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The purpose of this chapter is to summarize some key topics discussed in this volume and describe trends suggesting the direction of future traumatic brain injury (TBI) research. Interest in, and funding for, TBI has ebbed and flowed with the public awareness of injury risk from combat, sports, or everyday life. Advances in acute resuscitation, emergency response systems, and early management have had a major impact on survival after TBI, while recent research has emphasized underlying genetic substrates and the molecular mechanisms of brain injury, repair, and neuroplasticity. This in turn impacts not only on primary and secondary neuroprotection strategies for minimizing injury, but also on the other critical remaining challenge, that of identification and validation of optimal strategies for physical and cognitive TBI rehabilitation. New information also highlights long-term degenerative conditions associated with earlier TBI and mediated by a signature cascade of abnormal molecular processes. Thus, TBI has emerged as a recognized significant public health risk with both immediate and lifelong repercussions. The linkage of a TBI to late-life neurodegenerative diseases, the observation of persistent pathologic processes including neuroinflammation and accumulation of tau protein, as well as individual differences in the genetic predisposition for brain repair and plasticity should lead to meaningful translational research with a significant impact on the efficacy and cost-efficiency of acute and chronic treatment for TBI survivors., (© 2015 Elsevier B.V. All rights reserved.)

Post-traumatic epilepsy (PTE) remains one of the most intractable consequences of traumatic brain injury (TBI) and its incidence and characteristics have remained relatively constant through the past century, in spite of significant advances in medical management. Survivors of military penetrating head injury (PHI) suffer by far the highest incidence of (PTE), ranging from 32% to 55%, and they are a particularly valuable group in which to study this complication. Clues to the high incidence of PTE in PHI survivors are likely related to dural penetration with free intracerebral blood, and perhaps to retained ferric metal fragments. The failure of well-reasoned and well-conducted trials evaluating conventional anticonvulsants for prevention of PTE also offers important clues and has forced us to reconsider our approach to management. Here we briefly review the clinical characteristics of PHI patients with PTE, with an emphasis on clues to pathogenesis that can generalize to other types of head injury; followed by a discussion of the pathogenetic mechanisms common to epilepsy, PHI, and TBI in general, with an eye to future neuroprotection and PTE prophylaxis. Future studies that more directly target the basic pathogenesis of TBI, including neuroinflammation and lipid peroxidation with their consequent excitotoxic mechanisms and aberrant regeneration, may ultimately prove to be more fruitful in the struggle to understand and control this especially stubborn complication of head injury., (© 2015 Elsevier B.V. All rights reserved.)

Objectives: To determine the relative efficacy of 2 different acute traumatic brain injury (TBI) rehabilitation approaches: cognitive didactic versus functional-experiential, and secondarily to determine relative efficacy for different patient subpopulations., Design: Randomized, controlled, intent-to-treat trial comparing 2 alternative TBI treatment approaches., Setting: Four Veterans Administration acute inpatient TBI rehabilitation programs., Participants: Adult veterans or active duty military service members (N=360) with moderate to severe TBI., Interventions: One and a half to 2.5 hours of protocol-specific cognitive-didactic versus functional-experiential rehabilitation therapy integrated into interdisciplinary acute Commission for Accreditation of Rehabilitation Facilities-accredited inpatient TBI rehabilitation programs with another 2 to 2.5 hours daily of occupational and physical therapy. Duration of protocol treatment varied from 20 to 60 days depending on the clinical needs and progress of each participant., Main Outcome Measures: The 2 primary outcome measures were functional independence in living and return to work and/or school assessed by independent evaluators at 1-year follow-up. Secondary outcome measures consisted of the FIM, Disability Rating Scale score, and items from the Present State Exam, Apathy Evaluation Scale, and Neurobehavioral Rating Scale., Results: The cognitive-didactic and functional-experiential treatments did not result in overall group differences in the broad 1-year primary outcomes. However, analysis of secondary outcomes found differentially better immediate posttreatment cognitive function (mean+/-SD cognitive FIM) in participants randomized to cognitive-didactic treatment (27.3+/-6.2) than to functional treatment (25.6+/-6.0, t332=2.56, P=.01). Exploratory subgroup analyses found that younger participants in the cognitive arm had a higher rate of returning to work or school than younger patients in the functional arm, whereas participants older than 30 years and those with more years of education in the functional arm had higher rates of independent living status at 1 year posttreatment than similar patients in the cognitive arm., Conclusions: Results from this large multicenter randomized controlled trial comparing cognitive-didactic and functional-experiential approaches to brain injury rehabilitation indicated improved but similar long-term global functional outcome. Participants in the cognitive treatment arm achieved better short-term functional cognitive performance than patients in the functional treatment arm. The current increase in war-related brain injuries provides added urgency for rigorous study of rehabilitation treatments. (http://ClinicalTrials.gov ID# NCT00540020.).

The objective of this study was to examine the prevalence of long-term psychiatric, neurologic, and psychosocial morbidities of self-reported mild traumatic brain injury (MTBI). A cross-sectional cohort sample of three groups was examined: those who had not been injured in a motor vehicle accident nor had a MTBI (n = 3,214); those who had been injured in an accident but did not have a MTBI (n = 539); and those who had a MTBI with altered consciousness (n = 254). Logistic regression analyses were used to model odds ratios for the association between group and outcome variables while controlling demographic characteristics, comorbid medical conditions, and early-life psychiatric problems. Compared with uninjured controls, MTBI increased the likelihood of depression and postconcussion syndrome. MTBI also was associated with peripheral visual imperceptions and impaired tandem gait. Similarly, the MTBI group had poorer psychosocial outcomes including an increased likelihood of self-reported disability, underemployment, low income, and marital problems. Results suggest that MTBI can have adverse long-term psychiatric, neurologic, and psychosocial morbidities.

Catechol-O-methyltransferase (COMT) is thought to functionally modulate dopamine neurons, thus likely influencing frontal-executive functioning. High enzyme activity (COMT Val) and low enzyme activity (COMT Met) are functional polymorphisms resulting from a G to A transition in exon 4 (codon 158) of the human COMT gene. Decreased cortical dopamine should result in poorer executive functioning. Therefore, the authors hypothesized that individuals with traumatic brain injury (TBI) and the low enzyme activity polymorphism would perform better on tests of executive functioning than individuals with the high enzyme activity polymorphism. One hundred thirteen individuals referred to the Defense and Veterans Brain Injury Center underwent a comprehensive TBI evaluation and were genotyped for the COMT polymorphism. Comparison of mean differences among the COMT genotype groups for several measures of aspects of executive functioning was conducted using analysis of variance (ANOVA) with adjustment for multiple comparisons. Homozygotes for the higher activity allele made more perseverative responses on the Wisconsin Card Sorting Test, while homozygotes for the lower activity allele had the least number of perseverative responses. While it cannot be determined whether TBI influenced the association of COMT Val158Met to executive functioning, these data extend the known relationship of genotype to executive performance seen in healthy comparison subjects and individuals with schizophrenia to individuals with TBI.

Background: This study presents self-reported traumatic brain injury (TBI) prevalence rates for 2,337 active duty U.S. Army soldiers who underwent baseline testing as part of a larger study of military TBI., Methods: A computerized self-report questionnaire was administered to a convenience sample of 2,337 highly functioning active-duty soldiers at Fort Bragg, North Carolina, who underwent baseline testing during a 13-month period in 1999 and 2000 as part of a larger ongoing Institutional Review Board-approved study examining the consequences of brain injuries among paratroopers., Results: Approximately 23% of all of the soldiers surveyed reported sustaining a TBI after joining the Army. More than twice as many paratroopers reported sustaining TBI after joining the Army than did nonparatroopers (p < 0.001). Parachute-related TBI accounted for this difference. Nearly all of these injuries were mild. Less than 2% of paratroopers and no nonparatroopers reported loss of consciousness lasting more than 20 minutes. It was also shown that paratroopers with a history of TBI before joining the Army had a higher prevalence of TBI while serving in the Army (35%) than paratroopers without prior TBI (27.2%) (p = 0.002)., Conclusion: This study demonstrates that parachuting appears to be a risk factor for mild TBI in the U.S. Army and that paratroopers with a history of TBI before joining the Army might be at somewhat increased risk of sustaining additional TBI while serving in the Army.

Crick and Koch proposed that the claustrum plays a crucial role in consciousness. Their proposal was based on the structure and connectivity of the claustrum that suggested it had a role in coordinating a set of diverse brain functions. Given the few human studies investigating this claim, we decided to study the effects of claustrum lesions on consciousness in 171 combat veterans with penetrating traumatic brain injuries. Additionally, we studied the effects of claustrum lesions and loss of consciousness on long-term cognitive abilities. Claustrum damage was associated with the duration , but not frequency , of loss of consciousness, indicating that the claustrum may have an important role in regaining, but not maintaining, consciousness. Total brain volume loss, but not claustrum lesions, was associated with long-term recovery of neurobehavioral functions. Our findings constrain the current understanding of the neurobehavioral functions of the claustrum and its role in maintaining and regaining consciousness. [ABSTRACT FROM AUTHOR]

Context: Functional outcome in relation to CT findings in traumatic brain injured (TBI) patients is not well established in relation to cognitive and vocational outcome. Objective: To investigate the possible correlation between relatively simple quantitative radiological measurements and cognitive and vocational outcome. Design: Retrospective analysis of quantitative assessment of CT studies in relation to post-injury cognitive changes and vocational outcome. Setting: US Army Medical Centre. Patients: 74 penetrating head injured (PHI) and 37 closed head injured (CHI) Vietnam war veterans. Outcome measures: The Armed Forces Qualification Test (AFQT); Disability score; Return to work. Results: Total brain volume loss, third ventricle width (3VW), ventricular score (VS), and septumcaudate distance (SCD) were significantly related to cognitive change and return to work in PHI patients. Volume loss and 3VW were the most valuable radiologic predictors of outcome in multivariate linear and logistic regression models for both CHI and PHI. Conclusion: 3VW on late CT scans following traumatic brain injury is a powerful predictor of overall long-term cognitive outcomes and potential for return to work. [ABSTRACT FROM AUTHOR]

Objective: To ascertain the value of relatively simple quantitative radiologic measurements after head injury. Despite major advances in neuroradiology, analysis and reporting of imaging studies is based primarily on individual subjective and local experience, rather than on reproducible, standardized parameters; reliance on newer technologies can improve care, but also raises diagnostic costs. Design: Blinded, retrospective, quantitative assessment of computerized tomography studies done some 14 years post-injury. Outcome measures: Frontal horn width (FHW); septum-caudate distance (SCD); temporal horn width (THW); interuncal distance (IUD); third ventricle width (3VW); ventricular score (VS); sulcal width (SW); gray-white matter discriminability (GWMD) and subjective assessment of atrophy (SAOA). Results: Diffuse and frontal damage was noted in both closed (CHI) and penetrating (PHI) head injury groups. Enlargement of frontal lobe parameters (septum caudate distance and frontal horn width suggest frontal injury in both closed and penetrating traumatic brain injury (TBI). Temporal horn width and inter-uncal distance were related to VS, 3VW and FHW in closed, but not in penetrating head injury. Conclusions: Simple linear CSF space measurements are correlated with volumetric and parenchymal measures, and can represent valuable and reliable low-cost quantitative measures of long term brain damage after TBI. [ABSTRACT FROM AUTHOR]

Biased responding on the Sternberg Recognition Memory Test was observed in four patients with traumatic brain injury. None of these individuals met the Diagnostic and Statistical Manual's (DSM-IV) criteria for malingering. Individual recognition memory scores were high shortly after injury, declined to chance or below at the 6- and 12-month evaluations, and then showed substantial recovery by the 24-month evaluation. Recall memory performance actually declined slightly across this same 2-year period. Recognition memory scores were related to the extent to which the patients endorsed somatic items on the Hamilton Rating Scale for Depression (HAM-D). Poor performance was associated with high somatic scores. The relationship between memory and somatic scores on the HAM-D in this case series suggests that unconscious processes can influence memory performance and, because of this, that clinicians should not use such performance as a primary indicator of malingering. More importantly, biased responding and actual memory deficits may coexist. This is indicated in the current cases by the failure of recall memory to improve during the 2 years these patients were followed. [ABSTRACT FROM AUTHOR]

Presents a study to evaluate the efficacy of inpatient cognitive rehabilitation for patients with Traumatic Brain Injury (TBI). Context; Objective; Design and Setting; Patients; Interventions; Main outcome measures; Results; Conclusions.

Objective : To design and describe an effective rehabilitation programme for use in an ongoing trial on the efficacy of multidisciplinary brain injury rehabilitation for moderately head injured military service members. Design : Treatment arm of a randomized control trial. Setting : US military tertiary care hospital inpatient rehabilitation programme. Patients : Sixty seven active duty military with moderate to severe TBI who were randomized to the treatment arm of the protocol. Intervention : Eight week rehabilitation programme combining group and individual therapies with an inpatient milieu-oriented neuropsychological focus. Group therapies included fitness, planning and organization, cognitive skills, work skills, medication, and milieu groups, and community re-entry outings. Individual therapy included neuropsychology, work therapy, occupational therapy, and speech and language pathology. Main outcome measures : Successful return to work and return to duty. Results : At 1 year follow-up, 64 patients returned to work (96%) and 66% (44/67) returned to duty. Conclusion : The described rehabilitation programme demonstrates one successful effort to rehabilitate active duty military service members with TBI who have the potential to return to duty. [ABSTRACT FROM AUTHOR]