Compensation and malingering in traumatic brain injury: a dose-response relationship?

The purpose of this study was to determine if there is a dose-response relationship between potential monetary compensation and failure on psychological indicators of malingering in traumatic brain injury. 332 traumatic brain injury patients were divided into three groups based on incentive to perform poorly on neuropsychological testing: no incentive; limited incentive as provided by State law; high incentive as provided by Federal law. The rate of failure on five well-validated malingering indicators across these groups was examined. Cases handled under Federal workers compensation laws showed considerably higher rates of failure and diagnosable malingering than cases handled under State law. The findings indicate that monetary compensation associated with workers compensation claims is a major motive for exaggeration and malingering of problems attributed to work-related brain injuries. The clinician's index of suspicion regarding exaggeration and malingering of symptoms and deficits should be much higher in the context of Federal workers compensation claims, particularly in patients who have suffered only mild traumatic brain injury.     

The predictive brain state: timing deficiency in traumatic brain injury?

Attention and memory deficits observed in traumatic brain injury (TBI) are postulated to result from the shearing of white matter connections between the prefrontal cortex, parietal lobe, and cerebellum that are critical in the generation, maintenance, and precise timing of anticipatory neural activity. These fiber tracts are part of a neural network that generates predictions of future states and events, processes that are required for optimal performance on attention and working memory tasks. The authors discuss the role of this anticipatory neural system for understanding the varied symptoms and potential rehabilitation interventions for TBI. Preparatory neural activity normally allows the efficient integration of sensory information with goal-based representations. It is postulated that an impairment in the generation of this activity in traumatic brain injury (TBI) leads to performance variability as the brain shifts from a predictive to reactive mode. This dysfunction may constitute a fundamental defect in TBI as well as other attention disorders, causing working memory deficits, distractibility, a loss of goal-oriented behavior, and decreased awareness.     

Dysautonomia after traumatic brain injury: a forgotten syndrome?

OBJECTIVES: To better establish the clinical features, natural history, clinical management, and rehabilitation implications of dysautonomia after traumatic brain injury, and to highlight difficulties with previous nomenclature. METHODS: Retrospective file review on 35 patients with dysautonomia and 35 sex and Glasgow coma scale score matched controls. Groups were compared on injury details, CT findings, physiological indices, and evidence of infections over the first 28 days after injury, clinical progress, and rehabilitation outcome. RESULTS: the dysautonomia group were significantly worse than the control group on all variables studied except duration of stay in intensive care, the rate of clinically significant infections found, and changes in functional independence measure (FIM) scores. CONCLUSIONS: Dysautonomia is a distinct clinical syndrome, associated with severe diffuse axonal injury and preadmission hypoxia. It is associated with a poorer functional outcome; however, both the controls and patients with dysautonomia show a similar magnitude of improvement as measured by changes in FIM scores. It is argued that delayed recognition and treatment of dysautonomia results in a preventable increase in morbidity.     

Barriers in the brain: a renaissance?

Barrier mechanisms regulate the exchange of molecules between the brain's internal milieu and the rest of the body. Correct functioning of these mechanisms is critical for normal brain activity, maintenance and development. Dysfunctional brain barrier mechanisms contribute to the pathology of neurological conditions, ranging from trauma to neurodegenerative diseases, and provide obstacles for successful delivery of potentially beneficial pharmaceutical agents. Previous decades of research have yielded insufficient understanding for solving brain barrier problems in vivo. However, an awakening of interest and novel approaches are providing insight into these mechanisms in developing and dysfunctional brain, as well as suggesting new approaches to circumventing brain barrier mechanisms to get therapeutic agents into the central nervous system.     

Connective tissue growth factor: a novel player in tissue reorganization after brain injury?

Recent studies have suggested a role of connective tissue growth factor (CTGF) in repair processes of the skin as well as in various types of fibrotic disease. However, a function of this molecule in central nervous system (CNS) repair has not been demonstrated yet. In this study we analysed the temporal and spatial expression pattern of CTGF after unilateral kainic acid lesions of the hippocampal CA3 region in mice. We found a strong induction of CTGF mRNA and protein expression in neurons and glial cells of the lesioned hippocampus. Interestingly, increased expression of this mitogen was accompanied by elevated levels of the extracellular matrix molecule fibronectin, which is a known target of CTGF action. Therefore, our data indicate a novel function of CTGF in postlesional restructuring of the hippocampus, where it possibly participates in glial scar formation.     

Targeting inflammation to reduce brain injury in growth restricted newborns: a potential treatment?

<正>Introduction:Intrauterine growth restriction(IUGR)is commonly caused by placental insufficiency,resulting in a chronic hypoxic environment and subsequent abnormal fetal development.The developing brain is particularly vulner-     

Neuroprotective effects of lithium treatment following hypoxic–ischemic brain injury in neonatal rats

Purpose  

Increasing evidence indicates that lithium is a neuroprotective agent against transient focal and global ischemic injury in the adult animal. In the developing brain, lithium has shown protective effects against neuroapoptosis induced by drugs. This study was designed to investigate the neuroprotective effects of lithium on hypoxic–ischemic brain injury in the neonatal rat.     

Apolipoprotein E and traumatic brain injury in a military population: evidence of a neuropsychological compensatory mechanism?

Objective

Although research has implicated the apolipoprotein E (APOE) epsilon‐4 genotype as having a negative effect on neuropsychological outcomes following traumatic brain injury (TBI), the potentially negative role of the ε4 allele on TBI outcomes has recently been challenged. In light of this debate, the present study served to examine the role of APOE genotype on neuropsychological outcomes approximately 1 month following mild to moderate TBI in a military population. Because of the well documented role of the APOE‐ε4 allele in increasing the risk of Alzheimer''s disease, we predicted that persons with the APOE‐ε4 genotype would display relatively greater deficits in cognition than their non‐ε4 counterparts.

Methods

78 participants were consecutively recruited following a mild to moderate TBI and were divided into two groups based on the presence or absence of an APOE ε4 allele. Groups were comparable on demographic characteristics and psychosocial outcomes. Participants were administered a comprehensive neuropsychological battery.

Results

Analyses revealed comparable performances on most neuropsychological measures and better performances by ε4 carriers on select measures of attention, executive functioning and episodic memory encoding. Furthermore, differences remained after accounting for the effects of TBI severity.

Conclusions

Evidence from these analyses supports current literature refuting the notion of relatively poorer neuropsychological functioning associated with the APOE‐ε4 genotype among young adult participants shortly following mild or moderate brain injury. Neuropsychological performance differences by APOE genotype following TBI are discussed in terms of the importance of considering severity of injury, timing of postinjury assessment and possible neurocognitive compensatory mechanisms.Traumatic brain injury (TBI) represents one of the most significant health risks related to military duty. Previous work has demonstrated that memory, attention and executive functions can be significantly impaired following TBI.^1,2 Specifically, patients with TBI often have problems learning and recalling recent information, attending to multiple pieces of information simultaneously, manipulating information mentally and solving novel problems.^1,3,4 In addition to their cognitive impairments, TBI patients can also experience dramatic changes in emotionality and personality, which include depression, anxiety, irritability, euphoria and decreased motivation,⁵ which may further impact cognitive functioning negatively. Moreover, the cognitive impairments of TBI have been associated with a decrease in quality of life.⁶The potentially negative consequences of TBI highlight the need for predicting which patients will have a poorer outcome. A recent advancement has been the finding that there could be a genetic predisposition to poorer outcome following TBI, and one such candidate gene is the apolipoprotein E (APOE) gene. Located on chromosome 19, the APOE gene is responsible for the production of apolipoprotein, a protein that is produced in response to central nervous system insult and is involved in regulating the redistribution of cholesterol during the production of cell membranes.⁷ There is now strong evidence indicating that individuals with an ε4 allele of APOE (APOE‐ε4) have a greater likelihood of developing Alzheimer''s disease (AD).^8,9 The mechanism of the involvement of the gene in this disease is believed to be in its role of binding to amyloid beta peptide, which results in accumulation of this peptide and eventual development of the neuritic plaques characteristic of AD. Other work implicates the APOE‐ε4 allele in the formation of neurofibrillary tangles,^10,11 a direct neurotoxic role in hippocampal cell death,¹² as well as a reduced ability for central nervous system plastic response.¹³Past work has found indirect evidence of a relationship between the effects of TBI and the presence of the APOE‐ε4 allele. For example, Mayeux and colleagues¹⁴ found that patients with at least one APOE‐ε4 allele were approximately 10 times more likely to develop AD following a head injury. Other groups have also identified head injury as a risk factor for developing AD in individuals with the APOE‐ε4 genotype.^15,16,17 Furthermore, the APOE‐ε4 genotype is associated with greater neurological impairment in some boxers.¹⁸ Graham and colleagues¹⁹ found that 30% of individuals who died from a TBI displayed deposition of the β‐amyloid, and a significantly larger proportion of those individuals were APOE‐ε4 carriers. Other studies have also found an increased risk for fatal TBI in individuals with the APOE‐ε4 genotype.^20,21 It also appears that possession of the APOE‐ε4 genotype results in a greater risk of prolonged coma following TBI.²²To date, there have been few studies that have compared outcome in TBI in individuals with and without the APOE‐ε4 genotype. A study by Teasdale and colleagues²³ found that TBI patients with this genotype had a poorer outcome, as measured by the Glasgow Outcome Scale (GOS), 6 months postinjury. Friedman and colleagues²⁴ also found that patients with the APOE‐ε4 genotype had a greater likelihood of a poorer score on the Glasgow Coma Scale as well as loss of consciousness greater than 7 days. Taken together, these studies suggest that the presence of the APOE‐ε4 genotype is a risk factor for poorer outcome following TBI when compared with those individuals without a copy of the ε4 allele. However, this association has also been contested by other studies. Chamelian and colleagues,²⁵ for example, presented evidence that not only failed to support an association between the APOE‐ε4 genotype and poorer neuropsychological outcomes following mild to moderate TBI, but also produced data revealing better (although not statistically significant) performances by ε4 subjects on various cognitive measures. In fact, there is growing evidence to suggest that normal young adult participants who are APOE‐ε4 positive may perform better than non‐ε4 subjects on a number of neuropsychological measures, regardless of a CNS insult. Papassotiropoulos and colleagues²⁶ found that the APOE‐ε4 allele was associated in a dose dependent manner with better memory performances among 340 healthy young adults. Hubacek and colleagues²⁷ found that among 366 participants, those with an ε4 allele generally achieved a higher level of education than those with an ε2 allele. Keltikangas‐Jarvinen and colleagues²⁸ found that possession of an ε4 allele correlated with increased “mental vitality” (ie, more active, energetic and alert), “socialability” (ie, responsivity) and “positive emotionality” (ie, a tendency to be happy and friendly) among 1577 randomly selected healthy children, adolescents and young adults.This apparent discrepancy in the literature regarding APOE‐ε4 association with poorer outcomes after mild–moderate TBI may be explained, at least in part, by the limitations of previous studies. Firstly, many of these studies used relatively narrow measures of outcome (eg, the GOS), which may not necessarily specify important characteristics of a patient''s neuropsychological functioning following TBI. Furthermore, recent studies have indicated that the cognitive deficits observed in severe TBI patients can best be identified using measures that examine multiple specific components of a particular cognitive domain.^29,30 Using participant groups equated on demographic and psychosocial functioning variables, the present study served to address this apparent discrepancy and provide evidence in support of an association between APOE‐ε4 status, TBI severity and neuropsychological functioning among young participants approximately 1 month following TBI.     

Pediatric traumatic brain injury: quo vadis?

In this review, five questions serve as the framework to discuss the importance of age-related differences in the pathophysiology and therapy of traumatic brain injury (TBI). The following questions are included: (1) Is diffuse cerebral swelling an important feature of pediatric TBI and what is its etiology? (2) Is the developing brain more vulnerable than the adult brain to apoptotic neuronal death after TBI and, if so, what are the clinical implications? (3) If the developing brain has enhanced plasticity versus the adult brain, why are outcomes so poor in infants and young children with severe TBI? (4) What contributes to the poor outcomes in the special case of inflicted childhood neurotrauma and how do we limit it? (5) Should both therapeutic targets and treatments of pediatric TBI be unique? Strong support is presented for the existence of unique biochemical, molecular, cellular and physiological facets of TBI in infants and children versus adults. Unique therapeutic targets and enhanced therapeutic opportunities, both in the acute phase after injury and in rehabilitation and regeneration, are suggested.     

Neuroprotective effect of human placental extract on hypoxic–ischemic brain injury in neonatal rats

We investigated the neuroprotective effects of human placental extracts (HPE) and the effects of HPE on recovery of cognitive and behavioral function on hypoxic–ischemic brain injury in the newborn rat. The right common carotid arteries of 7-day-old rats were coagulated, and rats were then exposed to 8% oxygen. Immediately before and again at three times after the hypoxia–ischemia (pre-treatment group), and immediately after and three times again after hypoxia–ischemia (post-treatment group), the rats were intraperitoneally injected with HPE (0.1, 0.25, or 0.5 mL/10 g/dose). No-treatment rats received saline only. On postnatal day 12, brains were removed and gross morphological damage was evaluated. To quantify the severity of brain injury, bilateral cross-sectional areas of the anterior commissural and posterior hippocampal levels were analyzed with NIH Image. Assessments of the open field activity levels at 2, 4, 6 and 8 week and, the Morris water maze test at 8 weeks after hypoxia–ischemia were carried out according to standard methods. HPE pre-treatment decreased the incidence of liquefactive cerebral infarction, at an optimally neuroprotective dose of 0.5 mL/10 g/dose (P < 0.05). In the Morris water maze test, the group injected with HPE at 0.5 mL/10 g/dose concentration showed shorter escape latencies than the no-treatment group (P < 0.05). These findings support a protective effect of the HPE treatment on neuronal integrity and cognitive function following hypoxic–ischemic brain injury. Injected at an appropriate dose prior to exposure, HPE may significantly reduce or prevent hypoxic–ischemic injury in the immature brain.     

Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease?

The immunological mechanisms leading to tissue damage in inflammatory brain diseases are heterogeneous and complex. They may involve direct cytotoxicity of T lymphocytes, specific antibodies and activated effector cells, such as macrophages and microglia. Here we describe that in certain inflammatory brain lesions a pattern of tissue injury is present, which closely reflects that found in hypoxic conditions of the central nervous system. Certain inflammatory mediators, in particular reactive oxygen and nitrogen species, are able to mediate mitochondrial dysfunction, and we suggest that these inflammatory mediators, when excessively liberated, can result in a state of histotoxic hypoxia. This mechanism may play a major role in multiple sclerosis, not only explaining the lesions formed in a subtype of patients with acute and relapsing course, but also being involved in the formation of diffuse neurodegenerative lesions in chronic progressive forms of the disease.     

Reversible dysfunction of receptors in traumatic brain injury?

In many brain disorders reduced binding of central benzodiazepine receptor ligands indicates irreversible neuronal damage. The data presented by Koizumi et al (2010) demonstrate that this is not the case in traumatic brain injury suggesting different pathogenetic mechanisms leading to tissue damage. The proof for this hypothesis requires further studies that should also consider thresholds of ligand binding as indicators of irreversible damage.     

Sleep disturbance after mild traumatic brain injury: indicator of injury?

Mild traumatic brain injury (mTBI) is a complex entity with no known objective diagnostic markers. To test the hypothesis that sleep disturbances in the acute mTBI period can serve as an indicator of brain injury, the authors compared sleep polysomnograms (PSG) and sleep EEG power spectra (PS) data in seven mTBI subjects with seven age- and race-matched healthy-control subjects. The two groups differed significantly on PS measures, suggesting that mTBI can result in a disruption of sleep microarchitecture and, in theory, could be of use as a marker for brain injury. These pilot findings need to be replicated on larger samples.     

Autophagy in acute brain injury: feast, famine, or folly?

In the central nervous system, increased autophagy has now been reported after traumatic brain and spinal cord injury, cerebral ischemia, intracerebral hemorrhage, and seizures. This increase in autophagy could be physiologic, converting damaged or dysfunctional proteins, lipids, and/or organelles to their amino acid and fatty acid components for recycling. On the other hand, this increase in autophagy could be supraphysiologic, perhaps consuming and eliminating functional proteins, lipids, and/or organelles as well. Whether an increase in autophagy is beneficial (feast) or detrimental (famine) in brain likely depends on both the burden of intracellular substrate targeted for autophagy and the capacity of the cell's autophagic machinery. Of course, increased autophagy observed after brain injury could also simply be an epiphenomenon (folly). These divergent possibilities have clear ramifications for designing therapeutic strategies targeting autophagy after acute brain injury and are the subject of this review. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."