Chronic Stage Of Traumatic Brain Injury Research Articles

Changes in Oral Microbial Diversity in a Piglet Model of Traumatic Brain Injury.

Dynamic changes in the oral microbiome have gained attention due to their potential diagnostic role in neurological diseases such as Alzheimer’s disease and Parkinson’s disease. Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, but no studies have examined the changes in oral microbiome during the acute stage of TBI using a clinically translational pig model. Crossbred piglets (4–5 weeks old, male) underwent either a controlled cortical impact (TBI, n = 6) or sham surgery (sham, n = 6). The oral microbiome parameters were quantified from the upper and lower gingiva, both buccal mucosa, and floor of the mouth pre-surgery and 1, 3, and 7 days post-surgery (PS) using the 16S rRNA gene. Faith’s phylogenetic diversity was significantly lower in the TBI piglets at 7 days PS compared to those of sham, and beta diversity at 1, 3, and 7 days PS was significantly different between TBI and sham piglets. However, no significant changes in the taxonomic composition of the oral microbiome were observed following TBI compared to sham. Further studies are needed to investigate the potential diagnostic role of the oral microbiome during the chronic stage of TBI with a larger number of subjects.

The Role of Neuroinflammatory Mediators in the Pathogenesis of Traumatic Brain Injury: A Narrative Review.

Traumatic brain injury (TBI) is a debilitating acquired neurological disorder that afflicts nearly 74 million people worldwide annually. TBI has been classified as more than just a single insult because of its associated risk toward various long-term neurological and neurodegenerative disorders. This risk may be triggered by a series of postinjury secondary molecular and cellular pathology, which may be dependent on the severity of the TBI. Among the secondary injury mechanisms, neuroinflammation may be the most crucial as it may exacerbate brain damage and lead to fatal consequences when prolonged. This Review aimed to elucidate the influence of neuroinflammatory mediators on the TBI functional and pathological outcomes, particularly focusing on inflammatory cytokines which were associated with neuronal dysfunctions in the acute and chronic stages of TBI. These cytokines include interleukins (IL) such as IL-1(beta)β, IL-4, IL-6, IL8, IL-10, IL-18, IL-33 and tumor necrosis factor alpha (TNF-α), which have been extensively studied. Apart from these, IL-2, interferon gamma (IFN-γ), and transforming growth factor-beta (TGF-β) may also play a significant role in the pathogenesis of TBI. These neuroinflammatory mediators may trigger a series of pathological events such as cell death, microglial suppression, and increased catecholaminergic activity. Interestingly, in the acute phase of TBI, most of these mediators may also play a neuroprotective role by displaying anti-inflammatory properties, which may convert to a pro-inflammatory action in the chronic stages post TBI. Early identification and treatment of these mediators may help the development of more effective treatment options for TBI.

Changes in Oral Microbial Diversity in a Piglet Model of Traumatic Brain Injury

The dynamic changes in the oral microbiome in response to disease has led to significant interest in utilizing microbiome analysis as a potential diagnostic and prognostic biomarker. Oral dysbiosis has been linked to the progression of neurological diseases such as Alzheimer’s and Parkinson’s diseases, however, no studies have been conducted to evaluate microbiome changes in traumatic brain injury (TBI). This study aimed to examine the changes in the oral microbiome structure during the acute stage of TBI in a clinically translational pig model.Landrace piglets (4‐5 weeks old, male) underwent either a controlled cortical impact surgery (TBI, n=6) or sham surgery (Sham, n=6). TBI was confirmed by magnetic resonance imaging 1 day post‐TBI. Oral swabs of the inside of upper and lower lips, both cheeks, and under the tongue were collected to sample the oral mucosa pre‐surgery and 1, 3, and 7 days post‐surgery (PS). Bacterial DNA was extracted and the V3‐V4 region of 16s rRNA gene was amplified and sequenced using an Illumina NovaSeq platform. Alpha‐, beta‐diversity, and oral microbial composition at the phylum (P), family (F), genus (G), and species (S) level were examined using Qiime2 plugins. Mixed effects ANOVA was used to compare differences between the groups and time points.Significant time effects were identified in several alpha‐diversity indexes during the acute stage of TBI: The number of observed features, Faith’s Phylogenetic Diversity, Shannon Index, and Pielou’s Evenness. However, no group effects were found between TBI and Sham groups, except for Faith’s Phylogenetic Diversity. Faith’s Phylogenetic Diversity showed group and time‐by‐group effects including a significant difference between groups at 7 days PS. In both TBI and Sham groups, beta‐diversity was significantly different between time points and distinct microbial patterns were observed between TBI and Sham groups at 1, 3, and 7 days PS, with the most apparent difference at 7 days PS. Changes in oral microbial composition did not differ between TBI and Sham groups at any taxonomic level (P, F, G, and S), while significant time effects were found in several microbial taxa. Interestingly, significant time‐by‐group effects were found in P_Proteobacteria, F_Leptotrichiaceae, F_Micrococcaceae, and G_Rothia.In conclusion, species diversity as measured by Faith’s Phylogenetic Diversity was lowest at 7 days PS in TBI group compared to Sham group, and TBI and Sham groups showed significant differences in beta‐diversity. With respect to individual microbial taxa, the oral microbial composition was not significantly different between the two groups during the acute stage of TBI. Future studies are needed to investigate further changes in oral microbiome during the chronic stages of TBI.

Insulin-Like Growth Factor-2 (IGF-2) Does Not Improve Memory in the Chronic Stage of Traumatic Brain Injury in Rodents.

Persistent cognitive impairment(s) can be a significant consequence of traumatic brain injury (TBI) and can markedly compromise quality of life. Unfortunately, identifying effective treatments to alleviate memory impairments in the chronic stage of TBI has proven elusive. Several studies have demonstrated that insulin-like growth factor-2 (IGF-2) can enhance memory in both normal animals and in experimental models of disease. In this study, we questioned whether IGF-2, when administered before learning, could enhance memory performance in the chronic stage of TBI. Male C57BL/6 mice (n = 7 per group) were injured using an electronic cortical impact injury device. Four months later, mice were tested for their cognitive performance in the fear memory extinction, novel object recognition (NOR), and Morris water maze tasks. Twenty minutes before each day of training, mice received a subcutaneous injection of either 30 μg/kg of IGF-2 or an equal volume of vehicle. Memory testing was carried out 24 h after training in the absence of the drug. Uninjured sham animals treated with IGF-2 (or vehicle) were trained and tested in the fear memory extinction task as a positive control. Our data show that although IGF-2 (30 μg/kg) improved memory extinction in uninjured mice, it was ineffective at improving fear memory extinction in the chronic stage of TBI. Similarly, IGF-2 administration to chronically injured animals did not improve TBI-related deficits in either NOR or spatial memory. Our results indicate that IGF-2, administered in the chronic stage of injury, is ineffective at enhancing memory performance and therefore may not be a beneficial treatment option for lingering cognitive impairments after a TBI.

Investigating whole-brain metabolite abnormalities in the chronic stages of moderate or severe traumatic brain injury.

Evidence suggests that neurometabolic abnormalities can persist after traumatic brain injury (TBI) and drive clinical symptoms such as fatigue and cognitive disruption. Magnetic resonance spectroscopy has been used to investigate metabolite abnormalities following TBI, but few studies have obtained data beyond the subacute stage or over large brain regions. To measure whole-brain metabolites in chronic stages of TBI. Observational study. University. Eleven men with a moderate or severe TBI more than 12 months prior and 10 age-matched healthy controls completed whole-brain spectroscopic imaging. Ratios of N-acetylaspartate (NAA), choline (CHO), and myo-inositol (MI) to creatine (CR) were measured in whole-brain gray and white matter as well as 64 brain regions of interest. Arterial spin labeling (ASL) data were also collected to investigate whether metabolite abnormalities were accompanied by differences in cerebral perfusion. There were no differences in metabolite ratios within whole-brain gray and white matter regions of interest (ROIs). Linear regression showed lower NAA/CR in the white matter of the left occipital lobe but higher NAA/CR in the gray matter of the left parietal lobe. Metabolite abnormalities were observed in several brain regions in the TBI group including the corpus callosum, putamen, and posterior cingulate. However, none of the findings survived correction for multiple comparison. There were no differences in cerebral blood flow between patients and controls. Higher MI/CR may indicate ongoing gliosis, and it has been suggested that low CHO/CR at chronic time points may indicate cell death or lack of healthy turnover and repair. However, with the small sample size of this study, we caution against the over interpretation of our results. None of the findings within ROIs survived correction for multiple comparison. Thus, they may be considered possible avenues for future research in this area.

Relationship of medical comorbidities to psychological health at 2 and 5 years following traumatic brain injury (TBI).

Objective: To examine the relationship between medical comorbidities and psychological health outcomes at 2 and 5 years following traumatic brain injury (TBI). Method: Veterans Affairs (VA) TBI Model System participants who completed a 2-year (n = 225) and/or 5-year (n = 283) follow-up with a comorbidities interview were included in the current study. Psychological health outcomes were assessed using the Patient Global Impression of Change (PGIC), Patient Health Questionnaire-9 (PHQ-9), and Satisfaction with Life Scale (SWLS). While controlling for known predictors of outcome, the relationship of overall comorbidity burden to psychological outcomes was examined cross-sectionally using generalized linear regression at 2 and 5 years post-TBI. Lasso regularization was used to examine relationships of specific comorbid conditions to outcome. Results: Greater comorbidity burden was significantly associated with lower satisfaction with life at 2 and 5 years post-TBI and was associated with greater depressive symptomatology at 5 years post-TBI. Chronic pain was associated with lower satisfaction with life and greater depressive symptoms at both 2- and 5-year follow-up. Sleep apnea was associated with lower satisfaction with life and greater depressive symptoms at 5-year follow-up. Rheumatoid arthritis was associated with lower satisfaction with life and lower levels of perceived improvement in health and well-being at the 5-year follow-up. Implications: Results suggest that medical comorbidities may have a cumulative impact on adverse psychological health outcomes in chronic stages of TBI. This study further highlights the complexity of patients with TBI and the importance of identifying medical comorbidities as they provide potential targets for intervention. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The relationship between consciousness and the ascending reticular activating system in patients with traumatic brain injury

BackgroundWe investigated the relationship between consciousness and the ascending reticular activating system (ARAS) by using diffusion tensor tractography (DTT) in patients with traumatic brain injury (TBI).MethodsTwenty-six patients with TBI and 13 healthy control subjects were recruited for this study. Glasgow Coma Scale (GCS) scores were used for evaluation of subject consciousness state at the chronic stage of TBI (at DTT scanning), According to the GCS score, the patient group was divided into two subgroups: A (14 patients;impaired consciousness: GCS score < 15, and B (12 patients;intact consciousness;GCS score = 15). Fractional anisotropy (FA) and tract volume (TV) values were assessed in the lower dorsal and upper ARAS.ResultsThe FA values of the lower dorsal ARAS and the upper ARAS in patient subgroup A were significantly lower than those in patient subgroup B and the control group(p < 0.05). However, the FA and TV values for the lower dorsal ARAS and the upper ARAS were not significantly different between patient subgroup B and the control group(p > 0.05). The FA value of the lower dorsal ARAS(r = 0.473,p < 0.05) and the TV of upper ARAS(r = 0.484,p < 0.05) had moderate positive correlations with the GCS score. The FA value of the upper ARAS had a strong positive correlation with the GCS score of the patient group(r = 0.780,p < 0.05).ConclusionsWe detected a close relationship between consciousness at the chronic stage of TBI and injuries of the lower dorsal and upper ARAS (especially, the upper ARAS) in patients who showed impaired consciousness at the onset of TBI. We believe that our results can be useful during the development of therapeutic strategies for patients with impaired consciousness following TBI.Trial registrationYUMC 2019–06–032-003. Retrospectively registered 06 Jun 2020.

Metabolomics Deciphers Potential Targets of Xuefu Zhuyu Decoction Against Traumatic Brain Injury in Rat.

Xuefu Zhuyu decoction (XFZYD) performs multiple functions for traumatic brain injury (TBI) treatment. However, its clinical application is limited by the incomplete exploration of targets and inadequate discussion of mechanisms. We aimed to investigate the metabolic alterations of XFZYD in acute and chronic stages of TBI. Sprague-Dawley rats were randomly divided into the sham, controlled cortical impact (CCI) and XFZYD group. Behavioral and histopathological tests were used to evaluate the neuroprotective effects. Coagulation assays were performed to assess safety. Moreover, we analyzed the metabolomic profiling of hippocampal samples with different time intervals after CCI by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Differential metabolites were screened by multivariate data analysis. To further uncover the association between candidate metabolites and biological interaction networks, we applied bioinformatics analysis using MetaboAnalyst 4.0, STITCH 5.0 and TCMSP. The potential mechanism was verified by ELISA and Western blot. XFZYD ameliorated neurological deficiencies post-CCI without impairing blood coagulation in the rat’s model. Seventeen and fourteen metabolites were filtered on d 3 and 21, respectively. Eleven of potential metabolites were common at these time points, involving two significant pathways (arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis). Gamma-aminobutyric acid (GABA) and the related pathways were specifically affected by XFZYD at the acute phase of TBI, while biosynthesis of amino acids was the major pathway influenced at the chronic phase. This study provides broad insights into the therapeutic effects of XFZYD in treating TBI through the whole phases.

Cognitive training benefit depends on brain injury location in adolescents with traumatic brain injury: a pilot study.

Executive dysfunction after pediatric traumatic brain injury (TBI) has been linked to poor outcomes in school performance, social functioning and employment. The credibility of training-induced cognitive enhancement in TBI is threatened by its limited proof of benefit in executive skills of daily living. Our primary aim was to investigate if cognitive intervention for improving impairments in executive functions in the chronic stage of TBI is effective during adolescence. The secondary aim was to explore whether training benefit is driven by injury location. Prospective observational study. Child Rehabilitation Center of a University Hospital. Sixteen adolescents with moderate to severe TBI (mean age 15 years and 8 months) and 16 age and gender matched healthy peers were included. Effects of a new cognitive training program (BrainGames) were assessed postintervention and 6 months later utilizing a comprehensive neuropsychological test-battery and the Behavior Rating Inventory of Executive Function. In addition, subgroup analyses were performed to determine long-term training benefit in the presence of lesions in corpus callosum, deep-brain-nuclei and prefrontal cortex. Adolescents with TBI showed significant improvements on measures of executive functioning at completion of the training and at follow-up compared with the pre-tests. The presence or absence of diffuse-axonal-injuries (DAI) in the deep brain nuclei determined a significant difference in long-term training benefit. This study provides preliminary evidence that cognitive training, beyond the acute rehabilitation period in adolescents with TBI is effective to boost executive functioning in daily living. Furthermore, we indicated that DAI in deep brain nuclei may jeopardize long-term benefit from cognitive training. Individualized rehabilitation programs are crucial in adolescents with different locations of TBI-lesions. Long term follow-up of pediatric TBI is essential.

Chronic Upregulation of Cleaved-Caspase-3 Associated with Chronic Myelin Pathology and Microvascular Reorganization in the Thalamus after Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) is associated with long-term disabilities and devastating chronic neurological complications including problems with cognition, motor function, sensory processing, as well as behavioral deficits and mental health problems such as anxiety, depression, personality change and social unsuitability. Clinical data suggest that disruption of the thalamo-cortical system including anatomical and metabolic changes in the thalamus following TBI might be responsible for some chronic neurological deficits following brain trauma. Detailed mechanisms of these pathological processes are not completely understood. The goal of this study was to evaluate changes in the thalamus following TBI focusing on cleaved-caspase-3, a specific effector of caspase pathway activation and myelin and microvascular pathologies using immuno- and histochemistry at different time points from 24 h to 3 months after controlled cortical impact (CCI) in adult Sprague-Dawley rats. Significant increases in cleaved-caspase-3 immunoreactivity in the thalamus were observed starting one month and persisting for at least three months following experimental TBI. Further, the study demonstrated an association of cleaved-caspase-3 with the demyelination of neuronal processes and tissue degeneration in the gray matter in the thalamus, as reflected in alterations of myelinated fiber integrity (luxol fast blue) and decreases in myelin basic protein (MBP) immunoreactivity. The immunofluorescent counterstaining of cleaved-caspase-3 with endothelial barrier antigen (EBA), a marker of blood-brain barrier, revealed limited direct and indirect associations of cleaved caspase-3 with blood-brain barrier damage. These results demonstrate for the first time a significant chronic upregulation of cleaved-caspase-3 in selected thalamic regions associated with cortical regions directly affected by CCI injury. Further, our study is also the first to report that significant upregulation of cleaved-caspase-3 in selected ipsilateral thalamic regions is associated with microvascular reorganization reflected in the significant increases in the number of microvessels with blood-brain barrier alterations detected by EBA staining. These findings provide new insights into potential mechanisms of TBI cell death involving chronic activation of caspase-3 associated with disrupted cortico-thalamic and thalamo-cortical connectivity. Moreover, this study offers the initial evidence that this upregulation of activated caspase-3, delayed degeneration of myelinated nerve fibers and microvascular reorganization with impaired blood-brain barrier integrity in the thalamus might represent reciprocal pathological processes affecting neuronal networks and brain function at the chronic stages of TBI.

Protective Effects of Cornel Iridoid Glycoside in Rats After Traumatic Brain Injury.

Cornel iridoid glycoside (CIG) is the active ingredient extracted from Cornus officinalis. Our previous studies showed that CIG had protective effects on several brain injury models. In the present study, we aimed to examine the effects and elucidate the mechanisms of CIG against traumatic brain injury (TBI). TBI was induced in the right cerebral cortex of male adult rats. The neurological and cognitive functions were evaluated by modified neurological severity score (mNSS) and object recognition test (ORT), respectively. The level of serum S100β was measured by an ELISA method. Nissl staining was used to estimate the neuron survival in the brain. The expression of proteins was determined by western blot and/or immunohistochemical staining. We found that intragastric administration of CIG in TBI rats ameliorated the neurological defects and cognitive impairment, and alleviated the neuronal loss in the injured brain. In the acute stage of TBI (24-72h), CIG decreased the level of S100β in the serum and brain, increased the ratio of Bcl-2/Bax and decreased the expression of caspase-3 in the injured cortex. Moreover, the treatment with CIG for 30 days increased the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), enhanced the expression of synapsin I, synaptophysin and postsynaptic density protein 95 (PSD-95), and inhibited the apoptosis-regulating factors in the chronic stage of TBI. The present study demonstrated that CIG had neuroprotective effects against TBI through inhibiting apoptosis in the acute stage and promoting neurorestoration in the chronic stage. The results suggest that CIG may be beneficial to TBI therapy.

Editorial: Brain Injury as a Neurodegenerative Disorder.

The acute stage of moderate-severe traumatic brain injury (TBI) entails the rapid unfolding of pathophysiological processes secondary to biomechanical damage that eventually stabilize, typically leaving a combination of focal damage (visible as encephalomalacia) and more widespread lesions, both to the white matter (known as traumatic axonal injury) and to the microvasculature of the brain (Povlishock and Katz, 2005). It has long been assumed that following resolution of these acute neuropathological events, that the brain then remains stable throughout the chronic stages of injury. However, a growing body of research, much of it from the groups represented in this special topic, has revealed ongoing losses to volume and white matter integrity of the brain (Bendlin et al., 2008; Ng et al., 2008; Farbota et al., 2012a,b; Adnan et al., 2013). Findings from these longitudinal studies do not appear to reflect simply the brain's healing for example, the process of gliosis or the resolution of edema. Rather, deterioration is observed in a number of studies between two time points that are well within the chronic stages of injury (e.g., Greenberg et al., 2008; Green et al., 2014), thereby representing progressive and possibly neurodegenerative changes. With these important scientific developments in mind, the broad aims of this special topic of Frontiers in Human Neuroscience were three-fold: (i) To challenge the assumption of stability of the brain in chronic TBI and to advance a reconceptualization of moderate-severe TBI as a progressive, deteriorative disorder; (ii) to provide preliminary data on the characteristics and causes of deteriorative changes; and, (iii) to open a discussion about the clinical implications of these progressive changes observed in the chronic stages of TBI. The overarching goal of the issue is to stimulate further research into decline in the chronic stages of TBI, with a longer-term view to intervention research aimed at prevention or mitigation.

Functional Correlates of Midline Brain Volume Loss in Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with long-term changes in daily life functioning, yet the neuroanatomical correlates of these changes are poorly understood. This study related outcome assessed across several domains to brain structure derived from quantitative magnetic resonance imaging (MRI). Sixty individuals spanning a wide range of TBI severity participated 1-year post-injury as part of the Toronto TBI study. Volumetric data over 38 brain regions were derived from high resolution T1-weighted MRI scans. Functioning was assessed with a battery of self- and significant-other rated measures. Multivariate analysis (partial least squares) was used to identify shared variance between the neuroimaging and outcome measures. TBI was associated with item endorsement on outcome questionnaires without strong evidence for severity or focal lesion effects. Prefrontal midline, cingulate, medial temporal, right inferior parietal and basal ganglia/thalamic volumes were associated with measures of initiative, energization, and physical complaints. In the chronic stage of TBI, self-initiation, energization, and physical complaints related to a specific pattern of volume loss in midline and lateral regions known to be involved in motivation, apathy, and attention. These results suggest that crucial functional changes in chronic TBI may be associated with volume loss in established midline-frontal and attentional circuits.

Cognitive gains from gist reasoning training in adolescents with chronic-stage traumatic brain injury.

Adolescents with traumatic brain injury (TBI) typically demonstrate good recovery of previously acquired skills. However, higher-order and later emergent cognitive functions are often impaired and linked to poor outcomes in academic and social/behavioral domains. Few control trials exist that test cognitive treatment effectiveness at chronic recovery stages. The current pilot study compared the effects of two forms of cognitive training, gist reasoning (top-down) versus rote memory learning (bottom-up), on ability to abstract meanings, recall facts, and utilize core executive functions (i.e., working memory, inhibition) in 20 adolescents (ages 12–20) who were 6 months or longer post-TBI. Participants completed eight 45-min sessions over 1 month. After training, the gist reasoning group (n = 10) exhibited significant improvement in ability to abstract meanings and increased fact recall. This group also showed significant generalizations to untrained executive functions of working memory and inhibition. The memory training group (n = 10) failed to show significant gains in ability to abstract meaning or on other untrained specialized executive functions, although improved fact recall approached significance. These preliminary results suggest that relatively short-term training (6 h) utilizing a top-down reasoning approach is more effective than a bottom-up rote learning approach in achieving gains in higher-order cognitive abilities in adolescents at chronic stages of TBI. These findings need to be replicated in a larger study; nonetheless, the preliminary data suggest that traditional cognitive intervention schedules need to extend to later-stage training opportunities. Chronic-stage, higher-order cognitive trainings may serve to elevate levels of cognitive performance in adolescents with TBI.

Long-Term Upregulation of Inflammation and Suppression of Cell Proliferation in the Brain of Adult Rats Exposed to Traumatic Brain Injury Using the Controlled Cortical Impact Model

The long-term consequences of traumatic brain injury (TBI), specifically the detrimental effects of inflammation on the neurogenic niches, are not very well understood. In the present in vivo study, we examined the prolonged pathological outcomes of experimental TBI in different parts of the rat brain with special emphasis on inflammation and neurogenesis. Sixty days after moderate controlled cortical impact injury, adult Sprague-Dawley male rats were euthanized and brain tissues harvested. Antibodies against the activated microglial marker, OX6, the cell cycle-regulating protein marker, Ki67, and the immature neuronal marker, doublecortin, DCX, were used to estimate microglial activation, cell proliferation, and neuronal differentiation, respectively, in the subventricular zone (SVZ), subgranular zone (SGZ), striatum, thalamus, and cerebral peduncle. Stereology-based analyses revealed significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle. In parallel, significant decrements in Ki67-positive proliferating cells in SVZ and SGZ, but only trends of reduced DCX-positive immature neuronal cells in SVZ and SGZ were detected relative to sham control group. These results indicate a progressive deterioration of the TBI brain over time characterized by elevated inflammation and suppressed neurogenesis. Therapeutic intervention at the chronic stage of TBI may confer abrogation of these deleterious cell death processes.