Single voxel Magnetic Resonance Spectroscopic (1H-MRS) analysis of deep brain structures after traumatic prefrontal brain injury (TBI) in rat

Chronic difficulties arising from mild brain injury (TBI) are difficult to predict because the processes underlying changes after TBI are poorly understood. In mild brain injury the extent of neuropsychiatric and cognitive symptoms correspond poorly to overt tissue loss (Barth 1983; Liu 2010). Cellular, immune and hormonal cascades occurring after injury and continuing during the healing process may impact uninjured brain regions sensitive to the effects of physiological and emotional stress, which receive projections from the injury site. Changes in these most basic properties due to injury or disease have profound implications for virtually every aspect of brain function through disruption of neurotransmitter, neuroendocrine and metabolic systems. In order to screen for changes in transmitter and metabolic activity, in this study we developed Single voxel proton Magnetic Resonance Spectroscopy (1H-MRS) for use in both injured and control animals. We first evaluated if 1H-MRS could be used to evaluate in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus in both control and injured animals after controlled cortical impact injury to the rat prefrontal cortex. We found that metabolite measurements for Myo-Inositol, Choline, creatine, Glutamate+Glutamine, and N-acetyl-acetate are attainable in deep brain structures in vivo in injured and controls rats. We next seek to evaluate longitudinally, in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus during the first month after controlled cortical impact injury to the rat prefrontal cortex. These ongoing studies will provide data on the changes in transmitters and metabolites over time in injured and non-injured subjects. These studies address some of the fundamental questions about how mild brain injury has such diverse effects on overall brain health and function.

Healthcare professionals’ attitudes towards traumatic brain injury (TBI): The influence of profession, experience, aetiology and blame on prejudice towards survivors of brain injury

Primary objective: To investigate the attitudes of healthcare professionals towards individuals with traumatic brain injury (TBI) and their relationship to intended healthcare behaviour.

Research design: An independent groups design utilized four independent variables; aetiology, group, blame and gender to explore attitudes towards survivors of brain injury. The dependent variables were measured using the Prejudicial Evaluation and Social Interaction Scale (PESIS) and Helping Behaviour Scale (HBS).

Methods and procedures: A hypothetical vignette based methodology was used. Four hundred and sixty participants (131 trainee nurses, 94 qualified nurses, 174 trainee doctors, 61 qualified doctors) were randomly allocated to one of six possible conditions.

Main outcomes and results: Regardless of aetiology, if an individual is to blame for their injury, qualified healthcare professionals have more prejudicial attitudes than those entering the profession. There is a significant negative relationship between prejudice and helping behaviour for qualified healthcare professionals.

Conclusions: Increased prejudicial attitudes of qualified staff are related to a decrease in intended helping behaviour, which has the potential to impact negatively on an individual's recovery post-injury.

Traumatic brain injury (TBI) in a prison population: a systematic review

Objective: To systematically explore the literature surrounding TBI in adult prison populations. Method: Twenty six studies spanning six countries were included. All studies were published in peer reviewed journals and sampled adults from general prison populations (aged 18+). Results: Only seven studies employed valid and reliable measures of TBI. The presence of TBI related problems such as aggression, depression, substance abuse, psychiatric disorders, and neurocognitive deficits were evident within prisoner samples.

Immune response deviation and enhanced expression of chemokine receptor CCR4 in TBI patients due to unknown serum factors

BACKGROUND: Severe brain trauma leads to an activation of the immune system. To this date, neither the exact perturbation of the specific immune reaction induced by the traumatic brain injury (TBI), nor the interactions leading to the infiltration of peripheral immune cells into the brain are fully understood. PATIENTS AND METHODS: Serum was collected from 17 patients with TBI and a long bone fracture, 24 patients with an isolated long bone fracture and from healthy individuals. The effect of the serum on normal human monocytes and T-lymphocytes was tested in vitro by assessing proliferation and expression of surface markers, chemokine receptors and cytokines. RESULTS: Serum collected from patients with a TBI and a long bone fracture increased the expression of the chemokine receptor CCR4 in monocytes when compared to patients with an isolated long bone fracture. Extending this comparison to T-lymphocytes, the serum from TBI patients induced lower proliferation rates and decreased expression of the pro-inflammatory cytokine TNF-alpha, while simultaneously increasing the secretion of immune-modulatory cytokines (IL-4, IL-10 and TGF-beta) (p<0.05). CONCLUSION: Patients with a TBI release currently unknown soluble factors into the circulating blood that up regulate expression of chemokine receptor CCR4 in peripheral blood monocytes whilst concurrently inducing expression of immunosuppressive cytokines by activated T-lymphocytes.

Traumatic brain injury (TBI) produces cytoskeletal protein derangements within cortical neurons that can be attenuated by protease inhibition

TBI produces a consistent and extensive loss of neurofilament 68 (NF68) and neurofilament 200 (NF200), key intermediate cytoskeletal proteins found in neurons including axons and dendrites, in cortical samples from injured brain. The presence of low molecular weight NF68 breakdown products (BDPs) strongly suggest that calpain proteolysis at least in part contributes to neurofilament (NF) protein loss following injury. Furthermore, one and two-dimensional gel electrophoresis analyses of NF BDPs obtained from in situ and in vitro tissue also implicated the involvement of calpain 2 mediated proteolysis of neurofilaments following TBI. Immunohistochemical examination of derangements in cytoskeletal proteins following traumatic brain injury in rats indicated that preferential dendritic rather than axonal damage occurs within three hours post-TBI. Although proteolysis of cytoskeletal proteins occurred concurrently with early morphological alterations, evidence of proteolysis preceded the full expression of evolutionary histopathological changes. Furthermore, cytoskeletal immunofluorescence alterations were not restricted to the site of impact. Confocal microscopic investigations of NF68 and NF200 immunofluorescence within injured cortical neurons revealed alterations in neurofilament assembly in the absence of NF derangements detectable at the light microscopic level ($<$15 minutes post-TBI). Collectively immunohistochemistry studies suggest that derangements to neuronal processes are biochemical and evolutionary in nature, and not due solely to mechanical shearing. Importantly, a systemically administered calpain inhibitor (calpain inhibitor 2) significantly reduced NF200, NF68, and spectrin protein loss as well as providing marked preservation of NF proteins in neuronal somata, dendrites, and axons at 24 hours post-TBI. ^

The Use of the Rey 15-Item Test and Recognition Trial to Evaluate Suboptimal Effort in Neuropsychological Assessment with a Pediatric Mild TBI Sample

The utilization of symptom validity tests (SVTs) in pediatric assessment is receiving increasing empirical support. The Rey 15-Item Test (FIT) is an SVT commonly used in adult assessment, with limited research in pediatric populations. Given that FIT classification statistics across studies to date have been quite variable, Boone, Salazar, Lu, Warner-Chacon, and Razani (2002) developed a recognition trial to use with the original measure to enhance accuracy. The current study aims to assess the utility of the FIT and recognition trial in a pediatric mild traumatic brain injury (TBI) sample (N = 112; M = 14.6 years), in which a suboptimal effort base rate of 17% has been previously established (Kirkwood & Kirk, 2010). All participants were administered the FIT as part of an abbreviated neuropsychological evaluation; failure on the Medical Symptom Validity Test (MSVT) was used as the criterion for suspect effort. The traditional adult cut-off score of(99%), but poor sensitivity (6%). When the recognition trial was also utilized, a combination score of(sensitivity = 64%, specificity = 93%). Results indicate that the FIT with recognition trial may be useful in the assessment of pediatric suboptimal effort, at least among relatively high functioning children following mild TBI.

Development of the DORI-TBI: An Investigation to Develop a New Screening Measure to Determine Consultation with a School-Based Brain Injury Resource Team

Brain injury is the leading cause of disability and death in children in the United States. Student re-entry into the school setting following a traumatic brain injury is crucial to student success. Multidisciplinary teams within the school district comprised of individuals with expertise in brain injury are ideal in implementing student specific treatment plans given their specialized training and wide range of expertise addressing student needs. Therefore, the purpose of this study is to develop and initially validate a quantitative instrument that school personnel can use to determine if a student, identified as having a traumatic brain injury, will benefit from district-level consultation from a brain injury team. Three studies were designed to investigate the research questions. In study one, the planning and construction of the DORI-TBI was completed. Study two addressed the content validity of the DORI-TBI through a comparison analysis with other referral forms, content review with experts in the field of TBI, and cognitive interviews with professionals to test the usability of the new screening tool. In study three, a field administration was conducted using vignettes to measure construct validity. Results produced a valid and reliable new screening instrument that can aid school-based teams to more efficiently utilize district level consultation with a brain injury support team.

Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation

Host antigen-presenting cells (APCs) are known to be critical for the induction of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), but the relative contribution of specific APC subsets remains unclear. We have studied the role of host B cells in GVHD by using B-cell-deficient mu MT mice as BMT recipients in a model of CD4-dependent GVHD to major histocompatlibility complex antigens. We demonstrate that acute GVHD is initially augmented in mu MT recipients relative to wild-type recipients (mortality: 85% vs 44%, P < .01), and this is the result of an increase in donor T-cell proliferation, expansion, and inflammatory cytokine production early after BMT. Recipient B cells were depleted 28-fold at the time of BMT by total body irradiation (TBI) administered 24 hours earlier, and we demonstrate that TBI rapidly induces sustained interleukin-110 (IL-10) generation from B cells but not dendritic cells (DCs) or other cellular populations within the spleen. Finally, recipient mice in which B cells are unable to produce IL-10 due to homologous gene deletion develop more severe acute GVHD than recipient mice in which B cells are wild type. Thus, the induction of IL-10 in host B cells during conditioning attenuates experimental acute GVHD.

Theory of mind after mild TBI in preschool children : a longitudinal perspective

Les enfants d’âge préscolaire (≤ 5 ans) sont plus à risque de subir un traumatisme crânio-cérébral (TCC) que les enfants plus agés, et 90% de ces TCC sont de sévérité légère (TCCL). De nombreuses études publiées dans les deux dernières décennies démontrent que le TCCL pédiatrique peut engendrer des difficultés cognitives, comportementales et psychiatriques en phase aigüe qui, chez certains enfants, peuvent perdurer à long terme. Il existe une littérature florissante concernant l'impact du TCCL sur le fonctionnement social et sur la cognition sociale (les processus cognitifs qui sous-tendent la socialisation) chez les enfants d'âge scolaire et les adolescents. Or, seulement deux études ont examiné l'impact d'un TCCL à l'âge préscolaire sur le développement social et aucune étude ne s'est penchée sur les répercussions socio-cognitives d'un TCCL précoce (à l’âge préscolaire). L'objectif de la présente thèse était donc d'étudier les conséquences du TCCL en bas âge sur la cognition sociale. Pour ce faire, nous avons examiné un aspect de la cognition sociale qui est en plein essor à cet âge, soit la théorie de l'esprit (TE), qui réfère à la capacité de se mettre à la place d'autrui et de comprendre sa perspective. Le premier article avait pour but d'étudier deux sous-composantes de la TE, soit la compréhension des fausses croyances et le raisonnement des désirs et des émotions d'autrui, six mois post-TCCL. Les résultats indiquent que les enfants d'âge préscolaire (18 à 60 mois) qui subissent un TCCL ont une TE significativement moins bonne 6 mois post-TCCL comparativement à un groupe contrôle d'enfants n'ayant subi aucune blessure. Le deuxième article visait à éclaircir l'origine de la diminution de la TE suite à un TCCL précoce. Cet objectif découle du débat qui existe actuellement dans la littérature. En effet, plusieurs scientifiques sont d'avis que l'on peut conclure à un effet découlant de la blessure au cerveau seulement lorsque les enfants ayant subi un TCCL sont comparés à des enfants ayant subi une blessure n'impliquant pas la tête (p.ex., une blessure orthopédique). Cet argument est fondé sur des études qui démontrent qu'en général, les enfants qui sont plus susceptibles de subir une blessure, peu importe la nature de celle-ci, ont des caractéristiques cognitives pré-existantes (p.ex. impulsivité, difficultés attentionnelles). Il s'avère donc possible que les difficultés que nous croyons attribuables à la blessure cérébrale étaient présentes avant même que l'enfant ne subisse un TCCL. Dans cette deuxième étude, nous avons donc comparé les performances aux tâches de TE d'enfants ayant subi un TCCL à ceux d'enfants appartenant à deux groupes contrôles, soit des enfants n'ayant subi aucune blessure et à des pairs ayant subi une blessure orthopédique. De façon générale, les enfants ayant subi un TCCL ont obtenu des performances significativement plus faibles à la tâche évaluant le raisonnement des désirs et des émotions d'autrui, 6 mois post-blessure, comparativement aux deux groupes contrôles. Cette étude visait également à examiner l'évolution de la TE suite à un TCCL, soit de 6 mois à 18 mois post-blessure. Les résultats démontrent que les moindres performances sont maintenues 18 mois post-TCCL. Enfin, le troisième but de cette étude était d’investiguer s’il existe un lien en la performance aux tâches de TE et les habiletés sociales, telles qu’évaluées à l’aide d’un questionnaire rempli par le parent. De façon intéressante, la TE est associée aux habiletés sociales seulement chez les enfants ayant subi un TCCL. Dans l'ensemble, ces deux études mettent en évidence des répercussions spécifiques du TCCL précoce sur la TE qui persistent à long terme, et une TE amoindrie seraient associée à de moins bonnes habiletés sociales. Cette thèse démontre qu'un TCCL en bas âge peut faire obstacle au développement sociocognitif, par le biais de répercussions sur la TE. Ces résultats appuient la théorie selon laquelle le jeune cerveau immature présente une vulnérabilité accrue aux blessures cérébrales. Enfin, ces études mettent en lumière la nécessité d'étudier ce groupe d'âge, plutôt que d'extrapoler à partir de résultats obtenus avec des enfants plus âgés, puisque les enjeux développementaux s'avèrent différents, et que ceux-ci ont potentiellement une influence majeure sur les répercussions d'une blessure cérébrale sur le fonctionnement sociocognitif.

Theory of mind after mild TBI in preschool children : a longitudinal perspective

Les enfants d’âge préscolaire (≤ 5 ans) sont plus à risque de subir un traumatisme crânio-cérébral (TCC) que les enfants plus agés, et 90% de ces TCC sont de sévérité légère (TCCL). De nombreuses études publiées dans les deux dernières décennies démontrent que le TCCL pédiatrique peut engendrer des difficultés cognitives, comportementales et psychiatriques en phase aigüe qui, chez certains enfants, peuvent perdurer à long terme. Il existe une littérature florissante concernant l'impact du TCCL sur le fonctionnement social et sur la cognition sociale (les processus cognitifs qui sous-tendent la socialisation) chez les enfants d'âge scolaire et les adolescents. Or, seulement deux études ont examiné l'impact d'un TCCL à l'âge préscolaire sur le développement social et aucune étude ne s'est penchée sur les répercussions socio-cognitives d'un TCCL précoce (à l’âge préscolaire). L'objectif de la présente thèse était donc d'étudier les conséquences du TCCL en bas âge sur la cognition sociale. Pour ce faire, nous avons examiné un aspect de la cognition sociale qui est en plein essor à cet âge, soit la théorie de l'esprit (TE), qui réfère à la capacité de se mettre à la place d'autrui et de comprendre sa perspective. Le premier article avait pour but d'étudier deux sous-composantes de la TE, soit la compréhension des fausses croyances et le raisonnement des désirs et des émotions d'autrui, six mois post-TCCL. Les résultats indiquent que les enfants d'âge préscolaire (18 à 60 mois) qui subissent un TCCL ont une TE significativement moins bonne 6 mois post-TCCL comparativement à un groupe contrôle d'enfants n'ayant subi aucune blessure. Le deuxième article visait à éclaircir l'origine de la diminution de la TE suite à un TCCL précoce. Cet objectif découle du débat qui existe actuellement dans la littérature. En effet, plusieurs scientifiques sont d'avis que l'on peut conclure à un effet découlant de la blessure au cerveau seulement lorsque les enfants ayant subi un TCCL sont comparés à des enfants ayant subi une blessure n'impliquant pas la tête (p.ex., une blessure orthopédique). Cet argument est fondé sur des études qui démontrent qu'en général, les enfants qui sont plus susceptibles de subir une blessure, peu importe la nature de celle-ci, ont des caractéristiques cognitives pré-existantes (p.ex. impulsivité, difficultés attentionnelles). Il s'avère donc possible que les difficultés que nous croyons attribuables à la blessure cérébrale étaient présentes avant même que l'enfant ne subisse un TCCL. Dans cette deuxième étude, nous avons donc comparé les performances aux tâches de TE d'enfants ayant subi un TCCL à ceux d'enfants appartenant à deux groupes contrôles, soit des enfants n'ayant subi aucune blessure et à des pairs ayant subi une blessure orthopédique. De façon générale, les enfants ayant subi un TCCL ont obtenu des performances significativement plus faibles à la tâche évaluant le raisonnement des désirs et des émotions d'autrui, 6 mois post-blessure, comparativement aux deux groupes contrôles. Cette étude visait également à examiner l'évolution de la TE suite à un TCCL, soit de 6 mois à 18 mois post-blessure. Les résultats démontrent que les moindres performances sont maintenues 18 mois post-TCCL. Enfin, le troisième but de cette étude était d’investiguer s’il existe un lien en la performance aux tâches de TE et les habiletés sociales, telles qu’évaluées à l’aide d’un questionnaire rempli par le parent. De façon intéressante, la TE est associée aux habiletés sociales seulement chez les enfants ayant subi un TCCL. Dans l'ensemble, ces deux études mettent en évidence des répercussions spécifiques du TCCL précoce sur la TE qui persistent à long terme, et une TE amoindrie seraient associée à de moins bonnes habiletés sociales. Cette thèse démontre qu'un TCCL en bas âge peut faire obstacle au développement sociocognitif, par le biais de répercussions sur la TE. Ces résultats appuient la théorie selon laquelle le jeune cerveau immature présente une vulnérabilité accrue aux blessures cérébrales. Enfin, ces études mettent en lumière la nécessité d'étudier ce groupe d'âge, plutôt que d'extrapoler à partir de résultats obtenus avec des enfants plus âgés, puisque les enjeux développementaux s'avèrent différents, et que ceux-ci ont potentiellement une influence majeure sur les répercussions d'une blessure cérébrale sur le fonctionnement sociocognitif.

Controversies of prophylactic hypothermia and the emerging use of brain tissue oxygen tension monitoring and decompressive craniectomy in traumatic brain-injured children

Background Despite being the leading cause of death and disability in the paediatric population, traumatic brain injury (TBI) in this group is largely understudied. Clinical practice within the paediatric intensive care unit (PICU) has been based upon adult guidelines however children are significantly different in terms of mechanism, pathophysiology and consequence of injury. Aim To review TBI management in the PICU and gain insight into potential management strategies. Method To conduct this review, a literature search was conducted using MEDLINE, PUBMED and The Cochrane Library using the following key words; traumatic brain injury; paediatric; hypothermia. There were no date restrictions applied to ensure that past studies, whose principles remain current were not excluded. Results Three areas were identified from the literature search and will be discussed against current acknowledged treatment strategies: Prophylactic hypothermia, brain tissue oxygen tension monitoring and decompressive craniectomy. Conclusion Previous literature has failed to fully address paediatric specific management protocols and we therefore have little evidence-based guidance. This review has shown that there is an emerging and ongoing trend towards paediatric specific TBI research in particular the area of moderate prophylactic hypothermia (MPH).

Systematic variation of the severity of motor vehicle accident-related traumatic brain injury vignettes produces different post-concussion symptom reports

This study investigated the specificity of the post-concussion syndrome (PCS) expectation-as-etiology hypothesis. Undergraduate students (n = 551) were randomly allocated to one of three vignette conditions. Vignettes depicted either a very mild (VMI), mild (MI), or moderate-to-severe (MSI) motor vehicle-related traumatic brain injury (TBI). Participants reported the PCS and PTSD symptoms that they imagined the depicted injury would produce. Secondary outcomes (knowledge of mild TBI, and the perceived undesirability of TBI) were also assessed. After data screening, the distribution of participants by condition was: VMI (n = 100), MI (n = 96), and MSI (n = 71). There was a significant effect of condition on PCS symptomatology, F(2, 264) = 16.55, p < .001. Significantly greater PCS symptomatology was expected in the MSI condition compared to the other conditions (MSI > VMI; medium effect, r = .33; MSI > MI; small-to-medium effect, r = .22). The same pattern of group differences was found for PTSD symptoms, F(2, 264) = 17.12, p < .001. Knowledge of mild TBI was not related to differences in expected PCS symptoms by condition; and the perceived undesirability of TBI was only associated with reported PCS symptomatology in the MSI condition. Systematic variation in the severity of a depicted TBI produces different PCS and PTSD symptom expectations. Even a very mild TBI vignette can elicit expectations of PCS symptoms.

Method of symptom assessment influences cognitive, affective and somatic post-concussion-like symptom base rates

Primary objective: To investigate whether assessment method influences the type of post-concussion-like symptoms. Methods and procedures: Participants were 73 Australian undergraduate students (Mage = 24.14, SD = 8.84; 75.3% female) with no history of mild traumatic brain injury (mTBI). Participants reported symptoms experienced over the previous 2 weeks in response to an open-ended question (free report), mock interview and standardized checklist (British Columbia Post-concussion Symptom Inventory; BC-PSI). Main outcomes and results: In the free report and checklist conditions, cognitive symptoms were reported significantly less frequently than affective (free report: p < 0.001; checklist: p < 0.001) or somatic symptoms (free report: p < 0.001; checklist: p = 0.004). However, in the mock structured interview condition, cognitive and somatic symptoms were reported significantly less frequently than affective symptoms (both p < 0.001). No participants reported at least one symptom from all three domains when assessed by free report, whereas most participants did so when symptoms were assessed by a mock structured interview (75%) or checklist (90%). Conclusions: Previous studies have shown that the method used to assess symptoms affects the number reported. This study shows that the assessment method also affects the type of reported symptoms.

Current pre-hospital traumatic brain injury management in China

BACKGROUND Traumatic brain injury (TBI) is associated with mo st trauma-related deaths. Secondary brain injury is the leading cause of in-hospital deaths after traumatic brain injury. By early prevention and slowing of the initial pathophysiological mechanism of secondary brain injury, pre- hospital service can signifi cantly reduce case-fata lity rates of TBI. In China, the incidence of TBI is increasing and the proportion of severe TBI is much higher than that in other countries. The objective of this paper is to review the pre-hospital management of TBI in China. DATA SOURCES A literature search was conducted in January 2014 using the China National Knowledge Infrastructure (CNKI). Articles on the assessment and treatment of TBI in pre-hospital settings practiced by Chinese doctors were identified. The information on the assessment and treatment of hypoxemia, hypotension, and brain hern iation was extracted from the identifi ed articles. RESULTS Of the 471 articles identified, 65 met the selecti on criteria. The existing literature indicated that current practices of pre-hospital TBI management in China were sub-optimal and varied considerably across different regions. CONCLUSION Since pre-hospital care is the weakest part of Chinese emergency care, appropriate training programs on pre-hospital TBI management are urgently needed in China.