neuropsychiatric diagnosis and management of chronic sequelae · parsing symptoms into common...

JRRDJRRD Volume 46 Number 6 2009

Pages 757ndash796

Journal of Rehabil itation Research amp Development

Neuropsychiatric diagnosis and management of chronic sequelaeof war-related mild to moderate traumatic brain injury

Joshua D Halbauer MD1ndash3 J Wesson Ashford MD PhD1ndash3 Jamie M Zeitzer PhD1ndash3 Maheen M Adamson PhD1ndash3 Henry L Lew MD PhD14 Jerome A Yesavage MD1ndash31Department of Veterans Affairs (VA) Palo Alto Health Care System Palo Alto CA 2VA Sierra-Pacific Mental Illness Research Education and Clinical Center and War-Related Illness and Injury Study Center Palo Alto CA 3Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford University CA 4Physical Medicine and Rehabilitation VA Boston Healthcare System Boston MA

AbstractmdashSoldiers with a traumatic brain injury (TBI) presentwith an array of neuropsychiatric symptoms that can be groupedinto nosological clusters (1) cognitive dysfunctions difficultiesin memory attention language visuospatial cognition sensory-motor integration affect recognition andor executive func-tion typically associated with neocortical damage (2) neu-robehavioral disorders mood affect anxiety posttraumaticstress and psychosis as well as agitation sleep problems andlibido loss that may have been caused by damage to the cortexlimbic system andor brain stem monoaminergic projectionsystems (3) somatosensory disruptions impaired smell visionhearing equilibrium taste and somatosensory perception fre-quently caused by trauma to the sensory organs or their projec-tions through the brain stem to central processing systems(4) somatic symptoms headache and chronic pain and (5) sub-stance dependence TBI-related cognitive impairment is com-mon in veterans who have served in recent conflicts in the MiddleEast and is often related to blasts from improvised explosivedevices Although neurobehavioral disorders such as depres-sion and posttraumatic stress disorder commonly occur aftercombat the presentation of such disorders in those with headinjury may pass undetected with use of current diagnostic criteriaand neuropsychological instruments With a multidimensionalapproach (such as the biopsychosocial model) applied to eachsymptom cluster psychological occupational and social dys-function can be delineated and managed

Key words affective aggression agitation attention commu-nication executive function language memory pain PTSDrehabilitation

INTRODUCTION

Through the introduction of advanced warfare tech-nologies soldier mortality from bullets and bomb blastshas decreased [1] Soldiers are instead sustaining increased

Abbreviations AAN = American Academy of NeurologyACRM = American Congress of Rehabilitation Medicine AD =Alzheimer disease ADHD = attention deficit hyperactivity disor-der APOE = apolipoprotein E DSM-III = Diagnostic and Statisti-cal Manual of Mental Disorders (DSM)-Third Edition DSM-IV-TR = DSM-Fourth Edition-Text Revision DTI = diffusion tensorimaging FA = fractional anisotropy FDA = Food and DrugAdministration ICD-10 = International Classification of Dis-eases-10th Edition LOC = loss of consciousness MNI = mildneurocognitive impairment NMDA = N-methyl-D-aspartateOEF = Operation Enduring Freedom OIF = Operation Iraqi Free-dom PCD = postconcussion disorder PCS = postconcussion syn-drome PDGMC = personality disorder due to a general medicalcondition PTA = posttraumatic amnesia PTSD = posttraumaticstress disorder QOL = quality of life ROI = region of interestRR = risk ratio SSRI = selective serotonergic reuptake inhibitorTBI = traumatic brain injury VA = Department of Veterans AffairsWMLL = white matter load lesionAddress all correspondence to J Wesson Ashford MDPhD War-Related Illness and Injury Study Center VAPalo Alto Health Care System 151-W 3801 Miranda AvePalo Alto CA 94304 650-852-3287 fax 650-852-3297Email wesashfordvagovDOI101682JRRD2008080119

757

758

JRRD Volume 46 Number 6 2009

head face and neck injuries particularly traumatic braininjuries (TBIs) [2] Identifying areas of functional cogni-tive and psychiatric impairments in those with TBI fromthese conflicts has presented a variety of challenges Vari-ous organizations such as the American Congress ofRehabilitation Medicine (ACRM) the American Acad-emy of Neurology (AAN) and the American PsychiatricAssociation have different diagnostic classifications thatdelineate specific factors directly related to TBI and itslong-term sequelae These classifications are limited inmany respects and present challenges for diagnosis andultimately treatment These classifications will be dis-cussed in terms of their nosology possible underlying neu-robiology applicability and utility for patient treatmentparticularly from a psychopharmacological perspective

Although TBI is caused by physical head trauma thechronic sequelae of TBI are defined in terms of clusters ofneuropsychiatric symptoms (Figure 1) (1) cognitive dys-functions (memory attention language visuospatial cog-nition sensory-motor integration affect recognition andexecutive function) (2) neurobehavioral disorders (moodaffect anxiety posttraumatic stress psychotic sleep andlibidinal disorders) (3) somatosensory disruptions (changesin smell vision hearing equilibrium taste and soma-tosensory perception) (4) somatic symptoms (headachechronic pain) and (5) substance dependence This articlewill examine incidence prevalence neurobiological basesdiagnostic criteria and brief instruments for assessing thesesymptom clusters and then provide clinicians withapproaches for neuropsychiatric treatment Furthermorewith this organizational approach applied to patients withTBI impairments found in particular aspects of daily func-tioning (eg reduced employment impaired social relation-ships and decreased quality of life [QOL]) [3] can beidentified and referred for psychosocial interventions

A prior study examined TBI from a similar multifac-torial perspective but found little ldquohigh-classrdquo evidenceon which to base any treatment recommendations forpatients with TBI [4] In contrast the current formulationwith use of neurobiological understanding is based onparsing symptoms into common nosological classifica-tions not usually associated with TBI and on borrowingfrom the extensive experience with those related disor-ders for developing treatment options The applicablecommon diagnostic entities include Alzheimer disease(AD) posttraumatic stress disorder (PTSD) depressionand attention deficit hyperactivity disorder (ADHD) Inaddition the formulation presented in this review is

based on evidence that neuroplastic systems exist in thebrain for self-repair and adaptation after brain injury fur-thermore extensive evidence suggests that numerousinterventions can facilitate these repair mechanisms evenif memory function is impaired Accordingly a broadarray of reasonable treatments exists that can be appliedto managing the chronic sequelae of TBI

This review will emphasize the recognition of the typesof problems commonly seen in other disorders that areassociated with TBI and then discuss the application of themany specific psychopharmacological treatments that havebeen demonstrated to have substantial efficacy in thoserelated conditions to the treatment of patients with TBIThis review will mention rehabilitative neuropsychologicaland behavioral treatment options but a full review of theseis beyond the scope of this discussion

CURRENT SYSTEMS OF CLASSIFICATION OF TBI SEQUELAE

Current classifications of TBI-related problems cor-respond only roughly with the actual conditions andlong-term outcomes These classifications (delineated inthe following list) generally relate to the acute TBI par-ticularly the presentation and symptoms apparent in thefirst 24 hours after the TBI have not been based on lon-gitudinal observational studies [5] and provide little reli-able evidence for an association between clinical factorsand outcome [6] For example the International Classifi-cation of Diseases-10th Edition (ICD-10) lists the follow-ing relevant codesbull F068 Other specified mental disorders due to brain

damage and dysfunction and to physical disease indexbull F072 Postconcussion syndrome (PCS)bull F50ndashF59 Behavioral syndromes associated with physi-

ological disturbances and physical factorsbull G90ndashG99 Other disorders of the nervous systembull S060 Concussion

Clearly these classifications do not adequately coverthe complex problems that often result from TBI Someother classifications that have been applied to patients whohave suffered TBI are provided in the following sections

TBI SeverityA primary concern in treating a patient with a TBI is

determining the severity of the injury Injury severitydepends on a variety of factors related to the nature of the

759

HALBAUER et al Neuropsychiatric diagnosis and management of war-related TBI

physical force that caused the injury and the condition ofthe individual at the time of receiving the assault Thephysical force that causes an injury can be single or com-plex come from any direction and include secondaryrepercussions and consist of an energy shock wave thattraverses the brain or an object that penetrates the skullExamples of complexities that make TBI unique aremdashbull Individual head attributesmdashage skull thickness pro-

tective gear etcbull Brain reserve (cognitive neuronal) prior injury historybull Individual repair mechanisms (eg geneticsmdashapolipo-

protein E [APOE] genotype)bull Type of injury nonpenetrating penetrating (may not be

noted)bull Direction of physical force impacting headbull Orientationlocation of forcemdashtranslational vs rotational

bull Nature of physical energymdashamplitude risetime wave-length duration reflection

bull Effects on brainmdashbrain stem cortex white matterbull Complexitymdashmultiplicity of injury contusion bleeding

infectionbull Psychological stress social imperativesbull Immediate care after injurymdashobservation medication

interventionbull Chronic care after injurymdashrehabilitation support

Furthermore many premorbid psychological factorsinfluence an individualrsquos short- and long-term response toTBI The acute severity of a TBI is initially classifiedaccording to the individualrsquos immediate responses includ-ing loss of consciousness (LOC) and posttraumatic amne-sia (PTA) One must realize however that the severity ofthe acute phase related to damage of specific brain

Figure 1Clusters of neuropsychiatric symptoms of traumatic brain injury PTSD = posttraumatic stress disorder

760


regions such as the brain stem or the medial temporallobe may only loosely predict many other problems thatcan develop weeks and years later for an individual with aTBI These complexities lead to the conclusion that everyTBI has a unique pattern of presentation and sequelae

A definition of mild TBI developed by the ACRM[7] states that a person with mild TBI is one who hastraumatically induced changes as manifested by at leastone of the following1 Any period of LOC for less than 30 min and a Glas-

gow Coma Scale score of 13 to 152 Any loss of memory of events (PTA) immediately

before or after the accident and not exceeding 24 h3 Any alteration in mental state at the time of the acci-

dent (eg feeling dazed disoriented or confused)4 Focal neurological deficits

The ACRM also lists a number of other physicalcognitive and behavioral symptoms as further evidencethat mild TBI has occurred including nausea dizzinessvomiting headache disturbed vision decreased concen-tration fatigue lethargy memory loss irritability andemotional lability However these signs and symptomsare not adequately parsed into factors relating to themany different types of specific damage that can occurwithin the skull and how they relate to acute concernsversus long-term sequelae

Posttraumatic AmnesiaPart of the ACRM diagnosis of TBI depends on the

duration of PTA The duration of PTA is a good markerfor acutely estimating whether TBI is moderate to severeand especially predicts short-term prognosis when thepresenting individual is seen early in the course of PTAand when the time of the injury is known [8] Howeverthe duration of PTA is unlikely to be observed in a combatarena and this measure (when potential observers may befighting for their own lives or be even more severelyinjured) has not been demonstrated to be a reliable markerfor predicting the extent of impairment in mild TBI cases[9] The lack of sensitivity of PTA in mild TBI may be dueto the conditions that make mild TBI difficult to evaluateeven within 24 hours of the injury (1) the lack of a lowerlimit of PTA [7] which creates a situation in which anindividual can have PTA without it being observable ormeasurable [10ndash11] and (2) the lack of test-retest stability(patients are difficult to assess their levels fluctuate theavailable measures of memory are poor) within a 24-hourtime scale with use of the commonly available neuro-

psychological scales such as the Westmead PTA Scale[12] the Galveston Orientation and Amnesia Test [13] orthe Julia Farr Centre PTA Scale [14]

White Matter IntegrityDefining the neuropathology associated with persis-

tent cognitive deficits in mild TBI is problematic Fre-quently no demonstrable abnormalities can be found onstandard magnetic resonance imaging brain scans [15]An objective assessment of neuropathology may beachieved with use of diffusion tensor imaging (DTI) DTImeasures fractional anisotropy (FA) which relates to thediffusion of hydrogen atoms in particular directions atspecific points The FA can be used for tractography gen-erating white matter fiber tract maps [16] FA is believedto reflect many factors including the degree of myelina-tion and axonal density or integrity [17ndash20]

Kraus et al proposed a ldquowhite matter lesion loadrdquo(WMLL) score a measure of the total number of regionswith reduced FA as an index of white matter integrity[16] WMLL is calculated as the total number of regionsof interest (ROIs) which show impaired white matter rela-tive to values from controls The value of WMLL rangedfrom 0 to 13 (based on examination of 13 ROIs) WMLLwas then compared with the results of psychometric test-ing Results demonstrated that mild TBI showed reducedwhite matter integrity in the superior longitudinal fascicu-lus sagittal striatum and corticospinal tracts ReducedWMLL was greatest in groups with moderate to severeTBI and least in the controls while individuals with mildTBI fell between these two groups and were significantlydifferent than controls In cases with moderate to severeTBI reduction in both radial and axial diffusivity wasobserved in both the whole brain and in specific ROIsThese findings reflect damage to both myelin and axonsIn mild TBI radial diffusivity was relatively intact whileaxial diffusivity was increased suggesting axonal dam-age however irreversible damage to myelin is less com-mon in mild than moderate and severe TBI In terms ofcognitive function patients with moderate to severe TBIdiffered significantly from controls in almost all measuresof cognitive function but patients with mild TBI as agroup did not differ significantly from controls in anyneuropsychological domain scores The authors con-cluded that certain injuries classified as mild based onTBI variables such as LOC may actually be closer(based on actual brain injury) to moderate TBI in thedegree of neuropathology The authors proposed that DTIis a more sensitive delineator of TBI severity and may

761


help explain the discrepancies between clinically diag-nosed injury severity and cognitive outcome An addi-tional consideration is that mild TBI is associated withconsiderable heterogeneity particularly since variationsin where white matter injuries occur will cause dysfunc-tion only related to whether a critical pathway was dis-rupted so group predictions cannot be made

ConcussionThe AAN defines the severity of TBI based on a 5-point

concussion scale In grade I the individual is confused tem-porarily without any evidence of memory changes while ingrade II a brief period of disorientation is followed byanterograde amnesia of lt5 min In grades III through Vboth anterograde amnesia and retrograde amnesia arepresent Grades III through V are differentiated on theduration of LOC with each having PTA lt5 min for gradeIII 5ndash10 min for grade IV and gt10 min for grade V Thissystem of classification has limitations similar to those ofPTA and the recommended time frame (1 5 or 10 min)has even more limited reliability under combat condi-tions for the lower grades of concussion The proposedgradations of acute injury which are likely to be relatedto brain stem and medial temporal lobe injury are notclearly related to how numerous other cerebral regionsand structures may have been affected

TBI-Related Sequelae

Postconcussion SyndromeThe World Health Organization ICD-10 requires the

presence of three or more of the following eight symptomsfor classification as PCS (1) headache (2) dizziness(3) fatigue (4) irritability (5) insomnia (6) concentration or(7) memory difficulty and (8) intolerance of stress emo-tion or alcohol The criteria for PCS are complex define notime-interval parameters and include somatic symptomsand cognitive impairment that distinguish it from the syn-dromes that only involve behavioral symptoms [21] Fur-thermore the pathophysiological nature of PCS remainscontroversial In 175 individuals (90 with mild TBI 85 con-trols) the diagnosis of PCS had low specificity for mild TBI(433 of patients with mild TBI met criteria as did 435of controls) [22] The authors concluded that the use of theterm PCS may be misleading because it may incorrectlysuggest that the basis of PCS is clearly attributable to agrossly observable brain injury High rates of PCS havebeen reported in both nondisabled populations [23ndash26] andnon-brain-injured patients [27ndash28] Analyses of PCS patients

have found that a previous history of affective or anxietydisorders (including PTSD) being female a higher IQ(intelligence quotient) and pain significantly predictedacute PCS No difference was found in neuropsychologicaltest performance between patients with mild TBI and con-trols with or without defined PCS Acute pain appeared tomoderate acute outcome in mild TBI and symptoms weremore apparent in those individuals with mild TBI comorbidwith PTSD than those without comorbid PTSD [29] WhileTBI may indeed have a unique role in causing PCS thecommon association of PCS with other types of traumadecreases its value as an index of TBI severity or a prognos-tic indicator of TBI outcome

Neuropsychiatric SequelaeThe Diagnostic and Statistical Manual of Mental Dis-

orders-Fourth Edition-Text Revision (DSM-IV-TR) [30]of the American Psychiatric Association has several dif-ferent classifications that a clinician can use to describeneuropsychiatric sequelae following TBI Multiple psy-chiatric disorders listed in DSM-IV-TR may be found inpatients with TBI and classified with descriptions attribut-ing the disorders to TBI ldquoDelirium due to a general medi-cal conditionrdquo ldquoDementia due to a specific causerdquoldquoAmnesic disorder due to a specific causerdquo ldquoMood disor-der due to a specific causerdquo ldquoAnxiety disorder due to aspecific causerdquo ldquoPsychotic disorder due to a specificcauserdquo etc A recent review of TBI-related noncognitivepsychiatric disorders (depression mania PTSD psycho-sis agitation and aggression) found significant gaps inthe literature on post-TBI psychiatric conditions withrespect to nosology epidemiology and risk factors [21]Several of these conditions will be discussed here How-ever three classifications are particularly relevant forframing a discussion of the changes that occur in patientsrelated to mild and moderate TBI1 Mild neurocognitive impairment (MNI) As defined in

Appendix B of the DSM-IV-TR MNI describes cognitivedysfunction and encompasses the cognitive domains ofmemory attention language speed of processing percep-tual and motor abilities and executive function [30] Adiagnosis of MNI requires support of neuropsychologicaltesting (criterion C) and all individuals presenting withcognitive complaints should receive clinically appropriateneuropsychological testing MNI diagnostic criteria havebeen adopted by AD researchers and have beenexpanded to better characterize individuals whoseimpairments do not meet criteria for dementia but sug-gest increased risk of developing dementia in the near

762


term MNI classification is based on the number andtype of cognitive domains affected and the neuro-psychological test results For a single cognitive-domainimpairment that is memory-related in nature the diagno-sis is ldquomild cognitive impairmentrdquo and a nonmemory-related single cognitive- domain impairment diagnosis isdefined as ldquosingle mild nonmemory related cognitiveimpairmentrdquo If two or more cognitive domains areaffected regardless of the nature of the affected domainsthe diagnosis is MNI Following a diagnosis of MNI thelist or type specifiers are useful for treatment

2 Personality disorder due to a general medical condition(PDGMC) This condition is an axis I diagnosis (per-sonality disorder independently is an axis II diagnosis)Personality traits may be defined as an enduring patternof how we perceive our environment how we thinkabout it and how we relate to it General diagnostic cri-teria for this disorder require two of the followingdomains to be affected cognition affectivity interper-sonal functioning and impulse control Deficits must beenduring and pervasive and affect social and occupa-tional functioning PDGMC is limited in its applicabilitybecause its reference to cognitive dysfunction is listedonly in general terms ldquocognitionmdashie ways of perceiv-ing and interpreting self and othersrdquo This diagnosisdoes not define impairments in the cognitive domains ofattention memory language visuospatial abilities sen-sory-motor skills or executive function Specifiers arealso listed in general terms (labile disinhibited aggres-sive apathetic paranoid combined etc) and do notrelate directly to cognition but instead to affectivity andimpulse control Personality disorders are also generallythought of as ldquountreatablerdquo conditions that require inten-sive psychotherapy and for which limited pharmaceuti-cal or medical options exist personality issues are notwell managed by medical specialties in general Clini-cians applying this diagnosis may incorrectly attributemood or affect problems to this syndrome alone thusmissing the indication to treat an underlying depressionor other disorder Furthermore when applying the ldquoper-sonality disorder stigmardquo clinicians may also overlookindividual cognitive domains Rather than focusing onpersonality issues that are poorly defined neurobiologi-cally this review addresses those psychiatric disordersthat are relatively common in patients with TBI havebeen identified in the general population and have asso-ciated treatment options

3 Postconcussion disorder (PCD) This disorder is a DSM-IV-TR Appendix B-based diagnosis Criterion A requiresthree of the following to occur shortly after the traumafor at least 3 months fatigue disturbed sleep headachevertigo or dizziness irritability or aggression anxietydepression or affect lability changes in personality andapathy or lack of spontaneity Criterion B of PCD onlyaddresses attention and memory-type cognitive deficitsand does not mention domains such as language visuo-spatial or sensory-motor cognition Criterion C listsldquodepression anxiety personality changesrdquo that overlapcriterion B and also depression and anxiety syndromesTo address the complex needs of a patient with TBI cli-nicians need to fully characterize and diagnose depres-sion and anxiety so that these components can beappropriately treated and not simply be dismissed as acomponent of PCD Somatic symptoms such as hyper-sensitivity to sound and touch are common symptomsthat need to be examined and integrated into the diagno-sis and management

Clinical Biopsychosocial Approach to TBITraumatic injury is understood as causing a multisystem

condition interfering with the functioning of multiple organsand systems even with those not directly related to the siteof the initial impact [31] If a multidimensional approach(such as the biopsychosocial model) is followed the manyoverlapping symptoms and outcomes from combat-sustained injuries can be delineated and successfully treatedApplying the biopsychosocial model (a systems modeladdressing biological psychological and social approachesto diagnosis and treatment that is widely used in modernpsychiatry) to each symptom cluster clinicians can delineateand manage psychological occupational and social dys-function in combat veterans

The brain is composed of numerous systems and onepart may be selectively injured and another not Whileneurobehavioral and cognitive dysfunctions probably rep-resent an interruption of circuitry involving the cortex andsubcortical structures somatosensory symptoms are mostlikely due to damage of specific sensory organs or theirprojections Frequently no clear evidence exists to estab-lish a link between a specific cognitive dysfunction andspecific somatic symptoms Dizziness for example maybe associated with memory impairment in one individualand with language difficulties in another Peripheral dam-age can also be caused by TBI For example animalsexposed to isolated controlled cortical-impact TBI showmoderate histopathological changes in the lung and liver

763


which may represent a migration of immunocompetentcells to peripheral organs potentially leading to their dys-function [31] Therefore identifying the TBI symptomclusters (Figure 1) is essential cognitive dysfunctions(memory attention language visuospatial cognitionsensory-motor integration affect recognition and execu-tive function) neurobehavioral disorders (mood affectanxiety posttraumatic stress psychotic sleep and libidinaldisorders) somatosensory disruptions (changes in smellvision hearing equilibrium taste and somatosensory per-ception) and somatic symptoms (headache chronic pain)and substance dependence Each of these clusters of prob-lems can be dealt with appropriately In so doing the pri-mary care physician can coordinate a team to address thebiopsychosocial problems comprehensively recognizingthe specific impairments and needs of the patient with TBIto foster rehabilitation and better long-term function

Further understanding the underlying neurobiologyof TBI can help recognize problems and plan treatmentsappropriate to the problems Neural mechanisms in manyregions of the brain have neuroplastic properties and areable to reestablish connections [32] though correct resto-ration of function is probably more difficult and requiresmore targeted reinnervation [33] Neuroplastic processescan be utilized in recovery and rehabilitation but theirinstability may also lead to deterioration as may occur inAD and many types of dementia [34] Furthermore spe-cific genetic factors such as APOE genotype may affectthe capacity of neuroplastic processes to repair the brain[35ndash37] The ultimate issue is the impact of the patientrsquosbiological and psychological problems on social func-tion which must be included in the diagnostic considera-tions and management plans

NEUROPSYCHIATRIC SYMPTOMS ANDMANAGEMENT

The following review of specific neuropsychiatricmanifestations of symptom clusters following TBI gener-ally outlines the types of difficulties that are likely to beencountered in a clinical setting The discussion isdivided into five parts1 Cognitive dysfunctions2 Neurobehavioral disorders3 Somatosensory disruptions4 Somatic symptoms5 Substance dependence

Each aspect is considered in terms of definition and neu-robiological basis which includes some discussion ofknown epidemiology criteria and assessment whichaddresses the established diagnostic criteria brief bed-side assessments and formal psychological and neuro-psychological testing and treatment options including adiscussion of formal evidence and recommendations forevidence-based practice when available and practicalclinical recommendations The review introduces theneuropsychiatric management of patients with post-TBIemphasizing that much study still needs to be done toimprove the care of patients with TBI-related problemsWe focus on neurobiology and psychopharmacology andsummarize treatment considerations (Figures 2 and 3)Cognitive therapeutic approaches and general rehabilita-tion are not discussed in detail because their complexi-ties are beyond the scope of this review Important to noteis that such therapeutic intervention must be consideredindividually keeping the patientrsquos medical and psychiat-ric history in mind

Cognitive DysfunctionsThe International Classification of Functioning Dis-

ability and Health describes higher-level cognitive function-ing as ldquoSpecific mental functions especially dependent onthe frontal lobes of the brain including complex goal-directed behaviors such as decision making abstract think-ing planning and carrying out plans mental flexibility anddeciding which behaviors are appropriate under what cir-cumstances often called executive functions functionsof abstraction and organization of ideas time managementinsight and judgement concept formation categorizationand cognitive flexibilityrdquo [38] TBI may affect any of thesefunctions Though cognitive dysfunction is a common com-plaint its nature and prevalence are unclear partly becauseof the difficulties inherent in designing schema for classify-ing such conditions [4] Measurement and quantification ofcognition are problematic since cognition is neither a singleentity nor ability Cognitive functions are constructs andtheir conceptualization and assessment are constrained bythe tools used to measure them Furthermore trauma to thecentral nervous system can be diffuse and does not respectneuroanatomical boundaries or system classifications thusadding further complexity to the process of evaluationWhile neurocognitive deficits and neurobehavioral disor-ders frequently follow TBI such problems vary accordingto specific TBI impact sites and the intensities and uniquephysical properties of the traumatic force [39] as well as

764


the premorbid intellectual status of the patient and thenature of subsequent treatment and rehabilitation Anapproach to organizing the wide range of cognitive symp-toms that can occur after TBI is summarized in Figure 2Specific cognitive dysfunctions discussed here are memoryattention language visuospatial cognition sensory-motorintegration and executive function

MemoryDefinition and Neurobiological Basis Problems with

memory are among the most frequent dysfunctions andcomplaints following TBI [4] However the exact inci-dence and prevalence of various disorders of memory thatare TBI-related are unknown because of the complex rela-tionship between location and severity of TBI and theresulting impairments

Memory is the foundation for all cognitive functionand memory mechanisms are intricately involved in manycognitive operations Memory has many modes anddelineations Memory types are frequently specified as(1) implicit or nondeclarative memory which is responsi-ble for automatic priming (including semantic memory)and (2) explicit or declarative memory storage Thisformer mode of memory processing is responsible forsemantic memory (words) and the latter includes autobio-graphical memory (memory in context of time and place)

Declarative memory can be divided into separate cate-gories as ldquoworking memoryrdquo and ldquolong-term storagerdquoWorking memory (also referred to as immediate or short-term memory or attentive memory) allows one to hold inmind simultaneously several items needed for performing atask Working memory is closely associated with systems

I Memory ImpairmentA Cholinesterase inhibitors (donepezil galantamine rivastigmine)B NMDA receptor modulator (memantine)C Stimulants (methylphenidate)D Neurogenesis stimulation (SSRIs)

II Attention DeficitsA Texas Medication Algorithm Project

1 Stimulants (methylphenidate dextroamphetamine)2 Noradrenergic reuptake inhibitor (atomoxetine)3 Bupropion4 Alpha-2 agonists (clonidine)

B Other stimulants (modafinil)C Cholinesterase inhibitors (donepezil galantamine rivastigmine)D NMDA receptor modulator (memantine)E Noncompetitive NMDA receptor antagonists (amantadine)F Dopamine receptor agonist (bromocriptine)

III Communication LinguisticsmdashSpeech and Language (Primary TreatmentmdashSpeech and Language Therapy)A Monoaminergic agents (bromocriptine levodopa d-amphetamine)B Cholinesterase inhibitors (donepezil galantamine rivastigmine)C Nootropic agents (piracetam)D Experimental-repetitive transcortical magnetic stimulation

IV Communication Affect Recognition and Emotion ExpressionmdashComparison to Autism No PharmacologicalRecommendations

V Visuospatial Perception and Sensory-Motor IntegrationmdashBehavioral Training ProgramsA Neurogenesis promoters (SSRIs lithium)B Cholinesterase inhibitors (donepezil galantamine rivastigmine)

VI Executive FunctionA Dopamine receptor agonist (bromocriptine)B Treatment of individual cognitive domainsC Treatments developed for attention deficits (see II Attention Deficits)

Figure 2Neuropsychiatric symptoms and psychopharmacological management for cognitive dysfunctions NMDA = N-methyl-D-aspartate SSRI =selective serotonergic reuptake inhibitor

765


involving the dorsolateral prefrontal cortex and basal gan-glia and operates a ldquovisual spatial sketch padrdquo (images) anda ldquophonological looprdquo (acoustic) Long-term storage (alsoreferred to as short-term [sic] or long-term memory and epi-sodic memory) maintains perceived information in a solidi-fied form for a time period but is subject to decayparameters based on the nature and strength of the savedtrace This solidification of declarative or episodic informa-tion details occurs as a consolidation of neuronal firing-pattern traces in the association cortex regions which areposterior to the central sulcus (in the parietal and temporallobes) in the same distributed neural networks responsible

for perceiving information [40ndash41] The operations thatinduce solidification of a perception involve reciprocalconnections with two specific medial temporal lobestructures the hippocampus (autobiographic locationepisodic memory etc) and the amygdala (emotional con-ditioning information evaluation on its importance to theindividual) [40] and systems associated with the medialtemporal lobe including the Papez circuit (hippocampusfornix mammillary bodies and cingulum) and the Nautacircuit (basolateral limbic circuit that includes the amygdaladorsomedial nucleus of the thalamus and the frontal lobes)[42ndash44] Learning and memory are also influenced by

I DepressionA SSRIs (citalopram sertraline paroxetine fluoxetine)B SNRIs (duloxetine venlafaxine)C Tricyclics with noradrenergic predominance (nortriptyline desipramine)D Other antidepressants (mirtazapine bupropion)E Stimulants (methylphenidate dextroamphetamines)

II ManiaA Mood stabilizers (lithium)B Mood stabilizers anticonvulsants (valproate carbamazepine oxcarbazepine topiramate and lamotragine)C Atypical antipsychotics (aripiprazole olanzapine ziprazadone and quietapine)D Combinations of medications (including low-dose lithium)

III Posttraumatic Stress DisorderA SSRIs (citalopram sertraline paroxetine fluoxetine)B Serotoninmdash5HT2 agonistmdashtrazodone (especially for sleep)C Noradrenergic alpha-1 blockersmdashprazosin (especially for sleep)D Noradrenergic beta-blockers centrally actingmdashpropranololE Atypical neuroleptics with serotonergic effects (quetiapine olanzapine aripiprazole and ziprazadone)F Avoid typical neuroleptic agents (haloperidol)G Avoid sedative hypnotics (benzodiazepines)

IV PsychosisA Atypical neuroleptics (quetiapine olanzapine risperidone etc)B Typical neuroleptic agents (haloperidol)

V Agitation and AggressionA Beta-blockers with central effects (propranolol)B Alpha-2 antagonist (clonidine)C Stimulants (methylphenidate dextroamphetamines)D SSRIs (citalopram sertraline paroxetine and fluoxetine)E Tricyclic antidepressants (especially low doses of doxepin)F Mood stabilizers lithium (low dose eg 300 mg SA at bedtime)G Mood stabilizers anticonvulsants (valproate carbamazepine oxcarbazepine topiramate and lamotragine)H Atypical antipsychotics (aripiprazole olanzapine ziprazadone and quietapine)I Nonbenzodiazepine anxiolytics

VI Sexual Health and LibidoA Treatment for hypopituitarismB Avoid medications that decrease libido (note adverse effect of SSRIs)

Figure 3Summary of treatment considerations for neurobehavioral disorders (avoid narcotics benzodiazepines) SA = sustained action SNRI = serotonin-norepinephrine reuptake inhibitor SSRI = selective serotonergic reuptake inhibitor

766


neurons with thin unmyelinated corticopedal fibers pro-jecting from cell bodies in the brain stem including the ace-tylcholine neurons of the nucleus basalis of Meynert (detaillearning) the norepinephrine neurons of the locus coeruleus(reward-related learningSkinnerian conditioning) and theserotonin neurons of the dorsal raphe nucleus (classicalPavlovian conditioning)

A central issue concerning memory is relearning lostskills and abilities a critical part of rehabilitation Funda-mental neuroplastic mechanisms exist in the brain toform new connections and many neuroplastic processesare activated to recover from brain injury Some of theseprocesses are facilitated by dietary and hormonal factorsHowever some aspects of these processes require higherlevels of learning to activate the formation of the needednew pathways If fundamental memory mechanisms arenot working then recovery will be more difficult Poten-tially the neuroplastic processes may be augmented withmedications and complex stimulation

Criteria and Assessment Memory dysfunction fol-lowing TBI may be acute or chronic Acute dysfunctionis described in terms of PTA and PCS as just describedand is generally time-limited Sim et al for examplefound that postconcussive athletesrsquo reaction times andprocessing speeds returned to normal within 6 days andmemory impairment usually resolved without interven-tion within 10 days postconcussion [45] However suchrecovery will depend on the severity of damage to theaffected systems in a particular individual

Chronic memory impairment following TBI has notbeen labeled diagnostically Chronic memory storageimpairment may persist for years and involve deficits inmedial temporal lobe processing (particularly hippo-campal andor amygdaloid) as shown by difficulty encod-ing or retrieving recent memory Specific memory deficitscan be related to the damage of related cortical regions

Acute memory disturbances such as PTA may beassessed with use of the guidelines the AAN described orwith similar grading systems The Standardized Assessmentof Concussion includes measures of cognition includingorientation immediate recall concentration and delayedrecall (after few minutes and a distraction) Chronic disor-ders of memory may be assessed at the bedside and usuallyinvolve administration of simple cognitive tests thatmeasure various aspects of working memory and storageability This level of testing is useful for screening One ofthe most common assessments involves asking the patientto repeat a list of three items (immediate recall) and repeatthem again at the end of testing (delayed recall) [46] For

individuals with evidence of memory dysfunction a formalneuropsychological assessment is more detailed and mayinclude learning a variety of materials such as stories listsof words or pictures [46ndash49]

Treatment Options Treatment during the primaryphase of recovery from a TBI which is due to direct physi-cal insult and may involve damage to neuronal cell bodiesand their arborizations is difficult because of the short win-dow of opportunity [50] Treatment for secondary ordelayed injury which results from a complex cascade ofmolecular cellular and biochemical events lasting days toseveral months is more promising [51] Pharmacologicaltargets include neurotransmitter pathways excitatoryamino acids (modulators) calcium channels (blockers)reactive oxygen species (scavengers) inflammation(anti-inflammatory agents) caspases calpain (inhibitors)endocrine metabolism (treatments) and neurotrophic fac-tors Various agents targeting biochemical and cellularevents are in various phases of clinical trials [50] Treat-ment for long-term sequelae can be targeted with respectto treatments for the conditions that are comparable withthose seen in other clinical settings

Cholinesterase inhibitors for augmenting neurotrans-mitter function in acetylcholine systems are Food andDrug Administration (FDA)-approved for treating demen-tia related to AD and have been used increasingly off-labelfor a variety of cognitive deficits Although no drug usedfor treating dementia currently has FDA approval for alsotreating TBI several such compounds have been examinedin clinical studies For example donepezil has shownsome efficacy in the treatment of TBI-related memoryproblems [52ndash55] and rivastigmine has been shown to besafe and well tolerated in a prospective randomized dou-ble-blind placebo-controlled study of 157 patients withTBI with moderate to severe memory impairments [56]Galantamine has been beneficial in treating memory lossin long-term trials [57]

Other medications have been tried in treating memorylosses in patients with TBI For example memantine anN-methyl-D-aspartate (NMDA) receptor modulator whichmay protect against glutamatergic excitotoxicity and isFDA-approved for treating moderate to severe dementiaassociated with AD has been shown to prevent neuronalloss in rodent TBI models specifically in the hippocampus[58] and has shown promise in a pilot trial for treatingPTSD [59] Methylphenidate a catecholaminergic stimu-lant has been examined with studies suggesting varyingdegrees of efficacy [60ndash61] No large-scale trials of these

767


medications exist and little is known about the moderatorsor mediators of treatment response

Neurogenesis occurs in neural stem cells of the sub-ventricular zone of the lateral ventricles subgranularlayer of the dentate gyrus and olfactory bulbs Neuralstem cells express acetylcholine receptors and animalstudies have shown that treatment with acetylcholinest-erase inhibitors promote survival of these newborn neu-rons under both normal and stressed conditions [62]Selective serotonergic reuptake inhibitors (SSRIs) [63]and lithium [64ndash65] may also increase adult hippocampalneurogenesis and reverse stress-induced cognitive dam-age Bremner and Vermetten demonstrated that patientswith PTSD treated for 1 year with an SSRI increasedtheir hippo-campal volume 5 percent and improved theirverbal declarative memory function 35 percent [63]These treatment modalities that promote neurogenesisneed to be more fully explored in treatment of TBI-related cognitive deficits

AttentionDefinition and Neurobiological Basis Impairment of

attention focus is common following TBI and is seenacross the TBI severity spectrum [66] Attention can beunderstood as ldquoa control process that enables an individualto select from a number of alternatives the task to be per-formed or the stimulus to be processed and the cognitivestrategy to be adopted to carry out the operationrdquo [67]ldquoAttention is a multidimensional construct composed ofsuch phenomenon as strategic scanning exclusion ofirrelevant stimuli sustained attention divided attentioninhibition of impulsive action and selection and monitor-ing of responserdquo [68] Van Zomeren and Brouwer ini-tially proposed fundamental components of attentionldquofocusedrdquo ldquodividedrdquo and ldquosupervisoryrdquo [69]

Margulies proposed that the hippocampus mediatesselective attention in which sensory data are conveyed tothe hippocampus and matched against a cognitive ldquomaprdquoso as to determine whether or not a stimulus should benoteworthy determination-based novelty emotional val-ance and salience [70] Hippocampal selective attentionmay also be modulated phasically by norepinephrine diur-nally by serotonin and over the long term by corticoster-oids [68] This theory is contrasted with the noradrenergictheory of attention deficit disorder [71ndash72] which sug-gests that attention deficit and hyperactivity are due to anincrease in noradrenergic transmission from the locuscoeruleus A tonically high noradrenergic state may reducethe threshold of the hippocampus to stimuli thus leading

to increased distractibility a ldquomergerrdquo of the two theories[68] Of note the hippocampus is reciprocally connectedto posterior cortical regions which also receive norepi-nephrine input and processing is likely done in a masshierarchical parallel-distributed processing fashion as for-mulated by Ashford et al and others [40ndash4173ndash74]

Attention is generated by multifaceted neural pro-cessing that coordinates broad cortical integrative sys-tems for specific processing requirements [75] ratherthan locally restricted analyses [76ndash77] A variety of spe-cific neural networks responsible for attention are widelydistributed across various cortical regions with importantnodes in the brain stem frontal temporal and parietalregions and cingulate cortex [7577] The parietal or spa-tial attention networks interact with limbic and monoam-inergic systems to modulate motivation-induced attentionshifts [77] Thus attention coordination recruits largearrays of neural populations rather than restricting pro-cessing to a limited distribution

Disruption of any of the brain structures associatedwith coordinating cerebral processing can disrupt criticalaspects of attention Furthermore a pathophysiologicalrelationship could exist between TBI and ADHDAlthough TBI symptoms can mimic those of ADHD bythe DSM-IV definition ADHD cannot be diagnosed in thepresence of TBI ADHD is primarily recognized as a child-hood or developmental condition ADHD was formerlydescribed as minimal brain injury syndrome or minimalbrain dysfunction [78] that displays inattention impulsiv-ity and hyperactivity Although ADHD cannot be diag-nosed in the presence of head injury one may diagnoseMNI to capture the symptoms of inattention and use thisrelationship for evaluation and treatment development

Criteria and Assessment Patients with TBI typi-cally present with complaints of concentration difficul-ties distractibility difficulty multitasking and decreasedprocessing speed The patients may be impulsive andhyperactive Patients may not be able to verbalize ldquoI canrsquotfocusrdquo so symptoms of inattention should be soughtwhen a patient presents with many days of missed workor frequent job changes

A typical bedside assessment of attention involvesasking a patient to name as many animals as possible in1 min repeat a series of digits forward and backwardperform ldquoserial sevensrdquo or spell a common five-letterword backward The Conners Scale is an instrument thatuses observer ratings and self-report ratings to help a cli-nician assess ADHD and evaluate problem behavior inchildren and adolescents This scale has been modified

768


for assessing adults [79] and may help clinicians assessthe severity of ADHD symptoms and their response totreatment For moderate to severe TBI the Moss Atten-tion Rating Scale has been used during acute inpatientrehabilitation and exhibits good interrater reliability [80]

Based on the fundamental components of attentionmdashfocused divided and supervisory [69]mdashneuropsychologicalinstruments can be directed to each component of attentionincludingmdash1 ldquoFocused Attentionrdquo Stroop Color and Word Test

[81] TR Distraction Task [69]2 ldquoDivided Attentionrdquo test Trail Making Test parts A

and B [82] RT Dual Task [83ndash84] Paced AuditorySerial Addition Task or PASAT (modified from Gron-wall and Sampson [85ndash88])

3 ldquoSupervisory Attentionrdquo Relative Preservation ErrorScore or PERSREL (derived from the Modified CardSorting Test) [89] Lack of Consistency Score derivedfrom the 15 Words Test [90]

Spikman et al examined the construct validity of thesethree aspects of attention in nondisabled individuals andpatients with TBI [91] The results demonstrated no differ-ence in scores for focused attention and divided attentionHowever a difference was found in the supervisory atten-tion category The authors noted focused divided andsupervisory constructs are not separate entities and exist ina phenomenological context only Individuals with TBIapproach problem-solving tasks in a quantitatively differentway because of a shift in response control In response-con-trol shift patients may exert a greater or lesser amount ofexecutive control than they would have done before theirTBI a speed-accuracy trade-off emphasizing speed withincreased risk of errors versus emphasizing accuracy andsubsequently reducing speed of task performance Slowingof information processing following TBI has also beenextensively demonstrated [83ndash8492ndash93] Clinicians shouldconsider these elements when assessing an individualrsquosattention performance control and speed (also demon-strated in other studies see Spikman et al [91] along withtask structure) Several studies have led to the conclusionthat executive control should be viewed as a core compo-nent of performance in attention tasks Zoccolotti et al[94] examined selective (focused divided) attention andintensive (alertness vigilance) attention processing in 106patients at 5 months post-TBI Widespread deficits affect-ing selective and intensive attention processes were notobserved Factor analysis identified two main subgroupsPatients in the first subgroup characterized by more severeTBI as evidenced by a lengthier coma were more impaired

in selective and divided attention In the second patient sub-group alertness was indistinguishable from control but adecrease in divided attention abilities was observed in con-trast to the findings from Spikman et al [95] who attrib-uted attention deficits to a general slowness factor In athird small subgroup individuals reacted slowly to visualstimuli and were unable to perform divided attention tasks

In the Divided Attention test a subject is required todivide his attention between two tasks simultaneouslyone acoustic one visual [94] An inability to acquireinformation simultaneously from both sensory channelsresults in an omission of target response andor slowedresponse Patients ranked tasks of the Divided Attentiontest to be the most difficult The literature emphasizes theimportance of divided attention tasks because of theirrelevance to everyday functioning [69] The inability todivide attention into different channels may hinder apatientrsquos ability to effectively return to study or work [96]

Treatment Options As in the case of memory defi-cits no large-scale studies of treatments for attentiondeficits exist in TBI and consequently no treatments arespecifically or definitively recommended However theneed for management of attention problems has led clini-cians to consider attention deficit treatment models inother populations such as children with ADHD Forexample the Texas Medication Algorithm Project-guidedtreatment provides a useful treatment guideline forexamination because several medications used to treatADHD have been used to treat similar symptoms in TBI[4] The Texas Medication Algorithm Project delineates amultistage approach outlined as follows1 Stimulants are the drug of first choice in the treatment

of ADHD [97ndash101] because an extensive body of evi-dence indicates that 75 percent of those with ADHDare responders The effect size of this class of medica-tion reaches 10 one of the largest effect sizes of anypsychotropic medication [102] By analogy with TBIthe stimulant methylphenidate has been studied andsuggested to be helpful in TBI-related inattention[6166103ndash104] Though less well studied the stimu-lant dextroamphetamine has shown similar effects inTBI-related inattention [105ndash106]

2 For second-line treatment of ADHD atomoxetine is aspecific noradrenergic reuptake inhibitor with an effectsize of 07 However little evidence exists yet for the useof this medication in treating TBI-related inattention[107]

769


3 Bupropion has been well established as an off-labelagent in ADHD treatment but has not been studied inTBI-related ADHD-like symptoms

4 The alpha-2 agonists are frequently used as adjunctivetreatment in ADHD but specifically for the impulsiveand hyperactive components Individuals treated withclonidine following TBI demonstrated a reduction ofplasma norepinephrine and a normalization of plasmaepinephrine The reduction of sympathetic overactivityis probably due to the specific action of clonidine onalpha-2 adrenoceptors within the rostral ventrolateralmedulla [108]

The Texas Medication Algorithm Project also pro-vides additional treatment options of ADHD-associatedcomorbidities such as depression anxiety and aggres-sion Modafinil a currently available stimulant medica-tion while not incorporated into the Texas MedicationAlgorithm Project has improved significantly in bothinattentive and combined types of ADHD in three dou-ble-blind placebo-controlled studies [109] The effect ofmodafinil in treating TBI-related ADHD-like symptomshas not been demonstrated

Additional options for treating attention problems mayalso be considered Acetylcholinesterase inhibitors such asdonepezil have helped increase short-term memory scoresand attention in psychological testing during a 24-weekrandomized placebo-controlled double-blind crossoverstudy [54] Long-term use of donepezil may prove deleteri-ous because of the induction of cholinesterase overactivityalthough galantamine (now available in a generic formula-tion) may not have this adverse consequence Memantinean NMDA receptor modulator has been investigated byFindling et al in a pilot open-label 8-week evaluation ofpediatric ADHD using 10 to 20 mg doses a day [110] Dos-ages were well tolerated and were found to be effective inimproving inattention results appeared to be dose-relatedEffects of memantine on TBI-related inattention have notbeen examined Noncompetitive NMDA receptor antago-nists such as amantadine have received little attention asagents in treating TBI-related cognitive dysfunction Twocase reports three retrospective studies and two random-ized double-blind controlled trials of amantadine therapyhave been reported and indicate that this medication may bea promising therapy [111ndash112] One study of a dopaminereceptor agonist bromocriptine showed that it did notbenefit individuals presenting with inattention followingmoderate to severe TBI even possibly being associatedwith adverse events [113]

Communication LinguisticsmdashSpeech and LanguageDefinition and Neurobiological Basis TBI causes a

range of communication deficits that cannot be explainedin classical terms of aphasia [114ndash116] Rather these defi-cits are best described as cognitive-communication disor-ders or cognitive pragmatics [117] Language and thoughtare closely related in brain organization and social func-tion Language facilitates certain types of complex thoughtand cognition by allowing subvocalization and organiza-tion of thoughts for performing more complex mentaloperations Damage to the language centers therefore notonly impairs the ability to communicate but also interfereswith the ability to organize complex cognitive processing

The basis of communication is information exchangebetween two participants who attempt to achieve severalobjectives beginning with understanding the mind-set ofthe interlocutor For example in the act of being deceitfulwhat an actor intentionally communicates conflicts with theactorrsquos private mental state but that communicated infor-mation does not contrast with the knowledge that is dis-closed to the partner In case of deceit comprehension thepartner recognizes the difference between what is expressedand the ideation the actor privately entertains In additionin irony that which an actor intentionally communicatesalso contrasts with the knowledge heshe shares with thepartner This complex mixture of information makes anironic communication act more difficult for a listener to rec-ognize and understand than a deceitful one Linguistic(syntax lexical) extralinguistic (gesturing) and para-linguistic (tone intonation rhythm and prosody) elementsof communication are then set in motion During a commu-nicative exchange individuals will match their linguisticand extralinguistic acts with appropriate paralinguisticaspects Communication is also governed by cooperativeprincipals and rules of politeness (eg when how andwhat a person is allowed to say about social status hierar-chical position or level of formality) [118]

In TBI the location and extent of the injury deter-mine the type and the degree of language and speechimpairment Damage to certain regions of the languagecenters of the dominant hemisphere (for most individu-als the left hemisphere) produces aphasia Aphasia canbe differentiated clinically into two broad categoriesldquoimpaired repetitionrdquo (Broca Wernicke global and con-ductive aphasias) and ldquopreserved repetition or isolatedaphasiardquo (motor sensory mixed and anomic aphasias)[119] One can characterize these aphasias according tothe variation of the deficits in naming (object identifica-tion) fluency (smoothness or flow with which sounds

770


syllables words and phrases are joined when speaking)comprehension (verbal understanding) and repetition(ability to repeat a phrase) [120] Impaired repetition maybe related to damage to Wernickersquos area for languagereception producing a receptive aphasia to Brocarsquos areafor language expression producing an expressive apha-sia or to the arcuate fasciculus (a bundle of the superiorlongitudinal fasciculus) which connects Wernickersquos andBrocarsquos areas producing a conduction aphasia [119]

TBI-induced damage to the language centers mayimpair social functioning as well Although the dominanthemisphere is responsible for vocabulary and syntax con-cepts may originate in either hemisphere or may be a func-tion of cross-hemispheric interactions Pragmatic languageis located in the nondominant hemisphere and is disruptedby frontolimbic damage [121] Damage to this center mayimpair the patientrsquos ability to comprehend jokes irony oreven speaker intention Furthermore social language func-tioning may be compromised by dominant hemisphereinjury such as the capacity to organize discourse In addi-tion such damage may disturb speech prosody and theseindividuals may speak with disordered intonation rhythmor inflection

Criteria and Assessment Milton et al suggested thatinappropriate communication following TBI is the mostsevere obstacle for patients to surmount when socially rein-tegrating [122] Communication difficulties impair socialinteracting and changes in sociability may be the mostdestabilizing of sequelae following TBI and certainly themost invalidating [123ndash126] These disorders are signifi-cant factors in poor psychosocial adaptation followinginjury [127ndash129] Individuals with TBI have difficulty pro-cessing language efficiently [130] manifested as inappro-priate topic-switching and turn-taking poor conciseness[131] self-focused conversation inappropriate humorinappropriate levels of self-disclosure [132] and word-finding difficulties [133] Several studies have shown thatindividuals with TBI demonstrate impaired paralinguisticprocessing that may be due in part to an impairment in rec-ognizing emotions expressed by others both in their voiceand their facial expression [121134] This latter deficit maybe the causal factor for antisocial behavior and poor socialrelationships following TBI

Speech evaluation assesses the patientrsquos abilities inobject-naming fluency comprehension and repetitionLanguage can be measured at the bedside by listening tothe patient speak and using simple requests includingidentifying objects and repeating various words andphrases (eg ldquono ifs ands or butsrdquo) Collateral history

may be elicited by asking family members if their lovedones are able to read social cues enjoy jokes or under-stand irony Observation of specific language difficultiesor reports of nonspecific interaction problems should leadone to consider formal testing

One formal language test is the Assessment Battery ofCommunication which may help in evaluating pragmaticlanguage disorders in individuals with TBI [118] Thisassessment battery is made up of five different evaluationscales such as linguistic (syntax lexical) extralinguistic(gesturing) paralinguistic (tone intonation rhythm andprosody) context and conversation that investigate all theprincipal aspects involved in communicative exchange

Treatment Options Currently the main treatment foraphasia is conventional speech and language therapy thatdepends on the brainrsquos ability to recover function throughneuroplastic processes (learning and memory) which maybe activated and enhanced by exercise and medicationsEmpirical observation suggests that spontaneous biologi-cal recovery may also partly explain the improvement inlanguage function [135]

Pharmacotherapy adjuncts to speech and language ther-apy have been used and include monoaminergic (bro-mocriptine levodopa d-amphetamine) and cholinergic(donepezil rivastigmine galantamine) agents [136] Theefficacy of these treatments has not been determined how-ever limited results using piracetam and amphetamine havebeen demonstrated [137] Dextroamphetamines improveattention span and enhance learning and memory which areessential for acquiring new motor and cognitive skills thusleading to a more rapid recovery from aphasia Minimalinvestigation of these agents has been conducted in TBI-related aphasia and overall the literature is sparse regardingpharmacological treatments of pragmatic language disor-ders Specialized computer and Internet training materialshave been increasingly used and shown to benefit individu-als with TBI suffering from cognitive-linguistic impair-ments [138] Some studies have indicated that repetitivetranscortical magnetic stimulation may be an effectiveadjunct to speech and language therapy [139] but recom-mendation of this therapy awaits replication of the initialstudies and further demonstration in careful studies of spe-cific language disorders

Communication Affect Recognition and Emotion Expression

Definition and Neurobiological Basis Affect rec-ognition has been a study of science for decades but has

771


only been addressed recently concerning TBI Conse-quently little data are available concerning the incidenceand prevalence of disorders of affect recognition in TBIHowever inappropriate expression of emotion and lossof inhibitory control of affect ie lability are commonin patients with TBI

Generally functional impairments following TBImay be seen in all aspects of daily functioning includingreduced employment and impaired social relationshipswith subsequent reduction in QOL [3] Psychosocialimpairment is typically seen within the realm of interper-sonal communication [140] which involves the percep-tion of emotion empathy recognition of faux pas andbehavior Several studies have shown that individualswith TBI have significant difficulties recognizing non-verbal cues of affect [141ndash152] resulting in inappropri-ate behavior [153] thereby affecting social relationships[154] Emotion recognition is pivotal in engaging socialinteraction [155ndash159] and developing and maintainingsupport networks

Poor outcomes following TBI are associated withinadequate social support networks which are poorlymaintained when interpersonal skills deteriorate [160]LoBello et al found that not only those with TBI but alsotheir families experience a shrinking of social networks[161] and that one-third of families at follow-up haveproblematic interactions [162] Caretakers of individualswith diminished social support experience higher levels ofstress [163ndash164] Marriages are also found to be morelikely to end in divorce or separation due to lonelinessaltered interpersonal skills [165] and unpredictablebehavioral patterns [166] Problems with affect recogni-tion are also seen in individuals with autism spectrum dis-order [159167ndash169] which may be heuristically relatedto some varieties of TBI sequelae

Recognition and response to facial affect in othersand an individualrsquos facial affect expression are related toprocessing in the prefrontal parietal and temporal corti-ces and the limbic system The prefrontal cortex particu-larly the ventral medial aspect allows one to experienceonersquos own emotions and the absence of which impairsonersquos ability to recognize emotion in another [150170]The orbital frontal cortex is responsible for the intensityof emotional expression [171]

In conditions such as autism in which recognition ofaffect is problematic research has shown that the temporallobe and amygdala may analyze facial affect one feature ata time [156172ndash173] In contrast the fusiform area of the

temporal lobe in normal function processes facial featuresas a whole a ldquogestaltrdquo and in parallel [174ndash175] Theamygdala is pivotal in facial affect recognition especiallyfear [176ndash179] damage to which may cause an individ-ualrsquos innate fear response to change with subsequent diffi-culty in recognizing fear in others Adolphs et al foundthat individuals with such damage were unable to recog-nize emotion from faces in pictures where only the eyeswere visible [173] These individuals spend more timelooking at the nose and mouth regions than controls

Criteria and Assessment No specific post-TBIemotional affective or ldquopara-autisticrdquo syndromal criteria orassessment scales have been developed at this time TheDSM-IV-TR criteria for autism may help assess theseldquopara-autisticrdquo features that develop following TBI Thetwo criteria are qualitative impairments in (1) social interac-tion and (2) communication The first criterion impairedsocial interaction may be manifested as marked impair-ment in the use of multiple nonverbal behaviors such as eyegaze facial expression body posture and gestures to regu-late social interaction a failure to develop peer relation-ships a lack of spontaneous seeking to share enjoymentinterests or achievements (eg by lack of showing bring-ing or pointing out objects of interests) and a lack of socialor emotional reciprocity The second criterion impairedcommunication may be manifested by marked impair-ment in the ability to initiate or sustain conversation

Many families report that following TBI the veteran isldquonot the samerdquo or is just ldquoa shell of the prior selfrdquo The clini-cian needs to carefully observe the communicative transac-tion between patient and family members as well as theexchange with the clinician History-taking may beenriched with these ldquopara-autisticrdquo impairments in mind

Without specific criteria the clinician may appropri-ately use any of the several dozen autistic rating scalesavailable The Diagnostic Interview for Social and Com-munication Disorders used to assess children and adultsof any age is an interviewer-based schedule for use withparents and caregivers It primarily helps the clinicianobtain a developmental history and description of thechild or adult concerned It also helps the clinician tounderstand a pattern of skills and impairments that under-lie certain behaviors [180]

Treatment Options Cognitive strategies such as thoseused to treat autism may help treat communication andaffect issues related to TBI Such strategies may includeteaching patients to attend to relevant facial features suchas eyes and their openness and to be able to associate

772


certain facial features such as wide open eyes with fearClinicians may use static pictures initially followed by vid-eos demonstrating faces that vary in emotion and intensityNegative facial features should be used more because theyare more difficult to interpret Role playing and practicingfacial expression in a mirror for feedback may benefitpatients as well They should be encouraged to becomemore aware of their own emotional experiences and howtheir new limitations (eg difficulty reading people) affecttheir social and occupational functionings Family instruc-tion will help eliminate the idea that their loved one ldquojustdoesnrsquot want tordquo but instead is ldquounable tordquo [160]

Visuospatial Perception and Sensory-Motor IntegrationDefinition and Neurobiological Basis The incidence

and prevalence of apraxia and agnosia in mild or moderateTBI are unknown However deficits of the parietal andtemporal lobes are associated with agnosia and apraxiaAgnosia is difficulty identifying or recognizing varioussensory stimuli astereognosis (impaired tactile recogni-tion) due to lesions of the contralateral parietal lobes andvisual agnosia (impaired visual recognition) due to pari-eto-occipital lesions Apraxia is the inability to carry outa motor act despite intact motor and sensory pathwaysIdeomotor apraxia is the inability to perform motorresponses on verbal command (for example a patient can-not pinch his nose when asked but is able to do so sponta-neously) A variety of brain structures are implicated inideomotor apraxia including the corpus callosum thearcuate fasciculus and Brocarsquos area Ideational apraxia isinability to conceptualize movements and patients withthis disability have difficulty sequencing different compo-nents of a complex task although each separate compo-nent can be performed separately Ideational apraxia isseen following lesions of the left parieto-temporo-occipitalarea and frontal lobes Constructional apraxia is theinability to draw or construct two- or three-dimensionalfigures or shapes [120181]

The action of picking up a tool and using it requires acomplex hierarchy of parallel processing [4174] whichcan be described as a ldquoready set gordquo mechanismldquoReadyrdquo entails for example ldquodeciding to pick up a toolfor userdquo This decision may occur in the dorsolateral pre-frontal cortex ldquoSetrdquo determines the identity of the toolbased on intrinsic properties such as shape size andcolor which are analyzed along the ventral visual path-way that projects from the occipital cortex to the temporallobe Next the object needs to be located because of its

position in space which depends on the dorsal visualpathway which projects from the occipital cortex to theparietal lobe Then the status of the information of theshape color size and location of the object in space isprovided to the premotor areas to plan the execution of thetask The set of muscles to be used is determined and thentheir sequence force amplitude and speed of contractionare planned by the premotor areas This information issent to the ldquogordquo center the primary somatomotor cortexwhich executes this motor plan by way of the motor neu-rons projecting to the spinal cord The movement trajec-tory is modulated by neural loops involving thecerebellum and the basal ganglia Any of the neural fiberpathways subserving these systems and functions may bedisrupted by TBI and lead to consequent dysfunction

Criteria and Assessment Apraxia and agnosia arewell documented in individuals with stroke and severeTBI and symptoms are usually overt and relatively easyto detect In mild TBI deficits may be more subtle sosyndromal criteria are needed In review of these condi-tions asking the patient if she or he has any difficultywriting holding a pen buttoning clothes or ldquobeingclumsyrdquo can be useful Relatives may complain that thepatient is able to wash a cup by him- or herself but is tooldquostubbornrdquo to do so when asked which may indicate anideomotor apraxia In the assessment of agnosia patientsmay not be able to convey their difficulty finding wordsor remembering the names of objects so capacity shouldbe determined with specific questions

A clinician can identify disorders of perception andintegration in the neurological examination by requestingan individual to identify simple objects such as a key bysight using the visual system (apperceptive associative)or by touch using the somatosensory system (astereoag-nosia) Once motor and sensory pathways are deemedintact the patient may be asked to pick up a pen If thepatient is unable to perform this task despite collateralconfirmation to the contrary then ideomotor apraxia maybe considered In the assessment of apraxia a three-stepcommand such as ldquopoint to the door point the ceilingand then raise your right footrdquo may be given If thepatient is unable to perform the three-step command in itsentirety but is able to complete the task when commandsare given as individual steps ideation apraxia may beconsidered An inability to copy geometric figures suchas a cube may indicate a constructional apraxia

Assessment of perception and integration is part offormal neuropsychological testing for TBI Block design

773


test (Kohs 1923 [182]) is a test of parietal function andrequires the patient to take blocks that have all white sidesall red sides and red and white sides and arrange themaccording to a pattern Temporal lobe function is assessedby tests that require a patient to identify a sequence of pic-tures such as the Boston Naming Test [183]

Treatment Options For patients with apraxiacognitive-physical rehabilitation is the treatment modalityof choice [184] including such interventions as behavioraltraining programs consisting of gesture-production exer-cises [185] Medications that may promote neurogenesissuch as SSRIs [63] lithium [64ndash65] and cholinesteraseinhibitors [62] may potentially be used as adjuncts in cog-nitive rehabilitation although these agents have not beeninvestigated adequately in the population with TBI [4]

Executive FunctionDefinition and Neurobiological Basis The frontal

lobes are especially vulnerable to injury following a TBI[186] resulting in a variety of cognitive and behavioralchanges that significantly affect functional outcome[187] Although all cognitive functions are phenomena ofdistributed neural processing networks that do not pos-sess a singular location [40] executive processing occurslargely within the prefrontal cortex in collaboration withother cortical regions and systems [41] Important pre-frontal sites of coordination or executive control includethe anterior cingulate gyrus orbital frontal gyrus anddorsolateral prefrontal cortex [188] The prefrontal cor-tex in addition to being modulated by projections fromacetylcholine serotonin and norepinephrine neurons isunique among neocortical regions in that it also receivesprojections from dopamine neurons The prefrontal cor-tex works along with the basal ganglia in particular thenucleus accumbens which also receives projections fromserotonin norepinephrine and dopamine neurons andhas cholinergic and gamma-aminobutyric-ergic interneu-rons Consequently agents that affect any of these sys-tems can influence the function of the prefrontal cortex

Based on clinical experience with ADHD Brownconceptualizes executive function within six clusters ofcognitive functions (1) activation organizing prioritiz-ing and activating to work (2) focus focusing sustain-ing focus and shifting attention to tasks (3) effortregulating alertness sustaining effort and processingspeed (4) emotion managing frustration and regulatingemotions (5) memory utilizing working memory andaccessing recall and (6) action monitoring and regulat-

ing self-action [189] Thus executive function is an inte-gration of selected cognitive resources which allows anindividual to perform daily tasks (eg paying bills mak-ing and keeping appointments shopping cooking)

Criteria and Assessment TBI of the frontal lobes withsubsequent impairment of executive function [190] may beassociated with poor vocational functioning and communityintegration [191ndash192] and with apathy and disinhibitionSimple tests for executive function include asking a patientto name as many animals as they can in a minute as well assimilarities (How are a banana and orange alike) differ-ences (How are a lie and a mistake different) and abstrac-tion (proverb interpretation) However inquiring aboutinterests and the appropriateness of social behavior is alsoimportant

Large studies utilizing the National Institute on Dis-ability and Rehabilitation Research TBI Model Systemsdatabase have failed to demonstrate impaired executivefunction at 1 year postinjury [193] One possible explana-tion is that traditional neuropsychological testing meas-ures are less sensitive to behavioral changes such asapathy and disinhibition [194ndash196] although the greatheterogeneity of TBI presentation makes a single dys-function difficult to find among the extraordinarily com-plex array of possible problems that could occur Ratherthe important focus is on the individual patient definingthat patientrsquos difficulties and trying to help that patientcope with those difficulties

The Behavior Rating Inventory of Executive Function(for ages 0ndash18) [197] and the Frontal Systems BehaviorScale (for ages 18ndash95) [198] have good reliability andvalidity in distinguishing individuals with frontal lobeinjury from those with other lesions [199] The FrontalSystems Behavior Scale assesses apathy (anterior cingu-late gyrus) disinhibition (orbital frontal) and executivefunction (dorsolateral prefrontal cortex) [188] and effec-tively detects such changes in individuals with mild cog-nitive impairment AD [200] or polysubstance abuse[201] Importantly returning veterans may not be fullyaware (metacognition) of their deficits [202]

Metacognition is an important aspect of mental func-tion and is the capacity to ldquothink about thinkingrdquo themindrsquos creation of mental representations about itselfMetacognition involves the idea of appearance-realitydistinction ie things are not always the way theyappear One facet of metacognition is representationaldiversity essentially what one person thinks about anevent may be different from another In addition what

774


one thinks today about an event may be different fromwhat one thinks the following day (representationalchange) [68203] Patients with TBI score poorly on theself-awareness questionnaires and decreased metacogni-tive self-awareness is correlated with increased problemsin some components of the executive system even whenthe self-awareness questionnaire subscales are consid-ered separately [204] The literature has inconsistenciesregarding the concept of awareness A comprehensivemodel of awareness is needed to guide the developmentof measurement tools and interventions (for more infor-mation see Toglia and Kirk [205])

Treatment Options A few drug trials have examinedchanges in executive function in patients with TBI Bro-mocriptine a dopamine enhancer improved prefrontalfunctioning in such measures as initiation and mental flexi-bility in one double-blind placebo-controlled crossoverstudy [206] Treatment of individual cognitive domainssuch as attention or memory may improve overall execu-tive function Given the close interaction between studiesof executive function and ADHD [189] treatment of prob-lems in executive function may be best related to the treat-ments developed for ADHD (see the ldquoAttentionrdquo sectionunder ldquoTreatment Optionsrdquo for attention problems)

Neurobehavioral DisordersThe epidemiology and risk factors for noncognitive

psychiatric disorders associated with TBI (depressionmania PTSD psychosis agitation and aggression) haverecently been reviewed [21] A significant additional neu-robehavioral concern is sexual health and the impairmentof libido Numerous neurobehavioral syndromes are asso-ciated with TBI although the evidence of specific associ-ations in rigorous studies is lacking Again with the diver-sity of TBI the neurobiological bases of TBI contributionsto behavior problems are complex However clinicalexperience recommends practical management of theseproblems These suggestions are outlined in Figure 3

MoodDefinition and Neurobiological Basis Depression is

defined in DSM-IV-TR and is a fundamental problemaddressed in the field of psychiatry The incidence of post-TBI depression ranges from 153 to 330 percent [207ndash208] while the prevalence ranges from 185 to 610 percent[21209ndash216] These large ranges are likely due to the over-lap of depression and postconcussive type symptoms (egpoor concentration irritability fatigue sleep disturbances)

The clinician must elucidate whether these symptoms aredue to the emergence of a major depressive disorder or arerelated to PCS or apathy

Suicide is a severe and devastating outcome of manypsychiatric illnesses particularly depression In 200432439 Americans committed suicide the equivalent to 89suicides a day (11 per 100000) In the general populationsuicide is the twelfth leading cause of death while it is thethird leading cause of death in those aged 20 to 24 the sec-ond leading cause of death in those 25 to 34 and the fourthin those 35 to 44 ranging from 35 times higher in malesthan females aged 20 to 24 to 19 times higher in thoseaged 45 to 54 (Table) [217] Approximately 52 percent ofUS military personnel are aged 20 to 30 A TBI is likelyto put individuals at even greater risk for suicide becauseindividuals with TBI have a three- to fourfold increase insuccessful suicides an increase in suicide attempts (18)and an increase in suicidal ideation (21ndash22) [218] In2004 the US Army began using the Army Suicide EventReport a 12-page standardized Web-based report to col-lect data on suicide-related events According to thisreporting system an increasing trend exists in suicides 67suicides in 2004 (108 per 100000) 87 in 2005 (128 per100000) and 99 in 2006 (173 per 100000) althoughthese numbers need to be considered relative to age andsex with respect to the numbers for the general populationwhich are actually higher As of June 2007 44 suicidesoccurred among active duty personnel (including reserveand National Guard) 17 of which were completed duringOperation Iraqi Freedom and Operation Enduring Free-dom (OIFOEF) deployments in Iraq and Afghanistan Ofthe suicides 89 percent were male 64 percent were Cau-casian 49 percent were under the age of 25 91 percentwere in the regular Army division 49 percent were nevermarried and 36 percent were married In contrast to the

TableUS 2004 mortality statistics for suicide rate per 100000 by age rangeNote that suicide rate is two to four times higher for male than femaleOperation Iraqi Freedom and Operation Enduring Freedom veteranswith slightly higher rate for those gt35 than for those lt35 years of age

Age Range Male Female Total MaleFemale

20ndash24 208 36 125 3525ndash34 204 47 127 2735ndash44 230 71 150 2145ndash54 248 86 166 19

All Ages 177 46 110 24

775


Army data in the Marine Corpsmdasha smaller forcemdash24 sui-cides were recorded in 2006 (124 per 100000) with 4suicides occurring in a war zone The reliability of thesedata is unclear and may underestimate suicides becausesuicides may have been misclassified as accidents ldquounde-terminedrdquo or ldquopending determination statusrdquo [219] Themagnitude of suicide misclassification in a nonmilitaryenvironment is considerable with 20 to 30 percent of sui-cides being inaccurately assigned [220ndash223]

The neurobiology of depression remains unclear butsome relationship certainly exists between serotonin andnorepinephrine systems since medications that affectthese systems benefit patients with depression Seroton-ergic neurons (whose cell bodies are located in the raphenucleus of the brain stem) and norepinephrine neurons(whose cell bodies are in the locus coeruleus nearby)have unmyelinated axons that measure several centime-ters long and project throughout the brain and spinalcord These axons are prone to shearing forces and maybe damaged during TBI which could be a critical factorleading to depression in patients with TBI

The manifestations of depression might be related tothe site of cortical injury because the site of a braininjury may determine the expression of depression[21211ndash215] Post-TBI lethargic depression appears tobe related to left anterior hemispheric lesions while righthemispheric lesions are associated with anxious depres-sion Lateral lesions are more likely to produce depres-sion than are medial lesions Medial frontal injury mayproduce emotional dysregulation or inhibit experience ofmood changes Patients with left hemispheric strokes arealso more prone to depression [21] Patients with moder-ate to severe TBI who develop mood disorders have sig-nificantly smaller hippocampal volumes than patientswith equivalently severe TBI who do not develop mooddisturbance [224] Fatigue is also a common symptom inpatients with TBI While fatigue and lethargy may besymptoms of depression they may exist also as independ-ent entities and may be directly related to the brain injuryitself [225] The neural correlates of lethargy and fatigueare not known at this time Intensity of fatigue in patientswith TBI in first- and second-year follow-up studiesshows little attenuation [226]

Criteria and Assessment Depression criteria aredefined with use of DSM-IV-TR criteria although manyvariations of depression are listed The recognition ofdepression must begin with a patient or caregiver complaintor clinician vigilance A variety of depression scales is use-ful for screening evaluating and measuring depression

However the capability of psychological instruments todetect depression in patients with TBI varies considerablyIn individuals with TBI the Beck Depression Inventory hasa sensitivity of 36 percent and a specificity of 80 percent[227] Jorge et al found that four symptoms consistentlydifferentiated depressed from nondepressed individualswith TBI [211ndash215] depressed mood feelings of worth-lessness reduced energy and suicidal ideation They alsofound that early awakening and difficulty concentratingdistinguished groups only after 6 months suggesting thatthe nature of a post-TBI depressive disorder may changeover time The most accurate items to detect TBI-relateddepression that are present in the DSM-IV-TR-based Neu-robehavioral Functioning Inventory are reduced libidoanhedonia reduced appetite and lack of confidence [209]Suicide risk should be carefully assessed in all TBI cases

Treatment Options A paucity of TBI-related depres-sion management trials exists Most early studies of patientswith TBI with depression examined the efficacy of tricyclicantidepressants such as amitriptyline [228] (nortriptylinewould offer all the benefits of this medication without asmuch anticholinergic side effect) and monoamine oxidaseinhibitors such as phenelzine [229] neither of which dem-onstrated efficacy in treating TBI-related melancholicdepression Desipramine predominantly a norepinephrinereuptake inhibitor however clinically improved depressionsignificantly [230] Few studies have evaluated the efficacyof SSRIs in treating TBI-related depression Statisticallysertraline significantly improved psychological distressanger and aggression [231] Citalopram response andremission rates following treatment of patients with TBIwere comparable with patients with depression and withoutTBI [232] While these studies are helpful insufficientevidence exists for developing standards of treatment forTBI-related depression Other antidepressants such asbupropion mirtazapine venlafaxine and duloxetine remainto be explored in treating TBI-related depression Atpresent the clinician must determine treatment Large multi-center clinical trials are needed to establish practice parame-ters Psychostimulants such as methylphenidate have longbeen used as adjuncts in treating depression and they havebeen advocated for use in patients with TBI [233] Inpatients with human immunodeficiency virus fatiguemay be incapacitating and is significantly ameliorated witha psychostimulant subsequently improving QOL [226]mdashthis benefit may also extend to individuals with TBI whoexperience fatigue with or without depression

776


AffectDefinition and Neurobiological Basis DSM-IV-TR

criteria are also used for defining manifestations of maniawhen they occur after TBI The incidence of post-TBImania is 9 percent [211ndash215] and the prevalence is 08 to22 percent [234ndash236] Risk factors include seizures pro-longed PTA and varied lesion types including multifocalorbitofrontal temporal and nondominant hemisphericlesions [237ndash239]

Criteria and Assessment Patients with post-TBI-related mania typically present with sleeplessness grandi-osity impaired judgment irritability pressured speech(80ndash100 of cases) hyperactivity (65) and hyper-sexual behavior (50) [234] The majority of manic casesdevelop after at least 1 year post-TBI and some studieshave reported a delay of 4 to 5 years post-TBI [234240]

Several approaches have been used for diagnosingpost-TBI mania based on the Research Diagnostic Crite-ria DSM-III (Third Edition) DSM-III-Revised andDSM-IV-TR See Kim et al for full discussion [21]

Treatment Options Common approaches for treatingmania namely lithium [241] and valproate [242] havebeen shown to be effective in TBI-related mania The pos-sibility has also been raised that lithium can not onlyimprove neuronal function but also stabilize behavior Fur-thermore lithium has been shown to increase gray mattervolume [243] Clinically in the population with non-TBIantiseizure medications such as carbamazepine oxcarba-zepine topiramate and lamotragine are used off-label asmood stabilizers Lamotragine is also FDA-approved forthe maintenance treatment of bipolar mood disorder Sev-eral atypical antipsychotics now carry FDA approval forthe treatment of bipolar disorder including aripiprazoleolanzapine ziprazadone and quietapine Combinationsof several of these medications have also been studied inpatients with mania and found to be effective Of particularinterest is the option of using low-dose lithium as a neuro-protective medication with antisuicidal features [244]along with other agents so that the chronic toxicity of lith-ium can be minimized However the effectiveness of anyof these medications in the treatment of TBI-related maniahas not been established

PTSD and Other Anxiety DisordersDefinition and Neurobiological Basis Civilians with

a history of TBI compared with those without TBI haveincreased risk ratios (RRs) for PTSD (RR = 18) general-ized anxiety disorder (RR = 23) obsessive compulsive

disorder (RR = 26) and panic disorder (RR = 58) [245]Following TBI a 13 to 27 percent incidence [29246ndash248]and 3 to 59 percent prevalence of PTSD can be found[249ndash251] The wide range reported for prevalence islikely due in part to the diverse manifestations of PTSDconcerning TBI [21]

Among veterans a strong relationship also existsbetween TBI and PTSD OIFOEF soldiers with mild TBIare likely to develop PTSD soon after their return home[252] While 11 percent of returning soldiers screen posi-tive for PTSD of those with mild TBI 62 percent screenpositive for PTSD [253] Thus the occurrence of PTSDand related disorders may be much higher in veterans withcombat-related TBI A significant question has been askedabout the interaction between TBI and PTSD The evi-dence indicates that many symptoms of mild TBI arerelated to the development of PTSD and in particularPTSD is an important mediator of the relationship betweenmild TBI and physical health problems [252] Furtherquestions need to be addressed as to whether combat-related mild TBI is more likely to cause particular neuro-logical damage that will predispose to PTSD or whetherthe increased incidence of PTSD is related to premorbid orenvironmental factors such as the stress of combat

As defined by the DSM-IV-TR PTSD is classified asan anxiety disorder that is induced by hypersensitiveresponse to threat and includes reexperiencing avoidanceand numbing PTSD has also been considered a disorder ofmemory organization and may involve the intrinsic non-declarative amygdala-based memory processing systemsand the extrinsic declarative hippocampal-based memory-processing systems Patients with PTSD typically presentwith intrusive memories fragmentation of autobiographicalmemories fragmentation of trauma-related memoriesdeficits in declarative memory and the presence of trauma-related amnesia [254] The linking of PTSD to anxiety andmemory is not necessarily a conflict but rather suggeststhat many of the involved brain systems are interrelated

Elzinga and Bremner have proposed that the neuralsubstrates of memory may be a final common pathway ofPTSD neuropathophysiology [254] Memory informationdetails are stored throughout the cortex mainly posteriorto the central sulcus The storage of information is medi-ated by reciprocal connections between the cortex andthe hippocampus (autobiographical and semantic mem-ory) and amygdala (emotional conditioning) Since mem-ory is a cognitive domain PTSD has also been framedwithin a cognitive model that is still compatible with

777


concepts of an anxiety disorder since anxiety is the resultof cognitive appraisal of a threat PTSD may become per-sistent when individuals process the trauma in a way thatleads to a sense of serious current threat due to negativeappraisals of the trauma and a disturbance of autobio-graphical memory characterized by poor elaboration andpoor contextualization strong associative memory andstrong perceptual priming [255]

Another consideration is that basic neurophysiologicalmechanisms may alter serotonergic learning pathwayswhich cause reexperiencing particularly with nightmares[256] Additionally norepinephrine mechanisms affectinglevels of alertness and reward-orientation may be involvedin PTSD pathophysiology [257] Of particular interest isthat norepinephrine and serotonin medications are useful intreating depression and PTSD [256ndash257] Norepinephrineand serotonin neuron cell bodies that project throughout thecortex are located in the brain stem and their axons coursethrough the medial forebrain bundle Their axons are smallunmyelinated fibers and may be particularly vulnerable toshearing forces which occur in some types of TBI Conse-quently TBI damage to these neurons could result in symp-toms of PTSD and depression The linking of thesemonoaminergic systems to PTSD along with involvementof memory systems in the temporal lobe including theamygdala and hippocampus parallels the disruption ofbrain systems seen in AD [34258] which may be causallyrelated to TBI [259]

TBI can cause neurodegeneration in many brainstructures notably the hippocampus cortex and thalamus[63260] PTSD is also linked to decreased hippocampalvolume An ongoing debate exists as to whether PTSDcan damage the hippocampus through stress effects orwhether individuals with a smaller hippocampus are moreprone to develop PTSD [261] Regarding the relationshipbetween TBI and PTSD TBI may damage hippocampalconnections enough to prime the system for future devel-opment of PTSD Known risk factors for PTSD includeLOC following a TBI [262] the presence of acute stressdisorder following a TBI and poor coping skills [29]

Criteria and Assessment The criteria for diagnosingPTSD are outlined in DSM-IV-TR and these criteria arethe basis for scales that assess for the presence of PTSDUsing standard diagnostic tools that require ldquoreexperienc-ingrdquo symptoms to diagnose PTSD is problematic concern-ing TBI [821] because memory impairment during andfollowing TBI is common Thus while reexperiencingmay be central in diagnosing PTSD it may not be a pre-senting symptom in individuals suffering from PTSD who

have comorbid TBI Thus the use of unmodified DSM-IV-TR criteria and associated rating scales such as thePresent State Examination and Structured Clinical Inter-view will subsequently produce a significant number offalse negatives Adding an additional scale such as theImpact Event Scale in memory loss cases may be usefulto increase diagnostic sensitivity [246]

Treatment Options PTSD has been suggested tobecome persistent when the traumatic stress is processedso that it leads to a sense of current threat resulting fromimproperly encoded autobiographical memory and per-ceptual priming Changes in negative appraisal and thetrauma memory are prevented by certain problematicbehavioral and cognitive strategies [255] the targets ofcognitive behavioral therapy During the process of reap-praisal negative emotions are cognitively reframed toreduce physiological arousal without affecting the mem-ory In contrast behavioral regulation suppresses negativeemotions with a subsequent controlling of the traumaticmemory but an associated increase in sympathetic outputmay occur once the memory is experienced

The SSRIs are the most widely studied and best toler-ated medications for treating PTSD These medicationsare significantly more effective than placebo and havebeen shown to significantly reduce core symptoms ofPTSD (reexperiencing avoidance numbing and hyper-arousal) In addition to better tolerance than older antide-pressants they also appear more effective for PTSD [263]Trazodone a serotonergic agent has been widely pre-scribed for patients with PTSD both to control and reducenightmares and to alleviate anxiety during the daytime[256] Prazosin a noradrenergic alpha-1 blocker has alsobeen used to reduce nightmares and daytime anxiety[257264] Propranolol a centrally acting noradrenergicbeta-blocker has also been used to reduce anxiety Thebenefits of these medications support the concept thatboth serotonergic and noradrenergic pathways areinvolved in the hyperarousal and adverse rememberingassociated with PTSD and this insight can help managechronic PTSD symptoms Neuroleptics have been studiedin PTSD treatment and the typical dopaminergic blockingagents are considered detrimental to patients with PTSDin spite of the psychotic proportions that the symptomscan manifest [265] However the atypical neurolepticswith serotonergic effects have some use [266] Finallysedative hypnotics (eg benzodiazepines) can tempo-rarily relieve symptoms but rebound symptoms anddependence contraindicate these medications for PTSDtreatment

778


PsychosisDefinition and Neurobiological Basis The incidence

of psychosis following TBI is approximately 20 percent[267] the prevalence has not been determined Diagnosingpsychosis following a TBI falls into the DSM-IV-TR clas-sification of psychosis secondary to a general medical con-dition This characterization however has been usedinconsistently across studies and has significant limitation[21] Because the average time between a TBI and thedevelopment of psychosis is 12 years the causal relation-ship versus an idiopathic psychosis in patients with a his-tory of TBI is unclear without further understanding thepathophysiology underlying post-TBI psychosis

The range of psychotic disorders is detailed in DSM-IV-TR However psychosis occurs in many variations and maybe caused by numerous different and possibly unrelatedpathophysiological mechanisms operating in the brain

Dopamine is produced in the substantia nigra the ven-tral tegmental area of the midbrain and the arcuate nucleusof the hypothalamus Unlike serotonergic and noradrener-gic axons the dopaminergic neurons that project to thecerebrum only target the basal ganglia and frontal cortexThey too are unmyelinated and may be several centimeterslong Because of their length and fragility they may alsobe prone to axonal sheering A psychotic manifestation inTBI may be due to a combination of certain risk factorsincluding left temporal lobe injuries duration of LOC TBIbefore adolescence a genetic predisposition to schizophre-nia [268] and a prior history of substance abuse and cogni-tive impairment [269ndash270] A positive family history ofpsychosis and lengthy duration of LOC are the strongestpredictors of the development of schizophrenia-like psy-chosis after TBI

Criteria and Assessment Psychosis following TBItypically involves positive-type symptoms mainly para-noid delusions and auditory hallucinations [268] Clini-cians have used positive versus negative symptoms todifferentiate TBI-related psychosis and the developmentof schizophrenia This approach is problematic becausepatients with frontal lobe lesions present with significantnegative-type symptoms such as apathy

To assess for the presence of psychosis the clinicianposes questions regarding positive symptoms (hallucina-tions paranoia and delusions) and negative symptoms(anhedonia and blunting of affect) The nature and extentof the injury prior history of head injury substance abuseor psychological trauma are factors that must be consid-ered when psychosis is assessed Psychological testing is

usually not required although in equivocal cases a Min-nesota Multiphasic Personality Inventory may be helpful

Treatment Options Atypical and typical antipsychot-ics are the primary agents used for treating psychosis thechoice based on clinical judgment The literature does notdefine any guidelines for treating TBI-related psychosis Afew case studies are available for the use of individual atypi-cal antipsychotics [271ndash272] but comprehensive studieshave not been reported

Agitation and AggressionDefinition and Neurobiological Basis The term ldquoagi-

tationrdquo refers to nonpurposeful behaviors and can includeaggressive behavior physically nonaggressive behaviorand verbally agitated behavior [273] Agitation may beviewed as low frustration tolerance that may culminate inan act of aggression Loosely impulsive aggression hasbeen defined as a persistent uncontrolled loss of tempermanifested by verbal outbursts striking throwing anddamaging property or attacks on other persons [274] Whileneither aggression nor agitation is a syndrome agitation is apart of several syndromes such as depression mania anddelirium The DSM-IV-TR diagnostic criteria for PDGMCpartially capture the phenomenon of aggression in patientswith TBI Intermittent explosive disorder however is adiagnosis that cannot be made in the presence of TBI

The incidence of TBI-related aggression is 34 percent[275ndash276] while its prevalence ranges from 20 to 40 per-cent [277] Agitation occurs frequently during the acutestages of recovery following TBI and may be seen in 35 to96 percent of individuals [13278]

Numerous risk factors predispose to the development ofagitation and aggression Preinjury predictors of post-TBIaggression include family dysfunction history of mood dis-orders low socioeconomic status and alcohol and substanceabuse A childhood history of oppositional-defiant behavioralso predisposes to post-TBI aggression which may be anextension of premorbid impulsivity and aggression [274]Patients with such a risk-factor history showed increasingaggression with time as opposed to those patients without arisk-factor history [275] While injury severity correlateswith cognitive deficits accordingly many behavior prob-lems after TBI including aggression after TBI do not corre-late with levels of post-TBI aggression [21] Effectivescreening of risk factors especially childhood psychiatrichistory helps identify patients with high risk for more inten-sive screening follow-up and treatment

779


Criteria and Assessment Agitation may complicateand prolong a hospital stay and be associated withdecreased cognition [279] Agitation and aggression maypersist causing considerable disability in the workplaceand at home Individuals demonstrating agitation follow-ing TBI are frequently diagnosed with a bipolar disorderAlthough bipolar disorder and TBI-related aggression bothshare irritability and dysphoria the clinician should con-sider specific mood symptoms such as increased energydecreased sleep pressured speech and racing thoughts todifferentiate the two syndromes Agitation and aggressionare also seen following injury to the orbitofrontal lobe aregion that is specifically responsible for inhibiting primaldrives such as aggression and libido No DSM-IV-TR clas-sification captures aggressive outbursts as a pure entityconcerning TBI

Instruments used in the assessment of TBI-relatedaggression include the Overt Aggression Scale with38 percent accuracy at 6 months [276] and the DeBloisAggressive and Antisocial Behavior Scale mainly usedin children demonstrating an increase in aggression andantisocial behavior Both the Overt Aggression Scale andthe Neurobehavioral Rating Scale are effective for moni-toring changes across time

Treatment Options Extensive publications examinethe use of various pharmacological agents in treatingaggression most studies are limited in their study designthus precluding the development of standards of treatmentEvidence does exist for the use of beta-blockers such aspropranolol and pindolol for treating aggression in patientswith TBI [4] Clonidine an alpha-2 antagonist has longbeen used in children with ADHD who continue to behaveaggressively in spite of using a stimulant Furthermorestudies providing evidence for optional considerationsinclude the use of methylphenidate SSRIs valproate lith-ium tricyclic antidepressants and buspirone For fulldetails see Warden et al [4]

Sexual Health and LibidoDespite the high prevalence of sexual dysfunction fol-

lowing head injury a paucity of information exists describ-ing these problems and their treatment for soldiers withTBI returning from war Problems frequently encounteredinclude impulsiveness or inappropriateness changes inlibido (particularly a decrease) and sexual frequency globalsexual difficulties and specific sexual dysfunctions [280]The etiology of sexual dysfunction is likely multifactorialin nature and should also be examined biopsychosocially

Posttraumatic hypopituitarism is the failure of the hypo-thalamic-pituitary axis secondary to TBI Clinically hypopi-tuitarism may present with decreased muscle mass andlibido infertility and electrolyte abnormalities such ashyponatremia In addition patients may also present withfatigue depression and a variety of cognitive deficits Post-traumatic hypopituitarism is a diagnosis based on clinicalevaluation laboratory testing and neuroimaging [281]

Subjects with TBI frequently describe a discrepancybetween preinjury ldquoselfrdquo and postinjury ldquoselfrdquo Cloute etal discuss the importance of the reconstruction of iden-tity following injury [282] Schopp et al described themasculine role functioning in life domains such as voca-tional functioning sexual and interpersonal functioningand personal independence [283] Particular masculinerole variables corresponded to different functional andpsychological outcomes Understanding these differencesmay provide new direction for treatment and may offerimportant information about aspects of traditional mascu-line roles that could enhance adjustment to injury

One concern in managing the libido changes inpatients with TBI is to carefully assess the medicationregimen that a patient may have For example many anti-depressant medications are well known to adverselyaffect sexual desire Many other medications may simi-larly affect libido or other aspects of sexual function andthus should be used judiciously in patients with TBI

Somatosensory DisruptionsInjury to sensory organs or their projections through

the brain stem and elsewhere is frequently seen followingTBI and may also be caused by axonal shearing Eachsensory organ system should be independently evaluatedand day-to-day functional impairments resulting fromsuch injury should be delineated Issues regarding olfac-tory visual and auditory senses will be outlined brieflybull Olfactory dysfunction and disorders of taste have been

well documented in conditions such as AD Parkinsondisease and multiple sclerosis but they remain to befully characterized in TBI Fibers from the nasal epithe-lium running through the cribriform plate to the olfactorybulb are vulnerable to trauma particularly shearingDisruption of these fibers may account for the frequentsymptom of anosmia in patients with TBI and substan-tially alter the perception of taste Also the olfactorybulbs project through three branches to the basal fore-brain and medial temporal lobe limbic areas which areregions involved in motivation emotion and memory In

780


animal models bulbectomy procedures cause depressionand immune changes [284] Consequently changes inthe sense of smell may alter emotions and social interac-tions as well as immune function

bull Visual disturbances such as anomalies of accommoda-tion as evidenced by either intermittent or constantblurred vision may be present Patients with TBI mayalso present with anomalies of vision such as abnormalsaccades pursuit and fixation which impact readingefficacy Patients with TBI may complain of skippinglines inadvertently which can greatly reduce readingspeed and ultimately affect occupational functioningThey may also present with anomalies of vergencewhich may cause in intermittent or constant diplopliaand a sense the print is floating Anomalies of thevisual field result in spatial perceptual deficits Anoma-lies of light sensitivity such as photosensitivity andphotophobia may also be present [285]

bull Auditory problems are potentially extensive They canrelate to damage to the ear particularly the peripheralassociation of traumatic disruption of the tympanicmembrane or the cochlea Damage to delicate auditorypathways can also occur Tinnitus is a particularly com-mon and difficult-to-manage complaint but may berelated to cerebral processing

Another frequent problem in patients with TBI is diz-ziness Dizziness most likely results from damage to themiddle ear (vestibular apparatus) which includes thesemicircular canals that respond to rotations and theotolithic organs that respond to sense linear accelerationswith otoconia crystals Either system could be damagedby external physical forces causing rapid translation orrotation of the head permanently disturbing equilibriumNote that dizziness may be caused by other TBI-associ-ated problems including disturbance of other neural sys-tems and vascular damage

Somatic SymptomsmdashHeadache and Chronic Pain Syndromes

Chronic pain syndromes such as headache are anunderdiagnosed consequence of TBI Among civiliansthe prevalence of chronic pain was greater in patientswith mild TBI compared with those with moderate orsevere TBI Twenty studies including 3289 civilianpatients with TBI yielded a chronic pain prevalence of52 percent Three studies assessing TBI among 917 veter-ans yielded a pain prevalence of 43 percent PTSD maymediate some TBI physical health symptoms but brain

injury appears to correlate independently with chronicpain [252] Chronic pain is independent of psychologicaldisorders such as PTSD and depression and is commoneven among patients with apparently minor injuries to thebrain [286] More research is needed to understand thetreatment of chronic pain concerning mild TBI

Substance DependenceA common problem in most societies and among veter-

ans of all conflicts is substance dependence Substancedependence ranges from legitimate substance overuseincluding tobacco and alcohol to illicit substance useincluding narcotics stimulants (particularly methampheta-mine and cocaine) sedative hypnotics and hallucinogenics(marijuana LSD [lysergic acid diethylamide] phencyclid-ine) Substance dependence also includes use that is delete-rious to the long-range health and function of an individualeven if substance is legitimately prescribed by a licensedclinician Commonly prescribed drugs of particular con-cern include narcotics and benzodiazepines Cliniciansneed to consider substance dependence in patients withTBI for two reasons First TBI may predispose thepatient to developing substance dependence because ofweakened self-control or somatic pains that lead toexcessive use of a substance followed by dependenceSecond the patient with a TBI can be more impaired bysubstances because of deficiencies in brain functionThus a critical issue of which the primary-treating clini-cians in the chronic care environment need to be aware isthe possibility of substance dependence They need to bealert to recognize the signs and symptoms Also clini-cians should try to avoid the use of chronic narcotic andbenzodiazepine prescriptions in these patients

DISCUSSION

Cognitive dysfunctions (memory attention languagevisuospatial cognition sensory-motor integration affect rec-ognition and executive function) neurobehavioral disorders(mood affect anxiety posttraumatic stress psychoticsleep and libidinal disorders) somatosensory disruptions(changes in smell vision hearing equilibrium taste andsomatosensory perception) somatic symptoms (headachechronic pain) and substance dependence (in the contextof a post-TBI occurrence or relapse) define symptomclusters observed in many veterans returning from OIFOEF (Figure 1) Social and occupational dysfunctions

781


and the reduction in QOL may be attributed to any compo-nent of the post-TBI state therefore each facet of TBIshould be fully evaluated for the need of a comprehensiveand individualized treatment plan While cognitive dys-function and neurobehavioral disorders may be due to a cir-cuitry interruption involving the cortex and subcorticalstructures somatic symptoms are most likely due to damageto specific sensory organs or their projections Approachingthe myriad of post-TBI psychiatric symptoms as discreteclusters will help clinicians facilitate rehabilitation andensure that neurology and psychiatry resources know thegoals for each specialty thereby providing comprehensivediagnosis and care and minimizing the risk of missing sig-nificant problems in patients with TBI

Various rating scales and their sensitivities in detectingpsychiatric sequelae concerning TBI have been discussedonly briefly Many traditional psychiatric rating scales areproblematic concerning a TBI For example scales used todetect PTSD may not be sufficiently sensitive in thosepatients with TBI because these scales rely heavily onreexperiencing phenomena for diagnosis which may beabsent because of PTA Syndromal criteria and instrumentsof detection need to be redefined for individuals with TBIand rating scales need to be further developed using Mod-ern Test Theory so that they can be efficiently applied inthe clinical setting Until further study of patients with TBIis conducted to provide specific understanding of TBIramifications clinicians need to be vigilant for both typicaland atypical presentations of various chronic neuropsychi-atric sequelae of TBI

Once delineated capturing symptoms on a five-axisDSM-IV-TR diagnosis is problematic in view of the multi-tude of available diagnostic classifications MNI may beused to capture cognitive sequelae as an axis I diagnosisNeurobehavioral sequelae can be captured using standardtaxonomies for mood anxiety and psychotic disorders untilthe taxonomies are revised to include specific presentationsof these disorders concerning TBI Somatic symptoms canbe evaluated as a single entity and listed on axis III No clearevidence exists to establish a link between a specific cogni-

tive dysfunction and specific somatic symptoms Dizzinessfor example may be associated with memory impairment inone individual and with language difficulties in another Tofoster efficient care of the patient with TBI the primary carephysician should consider the biopsychosocial approach andcoordinate the care of the patient with a unique presentationworking with a team that includes psychiatrists neurolo-gists and rehabilitation medicine physicians as well aspsychologists and social workers to fully assess each com-ponent of the cognitive dysfunctions neurobehavioral dis-orders somatosensory disruptions and somatic symptomsas well as any possibility of substance dependence or otherrelated problem

For the most part clearly inadequate evidence-baseddata exist to support specific treatments for the neuropsychi-atric sequelae of TBI Consequently treatment considera-tions are based on experience with analogous conditionsStimulants (notably methylphenidate) have been studied inthe treatment of frontal lobe dysfunction (attention impul-sivity and hyperactivity) The Texas Medication AlgorithmProject while outlining a six-step treatment approach forADHD may be applied to individuals with TBI-relatedADHD-type symptoms Using this algorithm in individualswith TBI who present with ADHD-type symptoms couldhelp establish the use of ADHD medications in treatingTBI-related inattention impulsivity and hyperactivityThe Texas Medication Algorithm Project also providesadditional treatment options of ADHD-associated comor-bidities such as depression anxiety and aggressionMedications that promote neurogenesis are a promisingnew modality that needs significant investigation Thecritical issue in recovery from TBI is restoration of neu-robiological function and neuroplasticity is a fundamen-tal mechanism that must be used in rehabilitationAlthough medications may be less useful for fostering rede-velopment of function they may facilitate the intensiverelearning of lost skills and abilities In every case integra-tion of attention to the spectrum of biopsychosocial factorsand development of individualized treatment plans are likelyto be the most beneficial approaches

CONCLUSIONS

TBIs and the resulting symptoms are tragic life-changing events for many returning from the battlefieldInnovation in warfare technology has decreased the mor-tality of these soldiers but as a result incidents of TBIare being seen in unprecedented numbers Because of the

Modern Test Theory refers to ldquoItem Response Theoryrdquo and ldquoItem Char-acteristic Curve Analysisrdquo and is the approach used for all modern testssuch as the Scholastic Aptitude and intelligence quotient tests Howeverthis approach is not widely used in places where it could be of great usesuch as ldquoModern Medicinerdquo More information can be found in ReiseSP Haviland MG Item response theory and the measurement of clinicalchange J Pers Assess 200584(3)228ndash38 [PMID 15907159]

782


previous scarcity of these types of injuries research onthe symptoms assessment and treatment of TBI is lim-ited This article proposes a starting point and suggestsways for creating a differential diagnostic nosology thatwill help medical resources provide comprehensive treat-ment for both somatic and neuropsychiatric diagnosesthat are common in patients with TBI Further studiesshould be done on differential diagnostic models and theneurocognitive effects of TBI as well as treatmentapproaches As is clear from this article and others thathave noted the lack of evidence on which to base diag-nostic and management recommendations formal studiesof the incidence of specific sequelae of TBI are neededand research into the efficacy of probable treatmentmodalities is urgently indicated

ACKNOWLEDGMENTS

Author ContributionsAnalysis and interpretation of data J A Yesavage J W Ashford J D HalbauerDrafting of manuscript J D Halbauer J W Ashford J M ZeitzerCritical revision of manuscript for important intellectual content H L Lew M M Adamson J A YesavageSupervisors of manuscript J W Ashford J A Yesavage H L LewFinancial Disclosures The authors have declared that no competing interests existFundingSupport This material is the result of work supported with resources and the use of facilities at the Medical Research Service of the Department of Veterans Affairs (VA) Palo Alto Health Care Sys-tem and the VA Sierra-Pacific Mental Illness Research Education and Clinical Center and War-Related Illness and Injury Study Center The content is solely the responsibility of the authors and does not neces-sarily represent the official view of the VAAdditional Contributions This article was written as part of Dr Halbauerrsquos Mental Illness Research Education and Clinical Center VA Advanced Fellowship Program in Mental Illness Research and TreatmentAdditional Information Dr Henry L Lew is now with Harvard Medical School in Boston Massachusetts

REFERENCES

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2 Wade AL Dye JL Mohrle CR Galarneau MR Head faceand neck injuries during Operation Iraqi Freedom II Resultsfrom the US Navy-Marine Corps Combat Trauma Registry

J Trauma 200763(4)836ndash40 [PMID 18090014]DOI10109701ta00002514535466366

3 Teasdale TW Engberg AW Subjective well-being andquality of life following traumatic brain injury in adultsA long-term population-based follow-up Brain Inj 200519(12)1041ndash48 [PMID 16263647]DOI10108002699050500110397

4 Warden DL Gordon B McAllister TW Silver JM Barth JTBruns J Drake A Gentry T Jagoda A Katz DI Kraus JLabbate LA Ryan LM Sparling MB Walters B Whyte JZapata A Zitnay G Neurobehavioral Guidelines WorkingGroup Guidelines for the pharmacologic treatment of neu-robehavioral sequelae of traumatic brain injury J Neuro-trauma 200623(10)1468ndash1501 [PMID 17020483]DOI101089neu2006231468

5 Peloso PM Carrol LJ Cassidy JD Borg J Von Holst HHolm L Yates D Critical evaluation of the existing guide-lines on mild traumatic brain injury J Rehabil Med 200443 Suppl106ndash12 [PMID 15083974]DOI10108016501960410023868

6 Carroll LJ Cassidy JD Peloso PM Borg J Von Holst HHolm L Paniak C Peacutepin M WHO Collaborating CentreTask Force on Mild Traumatic Brain Injury Prognosis formild traumatic brain injury Results of the WHO Collabo-rating Centre Task Force on Mild Traumatic Brain InjuryJ Rehabil Med 200443 Suppl84ndash105 [PMID 15083873]DOI10108016501960410023859

7 Kay T Harrington DE Adams R Anderson T Berrol SCicerone K Dahlberg C Gerber D Goka R Harley P Hilt JHorn L Lehmkuhl D Malec J Definition of mild traumaticbrain injury J Head Trauma Rehabil 19938(3)86ndash87DOI10109700001199-199309000-00010

8 Feinstein A Hershkop S Ouchterlony D Jardine AMcCullagh S Posttraumatic amnesia and recall of a trau-matic event following traumatic brain injury J Neuro-psychiatry Clin Neurosci 200214(1)25ndash30[PMID 11884651]DOI101176appineuropsych14125

9 Borg J Holm L Cassidy JD Peloso PM Carrol LJ VonHolst H Ericson K WHO Collaborating Center Task Forceon Mild Traumatic Brain Injury Diagnostic procedures inmild traumatic brain injury Results of the WHO Collabo-rating Centre Task Force on Mild Traumatic Brain InjuryJ Rehabil Med 200443 Suppl61ndash75 [PMID 15083871]DOI10108016501960410023822

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11 De Monte VE Geffen GM May CR McFarland K Doublecross-validation and improved sensitivity of the rapid screenof mild traumatic brain injury J Clin Exp Neuropsychol

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200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443

12 Shores EA Further concurrent validity data on the West-mead PTA Scale Appl Neuropsychol 19952(3ndash4)167ndash69[PMID 16318522]DOI101207s15324826an0203amp4_11

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16 Kraus MF Susmaras T Caughlin BP Walker CJ SweeneyJA Little DM White matter integrity and cognition inchronic traumatic brain injury A diffusion tensor imagingstudy Brain 2007130(Pt 10)2508ndash19 [PMID 17872928]DOI101093brainawm216

17 Arfanakis K Haughton VM Carew JD Rogers BP Demp-sey RJ Meyerand ME Diffusion tensor MR imaging indiffuse axonal injury AJNR Am J Neuroradiol 200223(5)794ndash802 [PMID 12006280]

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19 Song SK Sun SW Ju WK Lin SJ Cross AH NeufeldAH Diffusion tensor imaging detects and differentiatesaxon and myelin degeneration in mouse optic nerve afterretinal ischemia Neuroimage 200320(3)1714ndash22[PMID 14642481]DOI101016jneuroimage200307005

20 Harsan LA Poulet P Guignard B Steibel J Parizel N DeSousa PL Boehm N Grucker D Ghandour MS Braindysmyelination and recovery assessment by noninvasivein vivo diffusion tensor magnetic resonance imagingJ Neurosci Res 200683(3)392ndash402 [PMID 16397901]DOI101002jnr20742

21 Kim E Lauterbach EC Reeve A Arciniegas DB CoburnKL Mendez MF Rummans TA Coffey EC ANPA Com-mittee on Research Neuropsychiatric complications of trau-matic brain injury A critical review of the literature (a reportby the ANPA Committee on Research) J Neuropsychiatry

Clin Neurosci 200719(2)106ndash27 [PMID 17431056]DOI101176appineuropsych192106

22 Meares S Shores EA Taylor AJ Batchelor J Bryant RABaguley IJ Chapman J Gurka J Dawson K Capon LMarosszeky JE Mild traumatic brain injury does not pre-dict acute postconcussion syndrome J Neurol NeurosurgPsychiatry 200879(3)300ndash306 [PMID 17702772]DOI101136jnnp2007126565

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25 Kashluba S Casey JE Paniak C Evaluating the utility ofICD-10 diagnostic criteria for postconcussion syndromefollowing mild traumatic brain injury J Int NeuropsycholSoc 200612(1)111ndash18 [PMID 16433950]

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28 McCauley SR Boak C Levin HS Contant CF Song JXPostconcussional disorder following mild to moderatetraumatic brain injury Anxiety depression and socialsupport as risk factors and comorbidities J Clin ExpNeuropsychol 200123(6)792ndash808 [PMID 11910545]DOI101076jcen2367921016

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54 Zhang L Plotkin RC Wang G Sandel ME Lee S Cholin-ergic augmentation with donepezil enhances recovery inshort-term memory and sustained attention after traumaticbrain injury Arch Phys Med Rehabil 200485(7)1050ndash55[PMID 15241749]DOI101016japmr200310014

55 Foster M Spiegel DR Use of donepezil in the treatmentof cognitive impairments of moderate traumatic braininjury J Neuropsychiatry Clin Neurosci 200820(1)106[PMID 18305293]DOI101176appineuropsych201106

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56 Silver JM Koumaras B Chen M Mirski D Potkin SGReyes P Warden D Harvey PD Arciniegas D Katz DIGunay I Effects of rivastigmine on cognitive function inpatients with traumatic brain injury Neurology 200667(5)748ndash55 [PMID 16966534]DOI10121201wnl000023406298062e9

57 Wilcock G Howe I Coles H Lilienfeld S Truyen L ZhuY Bullock R Kershaw P GAL-GBR-2 Study Group Along-term comparison of galantamine and donepezil inthe treatment of Alzheimerrsquos disease Drugs Aging 200320(10)777ndash89 [PMID 12875613]DOI10216500002512-200320100-00006

58 Rao VL Dogan A Todd KG Bowen KK Dempsey RJNeuroprotection by memantine a non-competitive NMDAreceptor antagonist after traumatic brain injury in ratsBrain Res 2001911(1)96ndash100 [PMID 11489449]DOI101016S0006-8993(01)02617-8

59 Battista MA Hierholzer R Khouzam HR Barlow AOrsquoToole S Pilot trial of memantine in the treatment of post-traumatic stress disorder Psychiatry 200770(2)167ndash74[PMID 17661541]DOI101521psyc2007702167

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65 Wada A Yokoo H Yanagita T Kobayashi H LithiumPotential therapeutics against acute brain injuries andchronic neurodegenerative diseases J Pharmacol Sci200599(4)307ndash21 [PMID 16340157]DOI101254jphsCRJ05009X

66 Whyte J Hart T Vaccaro M Grieb-Neff P Risser APolansky M Coslett HB Effects of methylphenidate onattention deficits after traumatic brain injury A multidi-mensional randomized controlled trial Am J Phys Med

Rehabil 200483(6)401ndash20 [PMID 15166683]DOI10109701PHM000012878975375D3

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71 Hunt R Cohen DJ Anderson G Noradrenergic mecha-nisms in ADHD In Bloomingdale LM editor Attentiondeficit disorder and hyperactivity Vol 3 New York (NY)Spectrum 1987

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74 Fuster JM Jackson and the frontal executive hierarchy IntJ Psychophysiol 200764(1)106ndash7 [PMID 16959349]DOI101016jijpsycho200607014

75 Mesulam MM Large-scale neurocognitive networks anddistributed processing for attention language and mem-ory Ann Neurol 199028(5)597ndash613 [PMID 2260847]DOI101002ana410280502

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77 Fan J McCandliss BD Sommer T Raz A Posner MITesting the efficiency and independence of attentionalnetworks J Cogn Neurosci 200214(3)340ndash47[PMID 11970796]DOI101162089892902317361886

78 Doyle R The history of adult attention-deficithyperactiv-ity disorder Psychiatr Clin North Am 200427(2)203ndash14[PMID 15063993]DOI101016jpsc200401001

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79 Goodman D Treatment and assessment of ADHD inadults In Biederman J editor ADHD Across the lifespan From research to clinical practicemdashAn evidence-based understanding Hasbrouck Heights (NJ) VeritasInstitute for Medical Education Inc 2005

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83 Van Zomeren AH Reaction time and attention afterclosed head injury Lisse (the Netherlands) Swets ampZeitlinger 1981

84 Van Zomeren AH Deelman BG Long-term recovery ofvisual reaction time after closed head injury J Neurol Neu-rosurg Psychiatry 197841(5)452ndash57 [PMID 660209]DOI101136jnnp415452

85 Gronwall DM Sampson HD The psychological effectsof concussion Auckland (New Zealand) Auckland Uni-versity Press 1974

86 Gronwall DM Paced auditory serial-addition task Ameasure of recovery from concussion Percept Mot Skills197744(2)367ndash73 [PMID 866038]

87 Tombaugh TN A comprehensive review of the Paced Audi-tory Serial Addition Test (PASAT) Arch Clin Neuro-psychol 200621(1)53ndash76 [PMID 16290063]DOI101016jacn200507006

88 Tombaugh TN Rees L Stormer P Harrison AG Smith AThe effects of mild and severe traumatic brain injury onspeed of information processing as measured by the com-puterized tests of information processing (CTIP) Arch ClinNeuropsychol 200722(1)25ndash36 [PMID 17071052]DOI101016jacn200606013

89 Nelson HE A modified card sorting test sensitive to frontallobe defects Cortex 197612(4)313ndash24 [PMID 1009768]

90 Deelman BG Brouwer WH Van Zomeren AH Saan RJ[Deficiencies in functioning following trauma capitis] InJennekens-Schinkel A editor [Neuropsychology in theNetherlands] Deventer (the Netherlands) Loghum Slat-erus 1980 p 253ndash81 Dutch

91 Spikman JM Kiers HA Deelman BG Van Zomeren AHConstruct validity of concepts of attention in healthy controlsand patients with CHI Brain Cogn 200147(3)446ndash60[PMID 11748900]DOI101006brcg20011320

92 Brouwer WH Van Wolffelaar PC Sustained attention andsustained effort after closed head injury Detection and

010 Hz heart rate variability in a low event rate vigilancetask Cortex 198521(1)111ndash19 [PMID 3987305]

93 Miller E Simple and choice reaction time following severehead injury Cortex 19706(1)121ndash27 [PMID 5426573]

94 Zoccolotti P Matano A Deloche G Cantagallo A Passa-dori A Leclercg M Braga L Cremel N Pittau P Renom MRousseaux M Trauche A Fim B Zimmermann P Patternsof attentional impairment following closed head injury Acollaborative European study Cortex 200036(1)93ndash107[PMID 10728900]DOI101016S0010-9452(08)70839-6

95 Spikman JM Van Zomeren AH Deelman BG Deficits ofattention after closed-head injury Slowness only J ClinExp Neuropsychol 199618(5)755ndash67 [PMID 8941860]DOI10108001688639608408298

96 Van Zomeren AH Van den Burg W Residual complaints ofpatients two years after severe head injury J Neurol Neuro-surg Psychiatry 198548(1)21ndash28 [PMID 3973618]DOI101136jnnp48121

97 Pliszka SR Greenhill LL Crismon ML Sedillo A CarlsonC Conners CK McCracken JT Swanson JM Hughes CWLlana ME Lopez M Toprac MG The Texas ChildrenrsquosMedication Algorithm Project Report of the Texas consen-sus conference panel on medication treatment of childhoodattention-deficithyperactivity disorder Part I Attention-deficithyperactivity disorder J Am Acad Child AdolescPsychiatry 200039(7)908ndash19 [PMID 10892234]DOI10109700004583-200007000-00021

98 Pliszka SR Greenhill LL Crismon ML Sedillo A CarlsonC Conners CK McCracken JT Swanson JM Hughes CWLlana ME Lopez M Toprac MG The Texas ChildrenrsquosMedication Algorithm Project Report of the Texas consen-sus conference panel on medication treatment of childhoodattention-deficithyperactivity disorder Part II TacticsAttention-deficithyperactivity disorder J Am Acad ChildAdolesc Psychiatry 200039(7)920ndash27 [PMID 10892235]DOI10109700004583-200007000-00022

99 Pliszka SR Browne RG Olvera RL Wynne SK A double-blind placebo-controlled study of Adderall and methylpheni-date in the treatment of attention-deficithyperactivitydisorder J Am Acad Child Adolesc Psychiatry 200039(5)619ndash26 [PMID 10802980]DOI10109700004583-200005000-00016

100 Pliszka S Dodson WW Spencer TJ Current treatments ofattention-deficithyperactivity disorder CNS Spectr 20005(5 Suppl 3)S1ndash7 [PMID 18268469]

101 Pliszka SR Liotti M Woldorff MG Inhibitory control inchildren with attention-deficithyperactivity disorder Event-related potentials identify the processing component and tim-ing of an impaired right-frontal response-inhibition mecha-nism Biol Psychiatry 200048(3)238ndash46[PMID 10924667]DOI101016S0006-3223(00)00890-8

787


102 Pliszka SR Pharmacologic treatment of attention-deficithyperactivity disorder Efficacy safety and mechanismsof action Neuropsychol Rev 200717(1)61ndash72[PMID 17242993]DOI101007s11065-006-9017-3

103 Plenger PM Dixon CE Castillo RM Frankowski RFYablon SA Levin HS Subacute methylphenidate treat-ment for moderate to moderately severe traumatic braininjury A preliminary double-blind placebo-controlledstudy Arch Phys Med Rehabil 199677(6)536ndash40[PMID 8831468]DOI101016S0003-9993(96)90291-9

104 Kaelin DL Cifu DX Matthies B Methylphenidate effecton attention deficit in the acutely brain-injured adult ArchPhys Med Rehabil 199677(1)6ndash9 [PMID 8554476]DOI101016S0003-9993(96)90211-7

105 Hornstein A Lennihan L Seliger G Lichtman S SchroederK Amphetamine in recovery from brain injury Brain Inj199610(2)145ndash48 [PMID 8696315]DOI101080026990596124647

106 Napolitano E Elovic EP Qureshi AI Pharmacologicalstimulant treatment of neurocognitive and functional defi-cits after traumatic and non-traumatic brain injury MedSci Monit 200511(6)RA212ndash20 [PMID 15917733]

107 Ripley DL Atomoxetine for individuals with traumaticbrain injury J Head Trauma Rehabil 200621(1)85ndash88[PMID 16456396]DOI10109700001199-200601000-00010

108 Payen D Quintin L Plaisance P Chiron B Lhoste FHead injury Clonidine decreases plasma catecholaminesCrit Care Med 199018(4)392ndash95 [PMID 2180636]

109 Biederman J Petty CR Fried R Kaiser R Dolan CRSchoenfeld S Doyle AE Seidman LJ Faraone SV Educa-tional and occupational underattainment in adults withattention-deficithyperactivity disorder A controlled studyJ Clin Psychiatry 200869(8)1217ndash22 [PMID 18681752]

110 Findling RL McNamara NK Stansbrey RJ Maxhimer RPericlou A Mann A Graham SM A pilot evaluation of thesafety tolerability pharmacokinetics and effectiveness ofmemantine in pediatric patients with attention-deficithyperactivity disorder combined type J Child Adolesc Psy-chopharmacol 200717(1)19ndash33 [PMID 17343551]DOI101089cap20060044

111 Sawyer E Mauro LS Ohlinger MJ Amantadine enhance-ment of arousal and cognition after traumatic brain injuryAnn Pharmacother 200842(2)247ndash52 [PMID 18212258]DOI101345aph1K284

112 Kraus MF Maki PM Effect of amantadine hydrochlorideon symptoms of frontal lobe dysfunction in brain injuryCase studies and review J Neuropsychiatry Clin Neuro-sci 19979(2)222ndash30 [PMID 9144101]

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117 McDonald S Togher L Code C Communication disor-ders following traumatic brain injury Hove (United King-dom) Psychology Press 1999

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119 Geschwind N The organization of language and thebrain Science 1970170(961)940ndash44 [PMID 5475022]DOI101126science1703961940

120 Waxman SG Clinical neuroanatomy 25th ed New York(NY) Lange Medical BooksMcGraw-Hill 2003 p 267ndash69

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124 Hartley LL Cognitive-communicative abilities followingbrain injury A functional approach San Diego (CA) Sin-gular 1995

125 Davis G Aphasiology Disorders and clinical practiceBoston (MA) Allyn and Bacon 2000

126 Ylvisaker M Hanks R Johnson-Greene D Perspectives onrehabilitation of individuals with cognitive impairment after

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127 Brooks N McKinlay W Symington C Beattie A CampsieL Return to work within the first seven years of severehead injury Brain Inj 19871(1)5ndash19 [PMID 3454672]DOI10310902699058709034439

128 Godfrey HP Shaum D Executive functioning and theapplication of social skills following traumatic braininjury Aphasiology 200014(4)433ndash44DOI101080026870300401441

129 Godfrey HP Bishara SN Partridge FM Knight RG Neu-ropsychological impairment and return to work followingsevere closed head injury Implications for clinical manage-ment N Z Med J 1993106(960)301ndash3 [PMID 8341452]

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131 Penn C Cleary J Compensatory strategies in the lan-guage of closed head injured patients Brain Inj 19882(1)3ndash17 [PMID 245879]DOI10310902699058809150928

132 McDonald S Flanagan S Rollins J Kinch J TASIT Anew clinical tool for assessing social perception after trau-matic brain injury J Head Trauma Rehabil 200318(3)219ndash38 [PMID 12802165]DOI10109700001199-200305000-00001

133 Larkins B The application of the ICF in cognitive-commu-nication disorders following traumatic brain injury SeminSpeech Lang 200728(4)334ndash42 [PMID 17935018]DOI101055s-2007-986530

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136 Korsukewitz C Breitenstein C Schomacher M Knecht S[Present status and future possibilities of adjuvant pharma-cotherapy for aphasia] Nervenarzt 200677(4)403ndash15German [PMID 16273340]DOI101007s00115-005-2006-6

137 De Boissezon X Peran P De Boysson C Deacutemonet JFPharmacotherapy of aphasia Myth or reality Brain Lang2007102(1)114ndash25 [PMID 16982084]DOI101016jbandl200607004

138 Egan J Worrall L Oxenham D An internet training inter-vention for people with traumatic brain injury Barriers and

outcomes Brain Inj 200519(8)555ndash68 [PMID 16175810]DOI10108002699050400013659

139 Jordan LC Hillis AE Disorders of speech and languageAphasia apraxia and dysarthria Curr Opin Neurol 200619(6)580ndash85 [PMID 17102697]DOI101097WCO0b013e3280109260

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142 Hornak J Bramham J Rolls ET Morris RG OrsquoDoherty JBullock PR Polkey CE Changes in emotion after circum-scribed surgical lesions of the orbitofrontal and cingulate cor-tices Brain 2003126(Pt 7)1691ndash1712 [PMID 12805109]DOI101093brainawg168

143 Spell LA Frank E Recognition of nonverbal communica-tion of affect following traumatic brain injury J NonverBehav 200024(4)285ndash300DOI101023A1006675230193

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146 Hopkins MJ Dywan J Segalowitz SJ Altered electroder-mal response to facial expression after closed head injuryBrain Inj 200216(3)245ndash57 [PMID 11874616]DOI10108002699050110103346

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148 Borgaro SR Prigatano GP Kwasnica C Alcott S Cutter NDisturbances in affective communication following braininjury Brain Inj 200418(1)33ndash39 [PMID 14660234]DOI1010800269905031000110562

149 Green RE Turner GR Thompson WF Deficits in facialemotion perception in adults with recent traumatic braininjury Neuropsychologia 200442(2)133ndash41[PMID 14644100]DOI101016jneuropsychologia200307005

789


150 Guercio JM Podolska-Schroeder H Rehfeldt RA Usingstimulus equivalence technology to teach emotion recog-nition to adults with acquired brain injury Brain Inj200418(6)593ndash601 [PMID 15204339]DOI10108002699050310001646116

151 McDonald S Flanagan S Social perception deficits aftertraumatic brain injury Interaction between emotion recog-nition mentalizing ability and social communication Neu-ropsychology 200418(3)572ndash79 [PMID 15291735]DOI1010370894-4105183572

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156 Schultz RT Gauthier I Klin A Fulbright RK AndersonAW Volkmar F Skudlarski P Lacadie C Cohen DJ GoreJC Abnormal ventral temporal cortical activity duringface discrimination among individuals with autism andAsperger syndrome Arch Gen Psychiatry 200057(4)331ndash40 [PMID 10768694]DOI101001archpsyc574331

157 Phillips ML Drevets WC Rauch SL Lane R Neurobiol-ogy of emotion perception I The neural basis of normalemotion perception Biol Psychiatry 200354(5)504ndash14[PMID 12946879]DOI101016S0006-3223(03)00168-9

158 Ogai M Matsumoto H Suzuki K Ozawa F Fukuda RUchiyama I Suckling J Isoda H Mori N Takei N fMRIstudy of recognition of facial expressions in high-functioning autistic patients Neuroreport 200314(4)559ndash63 [PMID 12657885]DOI10109700001756-200303240-00006

159 Wang AT Dapretto M Hariri AR Sigman M BookheimerSY Neural correlates of facial affect processing in childrenand adolescents with autism spectrum disorder J Am AcadChild Adolesc Psychiatry 200443(4)481ndash90[PMID 15187809]DOI10109700004583-200404000-00015

160 Radice-Neumann D Zupan B Babbage DR Willer BOverview of impaired facial affect recognition in personswith traumatic brain injury Brain Inj 200721(8)807ndash16[PMID 17676438]DOI10108002699050701504281

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163 Gan C Campbell KA Gemeinhardt M McFadden GTPredictors of family system functioning after brain injuryBrain Inj 200620(6)587ndash600 [PMID 16754284]DOI10108002699050600743725

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168 Piggot J Kwon H Mobbs D Blasey C Lotspeich LMenon V Bookheimer S Reiss AL Emotional attributionin high-functioning individuals with autistic spectrum dis-order A functional imaging study J Am Acad Child Ado-lesc Psychiatry 200443(4)473ndash80 [PMID 15187808]DOI10109700004583-200404000-00014

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790


171 Blair RJ Morris JS Frith CD Perrett DI Dolan RJ Disso-ciable neural responses to facial expressions of sadness andanger Brain 1999122(Pt 5)883ndash93 [PMID 10355673]DOI101093brain1225883

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179 Vuilleumier P Cognitive science Staring fear in the faceNature 2005433(7021)22ndash23 [PMID 15635392]DOI101038433022a

180 Leekam SR Libby SJ Wing L Gould J Taylor C TheDiagnostic Interview for Social and Communication Dis-orders Algorithms for ICD-10 childhood autism andWing and Gould autistic spectrum disorder J Child Psy-chol Psychiatry 200243(3)327ndash42 [PMID 11944875]DOI1011111469-761000024

181 Bartolo A Weisbecker A Coello Y Linguistic and spatialinformation for action Behav Brain Res 2007184(1)19ndash30[PMID 17681618]DOI101016jbbr200706011

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186 Graham DI Raghupathi R Saatman KE Meaney D McIn-tosh TK Tissue tears in the white matter after lateral fluidpercussion brain injury in the rat Relevance to human braininjury Acta Neuropathol 200099(2)117ndash24[PMID 10672317]DOI101007PL00007414

187 Reid-Arndt SA Nehl C Hinkebein J The Frontal Sys-tems Behaviour Scale (FrSBe) as a predictor of commu-nity integration following a traumatic brain injury BrainInj 200721(13ndash14)1361ndash69 [PMID 18066938]DOI10108002699050701785062

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791


193 Lehtonen S Stringer AY Millis S Boake C Englander JHart T High W Macciocchi S Meythaler J Novack TWhyte J Neuropsychological outcome and communityre-integration following traumatic brain injury Theimpact of frontal and non-frontal lesions Brain Inj 200519(4)239ndash56 [PMID 15832870]DOI1010800269905040004310

194 Mazaux JM Masson F Levin HS Alaoui P Maurette PBarat M Long-term neuropsychological outcome and lossof social autonomy after traumatic brain injury Arch PhysMed Rehabil 199778(12)1316ndash20 [PMID 9421984]DOI101016S0003-9993(97)90303-8

195 Kim E Agitation aggression and disinhibition syn-dromes after traumatic brain injury NeuroRehabilitation200217(4)297ndash310 [PMID 12547978]

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198 Grace J Malloy PF Frontal systems behavior scale Pro-fessional manual Lutz (FL) Psychological AssessmentResources Inc 2000

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200 Ready RE Ott BR Grace J Cahn-Weiner DA Apathyand executive dysfunction in mild cognitive impairmentand Alzheimer disease Am J Geriatr Psychiatry 200311(2)222ndash28 [PMID 12611752]

201 Verdejo-Garciacutea A Rivas-Peacuterez C Loacutepez-Torrecillas FPeacuterez-Garciacutea M Differential impact of severity of druguse on frontal behavioral symptoms Addict Behav200631(8)1373ndash82 [PMID 16326022]DOI101016jaddbeh200511003

202 Spinella M Yang B Lester D Prefrontal system dysfunc-tion and credit card debt Int J Neurosci 2004114(10)1323ndash32 [PMID 15370189]DOI10108000207450490476011

203 Flavell JH Green FL Flavell ER Childrenrsquos understandingof the stream of consciousness Child Dev 199364(2)387ndash98 [PMID 8477624]DOI1023071131257

204 Bivona U Ciurli P Barba C Onder G Azicnuda E Sil-vestro D Mangano R Rigon J Formisano R Executivefunction and metacognitive self-awareness after severetraumatic brain injury J Int Neuropsychol Soc 200814(5)862ndash68 [PMID 18764981]DOI101017S1355617708081125

205 Toglia J Kirk U Understanding awareness deficits follow-ing brain injury NeuroRehabilitation 200015(1)57ndash70[PMID 11455082]

206 McDowell S Whyte J DrsquoEsposito M Differential effect ofa dopaminergic agonist on prefrontal function in traumaticbrain injury patients Brain 1998121(Pt 6)1155ndash64[PMID 9648550]DOI101093brain12161155

207 Rapoport MJ McCullagh S Shammi P Feinstein A Cogni-tive impairment associated with major depression followingmild and moderate traumatic brain injury J NeuropsychiatryClin Neurosci 200517(1)61ndash65 [PMID 15746484]DOI101176appineuropsych17161

208 Rapoport MJ McCullagh S Steiner D Feinstein A Theclinical significance of major depression following mildtraumatic brain injury Psychosomatics 200344(1)31ndash37[PMID 12515835]DOI101176appipsy44131

209 Kreutzer JS Seel RT Gourley E The prevalence andsymptom rates of depression after traumatic brain injuryA comprehensive examination Brain Inj 200115(7)563ndash76 [PMID 11429086]DOI10108002699050010009108

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211 Jorge RE Robinson RG Arndt SV Are there symptomsthat are specific for depressed mood in patients with trau-matic brain injury J Nerv Ment Dis 1993181(2)91ndash99[PMID 8426177]DOI10109700005053-199302000-00004

212 Jorge RE Robinson RG Arndt SV Forrester AW GeislerF Starkstein SE Comparison between acute- and delayed-onset depression following traumatic brain injury J Neuro-psychiatry Clin Neurosci 19935(1)43ndash49[PMID 8428134]

213 Jorge RE Robinson RG Arndt SV Starkstein SE For-rester AW Geisler F Depression following traumaticbrain injury A 1 year longitudinal study J Affect Disord199327(4)233ndash43 [PMID 8509524]DOI1010160165-0327(93)90047-N

214 Jorge RE Robinson RG Starkstein SE Arndt SVDepression and anxiety following traumatic brain injuryJ Neuropsychiatry Clin Neurosci 19935(4)369ndash74[PMID 8286933]

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792


216 Jorge RE Robinson RG Moser D Tateno A Crespo-Facorro B Arndt SV Major depression following traumaticbrain injury Arch Gen Psychiatry 200461(1)42ndash50[PMID 14706943]DOI101001archpsyc61142

217 Heron MP Deaths Leading causes for 2004 Nationalvital statistics reports Vol 56 No 5 Hyattsville (MD)National Center for Health Statistics 2007

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219 Carr JR Hoge CW Gardner J Potter R Suicide surveil-lance in the US MilitarymdashReporting and classificationbiases in rate calculations Suicide Life Threat Behav200434(3)233ndash41 [PMID 15385178]DOI101521suli34323342785

220 Kleck G Miscounting suicides Suicide Life Threat Behav198818(3)219ndash36 [PMID 3188138]

221 OrsquoCarroll PW A consideration of the validity and reliabil-ity of suicide mortality data Suicide Life Threat Behav198919(1)1ndash16 [PMID 2652382]

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226 Bushnik T Englander J Wright J The experience offatigue in the first 2 years after moderate-to-severe trau-matic brain injury A preliminary report J Head TraumaRehabil 200823(1)17ndash24 [PMID 18219231]DOI10109701HTR00003087178059022

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232 Rapoport MJ Chan F Lanctot K Herrmann N McCul-lagh S Feinstein A An open-label study of citalopram formajor depression following traumatic brain injury J Psy-chopharmacol 200822(8)860ndash64 [PMID 18208921]DOI1011770269881107083845

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793


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242 Pope HG Jr McElroy SL Satlin A Hudson JI Keck PEJr Kalish R Head injury bipolar disorder and response tovalproate Compr Psychiatry 198829(1)34ndash38[PMID 3125002]DOI1010160010-440X(88)90035-1

243 Moore GJ Bebchuk JM Wilds IB Chen G Manji HKLithium-induced increase in human brain grey matterLancet 2000356(9237)1241ndash42 [PMID 11072948]DOI101016S0140-6736(00)02793-8

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245 Van Reekum R Cohen T Wong J Can traumatic braininjury cause psychiatric disorders J NeuropsychiatryClin Neurosci 200012(3)316ndash27 [PMID 10956565]DOI101176appineuropsych123316

246 Turnbull SJ Campbell EA Swann IJ Post-traumaticstress disorder symptoms following a head injury Doesamnesia for the event influence the development of symp-toms Brain Inj 200115(9)775ndash85 [PMID 11516346]DOI10108002699050110034334

247 Creamer M OrsquoDonnell ML Pattison P Amnesia trau-matic brain injury and posttraumatic stress disorder Amethodological inquiry Behav Res Ther 200543(10)1383ndash89 [PMID 16086988]DOI101016jbrat200411001

248 Gil S Caspi Y Ben-Ari IZ Koren D Klein E Does memoryof a traumatic event increase the risk for posttraumatic stressdisorder in patients with traumatic brain injury A prospec-tive study Am J Psychiatry 2005162(5)963ndash69[PMID 15863799]DOI101176appiajp1625963

249 Hibbard MR Uysal S Kepler K Bogdany J Silver JAxis I psychopathology in individuals with traumaticbrain injury J Head Trauma Rehabil 199813(4)24ndash39[PMID 9651237]DOI10109700001199-199808000-00003

250 Glaesser J Neuner F Luumltgehetmann R Schmidt R ElbertT Posttraumatic stress disorder in patients with traumaticbrain injury BMC Psychiatry 200445[PMID 15113439]DOI1011861471-244X-4-5

251 Sumpter RE McMillan TM Misdiagnosis of post-traumaticstress disorder following severe traumatic brain injury Br J

Psychiatry 2005186423ndash26 [PMID 15863748]DOI101192bjp1865423

252 Hoge CW McGurk D Thomas JL Cox AL Engel CCCastro CA Mild traumatic brain injury in US soldiersreturning from Iraq N Engl J Med 2008358(5)453ndash63[PMID 18234750]DOI101056NEJMoa072972

253 Schneiderman AI Braver ER Kang HK Understandingsequelae of injury mechanisms and mild traumatic braininjury incurred during the conflicts in Iraq and Afghani-stan Persistent postconcussive symptoms and posttrau-matic stress disorder Am J Epidemiol 2008167(12)1446ndash52 [PMID 18424429]DOI101093ajekwn068

254 Elzinga BM Bremner JD Are the neural substrates ofmemory the final common pathway in posttraumatic stressdisorder (PTSD) J Affect Disord 200270(1)1ndash17[PMID 12113915]DOI101016S0165-0327(01)00351-2

255 Ehlers A Clark DM A cognitive model of posttraumaticstress disorder Behav Res Ther 200038(4)319ndash45[PMID 10761279]DOI101016S0005-7967(99)00123-0

256 Ashford JW Miller TW Effects of trazodone on sleep inpatients diagnosed with post-traumatic disorder (PTSD)J Contemp Psychother 199626(3)221ndash33DOI101007BF02307588

257 Raskind MA Peskind ER Hoff DJ Hart KL HolmesHA Warren D Shofer J OrsquoConnell J Taylor F Gross CRohde K McFall ME A parallel group placebo con-trolled study of prazosin for trauma nightmares and sleepdisturbance in combat veterans with post-traumatic stressdisorder Biol Psychiatry 200761(8)928ndash34[PMID 17069768]DOI101016jbiopsych200606032

258 Ashford JW Jarvik L Alzheimerrsquos disease Does neuronplasticity predispose to axonal neurofibrillary degenera-tion N Engl J Med 1985313(6)388ndash89[PMID 4010760]

259 Van den Heuvel C Thornton E Vink R Traumatic braininjury and Alzheimerrsquos disease A review Prog BrainRes 2007161303ndash16 [PMID 17618986]DOI101016S0079-6123(06)61021-2

260 Hall ED Bryant YD Cho W Sullivan PG Evolution ofpost-traumatic neurodegeneration after controlled corti-cal impact traumatic brain injury in mice and rats asassessed by the de Olmos silver and Fluoro-jade stainingmethods J Neurotrauma 200825(3)235ndash47[PMID 18352837]DOI101089neu20070383

261 Bremner JD Elzinga B Schmahl C Vermetten E Structuraland functional plasticity of the human brain in posttraumatic

794


stress disorder Prog Brain Res 2008167171ndash86[PMID 18037014]DOI101016S0079-6123(07)67012-5

262 Mayou RA Black J Bryant B Unconsciousness amnesiaand psychiatric symptoms following road traffic accidentinjury Br J Psychiatry 2000177540ndash45[PMID 11102330]DOI101192bjp1776540

263 Stein DJ Ipser JC Seedat S Pharmacotherapy for posttraumatic stress disorder (PTSD) Cochrane Database SystRev 2006(1)CD002795 [PMID 16437445]

264 Krystal AD Davidson JR The use of prazosin for thetreatment of trauma nightmares and sleep disturbance incombat veterans with post-traumatic stress disorder BiolPsychiatry 200761(8)925ndash27 [PMID 17397667]DOI101016jbiopsych200702020

265 Friedman MJ Toward rational pharmacotherapy for post-traumatic stress disorder An interim report Am J Psychi-atry 1988145(3)281ndash85 [PMID 2894174]

266 Pae CU Lim HK Peindl K Ajwani N Serretti A PatkarAA Lee C The atypical antipsychotics olanzapine andrisperidone in the treatment of posttraumatic stress disor-der A meta-analysis of randomized double-blind pla-cebo-controlled clinical trials Int Clin Psychopharmacol200823(1)1ndash8 [PMID 18090502]DOI101097YIC0b013e32825ea324

267 Thomsen IV Late outcome of very severe blunt headtrauma A 10ndash15 year second follow-up J Neurol Neuro-surg Psychiatry 198447(3)260ndash68 [PMID 6707671]DOI101136jnnp473260

268 Sachdev P Smith JS Cathcart S Schizophrenia-like psy-chosis following traumatic brain injury A chart-baseddescriptive and case-control study Psychol Med 200131(2)231ndash39 [PMID 11232911]DOI101017S0033291701003336

269 Fujii DE Ahmed I Risk factors in psychosis secondary totraumatic brain injury J Neuropsychiatry Clin Neurosci200113(1)61ndash69 [PMID 11207331]DOI101176appineuropsych13161

270 Fujii DA Ahmed I Hishinuma E A neuropsychologicalcomparison of psychotic disorder following traumaticbrain injury traumatic brain injury without psychotic dis-order and schizophrenia J Neuropsychiatry Clin Neuro-sci 200416(3)306ndash14 [PMID 15377737]DOI101176appineuropsych163306

271 Butler PV Diurnal variation in Cotardrsquos syndrome (copre-sent with Capgras delusion) following traumatic braininjury Aust N Z J Psychiatry 200034(4)684ndash87[PMID 10954402]DOI101046j1440-1614200000758x

272 Umansky R Geller V Olanzapine treatment in an organichallucinosis patient Int J Neuropsychopharmacol 2000

3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723

273 Cohen-Mansfield J Marx MS Rosenthal AS A descrip-tion of agitation in a nursing home J Gerontol 198944(3)M77ndash84 [PMID 2715584]

274 Greve KW Sherwin E Stanford MS Mathias C Love JRamzinski P Personality and neurocognitive correlates ofimpulsive aggression in long-term survivors of severetraumatic brain injury Brain Inj 200115(3)255ndash62[PMID 11260773]DOI101080026990501300005695

275 Tateno A Jorge RE Robinson RG Clinical correlates ofaggressive behavior after traumatic brain injury J Neuro-psychiatry Clin Neurosci 200315(2)155ndash60[PMID 12724455]DOI101176appineuropsych152155

276 Max JE Robertson BA Lansing AE The phenomenologyof personality change due to traumatic brain injury in chil-dren and adolescents J Neuropsychiatry Clin Neurosci200113(2)161ndash70 [PMID 11449023]DOI101176appineuropsych132161

277 Gomez-Hernandez R Max JE Kosier T Paradiso S Rob-inson RG Social impairment and depression after trau-matic brain injury Arch Phys Med Rehabil 199778(12)1321ndash26 [PMID 9421985]DOI101016S0003-9993(97)90304-X

278 Rao N Jellinek HM Woolston DC Agitation in closedhead injury Haloperidol effects on rehabilitation out-come Arch Phys Med Rehabil 198566(1)30ndash34[PMID 3966865]

279 Bogner JA Corrigan JD Fugate L Mysiw WJ ClinchotD Role of agitation in prediction of outcomes after trau-matic brain injury Am J Phys Med Rehabil 200180(9)636ndash44 [PMID 11523965]DOI10109700002060-200109000-00002

280 Elliott ML Biever LS Head injury and sexual dysfunc-tion Brain Inj 199610(10)703ndash17 [PMID 8879661]DOI101080026990596123972

281 Makulski DD Taber KH Chiou-Tan FY Neuroimaging inposttraumatic hypopituitarism J Comput Assist Tomogr200832(2)324ndash28 [PMID 18379326]DOI101097RCT0b013e3181636ed4

282 Cloute K Mitchell A Yates P Traumatic brain injury andthe construction of identity A discursive approach Neuro-psychol Rehabil 200818(5ndash6)651ndash70 [PMID 17852757]DOI10108009602010701306989

283 Schopp LH Good GE Barker KB Mazurek MO Hatha-way SL Masculine role adherence and outcomes amongmen with traumatic brain injury Brain Inj 200620(11)1155ndash62 [PMID 17123932]DOI10108002699050600983735

795


284 Strous R Shoenfeld Y To smell the immune systemOlfaction autoimmunity and brain involvement Autoim-mun Rev 20066(1)54ndash60 [PMID 17110318]DOI101016jautrev200607002

285 Kapoor N Ciuffreda KJ Vision disturbances followingtraumatic brain injury Curr Treat Options Neurol 20024(4)271ndash80 [PMID 12036500]DOI101007s11940-002-0027-z

286 Nampiaparampil DE Prevalence of chronic pain aftertraumatic brain injury A systematic review JAMA 2008300(6)711ndash19 [PMID 18698069]DOI101001jama3006711

Submitted for publication September 3 2008 Acceptedin revised form May 7 2009

Neuropsychiatric diagnosis and management of chronic sequelae of war-related mild to moderate traumatic brain injury

Joshua D Halbauer MD1-3 J Wesson Ashford MD PhD1-3 Jamie M Zeitzer PhD1-3 Maheen M Adamson PhD1-3 Henry L Lew MD PhD14 Jerome A Yesavage MD1-3

1Department of Veterans Affairs (VA) Palo Alto Health Care System Palo Alto CA 2VA Sierra-Pacific Mental Illness Research E

INTRODUCTION


TBI Severity

Figure 1

Posttraumatic Amnesia

White Matter Integrity

Concussion


Postconcussion Syndrome

Neuropsychiatric Sequelae

Clinical Biopsychosocial Approach to TBI

NEUROPSYCHIATRIC SYMPTOMS AND MANAGEMENT

Cognitive Dysfunctions

Figure 2

Memory

Figure 3

Attention

Communication Linguistics-Speech and Language


Visuospatial Perception and Sensory-Motor Integration

Executive Function

Neurobehavioral Disorders

Mood

Table

Affect

PTSD and Other Anxiety Disorders

Psychosis

Agitation and Aggression

Sexual Health and Libido

Somatosensory Disruptions

Somatic Symptoms-Headache and Chronic Pain Syndromes

Substance Dependence

DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

758


head face and neck injuries particularly traumatic braininjuries (TBIs) [2] Identifying areas of functional cogni-tive and psychiatric impairments in those with TBI fromthese conflicts has presented a variety of challenges Vari-ous organizations such as the American Congress ofRehabilitation Medicine (ACRM) the American Acad-emy of Neurology (AAN) and the American PsychiatricAssociation have different diagnostic classifications thatdelineate specific factors directly related to TBI and itslong-term sequelae These classifications are limited inmany respects and present challenges for diagnosis andultimately treatment These classifications will be dis-cussed in terms of their nosology possible underlying neu-robiology applicability and utility for patient treatmentparticularly from a psychopharmacological perspective

Although TBI is caused by physical head trauma thechronic sequelae of TBI are defined in terms of clusters ofneuropsychiatric symptoms (Figure 1) (1) cognitive dys-functions (memory attention language visuospatial cog-nition sensory-motor integration affect recognition andexecutive function) (2) neurobehavioral disorders (moodaffect anxiety posttraumatic stress psychotic sleep andlibidinal disorders) (3) somatosensory disruptions (changesin smell vision hearing equilibrium taste and soma-tosensory perception) (4) somatic symptoms (headachechronic pain) and (5) substance dependence This articlewill examine incidence prevalence neurobiological basesdiagnostic criteria and brief instruments for assessing thesesymptom clusters and then provide clinicians withapproaches for neuropsychiatric treatment Furthermorewith this organizational approach applied to patients withTBI impairments found in particular aspects of daily func-tioning (eg reduced employment impaired social relation-ships and decreased quality of life [QOL]) [3] can beidentified and referred for psychosocial interventions

A prior study examined TBI from a similar multifac-torial perspective but found little ldquohigh-classrdquo evidenceon which to base any treatment recommendations forpatients with TBI [4] In contrast the current formulationwith use of neurobiological understanding is based onparsing symptoms into common nosological classifica-tions not usually associated with TBI and on borrowingfrom the extensive experience with those related disor-ders for developing treatment options The applicablecommon diagnostic entities include Alzheimer disease(AD) posttraumatic stress disorder (PTSD) depressionand attention deficit hyperactivity disorder (ADHD) Inaddition the formulation presented in this review is

based on evidence that neuroplastic systems exist in thebrain for self-repair and adaptation after brain injury fur-thermore extensive evidence suggests that numerousinterventions can facilitate these repair mechanisms evenif memory function is impaired Accordingly a broadarray of reasonable treatments exists that can be appliedto managing the chronic sequelae of TBI

This review will emphasize the recognition of the typesof problems commonly seen in other disorders that areassociated with TBI and then discuss the application of themany specific psychopharmacological treatments that havebeen demonstrated to have substantial efficacy in thoserelated conditions to the treatment of patients with TBIThis review will mention rehabilitative neuropsychologicaland behavioral treatment options but a full review of theseis beyond the scope of this discussion


Current classifications of TBI-related problems cor-respond only roughly with the actual conditions andlong-term outcomes These classifications (delineated inthe following list) generally relate to the acute TBI par-ticularly the presentation and symptoms apparent in thefirst 24 hours after the TBI have not been based on lon-gitudinal observational studies [5] and provide little reli-able evidence for an association between clinical factorsand outcome [6] For example the International Classifi-cation of Diseases-10th Edition (ICD-10) lists the follow-ing relevant codesbull F068 Other specified mental disorders due to brain

damage and dysfunction and to physical disease indexbull F072 Postconcussion syndrome (PCS)bull F50ndashF59 Behavioral syndromes associated with physi-

ological disturbances and physical factorsbull G90ndashG99 Other disorders of the nervous systembull S060 Concussion

Clearly these classifications do not adequately coverthe complex problems that often result from TBI Someother classifications that have been applied to patients whohave suffered TBI are provided in the following sections

TBI SeverityA primary concern in treating a patient with a TBI is

determining the severity of the injury Injury severitydepends on a variety of factors related to the nature of the

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All Ages 177 46 110 24

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DISCUSSION


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CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























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INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

759












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All Ages 177 46 110 24

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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












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INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

760














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All Ages 177 46 110 24

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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

761












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All Ages 177 46 110 24

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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













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INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

762








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All Ages 177 46 110 24

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DISCUSSION


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CONCLUSIONS



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ACKNOWLEDGMENTS


REFERENCES













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INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

763









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All Ages 177 46 110 24

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DISCUSSION


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CONCLUSIONS



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ACKNOWLEDGMENTS


REFERENCES













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INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

764
















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All Ages 177 46 110 24

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DISCUSSION


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CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

765











766











767












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All Ages 177 46 110 24

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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

766











767












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All Ages 177 46 110 24

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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

767












768













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All Ages 177 46 110 24

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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

768













769










770












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All Ages 177 46 110 24

775








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780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

769










770












771












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All Ages 177 46 110 24

775








776













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780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

770












771












772










773












774













All Ages 177 46 110 24

775








776













777









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780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























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3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

771












772










773












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All Ages 177 46 110 24

775








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DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

772










773












774













All Ages 177 46 110 24

775








776













777









778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

773












774













All Ages 177 46 110 24

775








776













777









778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

774













All Ages 177 46 110 24

775








776













777









778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

775








776













777









778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

776













777









778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

777









778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

778














779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

779













780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

780











DISCUSSION


781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

781







CONCLUSIONS



782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

782



ACKNOWLEDGMENTS


REFERENCES













783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

783


200426(5)628ndash44 [PMID 15370385]DOI10108013803390490504443























784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

784



























785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

785


























786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

786


























787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

787



























788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

788



























789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

789























790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

790
























791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

791

























792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

792


























793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

793

























794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

794














3(1)81ndash82 [PMID 11343582]DOI101017S1461145700001723












795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

795









INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES




INTRODUCTION


TBI Severity

Figure 1



Concussion







Figure 2

Memory

Figure 3

Attention




Executive Function


Mood

Table

Affect


Psychosis






DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

neuropsychiatric diagnosis and management of chronic sequelae · parsing symptoms into common...

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