modulation of non- 2003;82(11):871–9. spatial attention and the global/local processing bias. Yaffe K, Laffan AM, et al. Sleep-disordered breathing, Neuropsychologia. 2011;49(3):352–9. hypoxia, and risk of mild cognitive impairment andVanderploeg RD, Curtiss G, et al. Long-term neuropsy- dementia in older women. JAMA. 2011; chological outcomes following mild traumatic brain 306(6):613–9. injury. J Int Neuropsychol Soc. 2005;11(3):228–36. Yochim B, Baldo J, et al. D-KEFS Trail Making Test per-Vanderploeg RD, Belanger HG, et al. Mild traumatic brain formance in patients with lateral prefrontal cortex injury and posttraumatic stress disorder and their asso- lesions. J Int Neuropsychol Soc. 2007;13(4):704–9. ciations with health symptoms. Arch Phys MedRehabil. Yochim BP, Baldo JV, et al. D-KEFS Tower Test perfor- 2009;90:1084–93. mance in patients with lateral prefrontal cortexVas A, Chapman S, et al. Higher-order reasoning training lesions: the importance of error monitoring. J Clin years after traumatic brain injury in adults. J Head Exp Neuropsychol. 2009;31(6):658–63. Trauma Rehabil. 2011;26(3):224–39. Yoo SS, Hu PT, et al. A deficit in the ability to form newVasterling JJ, Brewin CR. Neuropsychology of PTSD. human memories without sleep. Nat Neurosci. New York: The Guilford Press; 2005. 2007;10(3):385–92.Vasterling JJ, Brailey K, et al. Attention and memory Yu W, Ravelo A, et al. Prevalence and costs of chronic dysfunction in posttraumatic stress disorder. Neuro- conditions in the VA health care system. Med Care psychology. 1998;12(1):125–33. Res Rev. 2003;60(3 Suppl):146S–67.
  • 40. 312 A.J.-W. Chen and T. Novakovic-AgopianZafonte R, Lombard L, et al. Antispasticity medications: Zhang ZG, Chopp M. Neurorestorative therapies for uses and limitations of enteral therapy. Am J Phys stroke: underlying mechanisms and translation to the Med Rehabil. 2004;83(10 Suppl):S50–8. clinic. Lancet Neurol. 2009;8(5):491–500.Zeitzer JM, Friedman L, et al. Insomnia in the context of Zhang L, Plotkin RC, et al. Cholinergic augmentation traumatic brain injury. J Rehabil Res Dev. 2009;46(6): with donepezil enhances recovery in short-term 827–36. memory and sustained attention after traumaticZelano C, Bensafi M, et al. Attentional modulation in brain injury. Arch Phys Med Rehabil. 2004;85(7): human primary olfactory cortex. Nat Neurosci. 2005; 1050–5. 8(1):114–20.