Sequelae Of Traumatic Brain Injury Research Articles

Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.

While stroke is a recognized short-term sequela of traumatic brain injury, evidence about long-term ischemic stroke risk after traumatic brain injury remains limited. The Atherosclerosis Risk in Communities Study is an ongoing prospective cohort comprised of US community-dwelling adults enrolled in 1987 to 1989 followed through 2019. Head injury was defined using self-report and hospital-based diagnostic codes and was analyzed as a time-varying exposure. Incident ischemic stroke events were physician-adjudicated. We used Cox regression adjusted for sociodemographic and cardiovascular risk factors to estimate the hazard of ischemic stroke as a function of head injury. Secondary analyses explored the number and severity of head injuries; the mechanism and severity of incident ischemic stroke; and heterogeneity within subgroups defined by race, sex, and age. Our analysis included 12 813 participants with no prior head injury or stroke. The median follow-up age was 27.1 years (25th-75th percentile=21.1-30.5). Participants were of median age 54 years (25th-75th percentile=49-59) at baseline; 57.7% were female and 27.8% were Black. There were 2158 (16.8%) participants with at least 1 head injury and 1141 (8.9%) participants with an incident ischemic stroke during follow-up. For those with head injuries, the median age to ischemic stroke was 7.5 years (25th-75th percentile=2.2-14.0). In adjusted models, head injury was associated with an increased hazard of incident ischemic stroke (hazard ratio [HR], 1.34 [95% CI, 1.12-1.60]). We observed evidence of dose-response for the number of head injuries (1: HR, 1.16 [95% CI, 0.97-1.40]; ≥2: HR, 1.94 [95% CI, 1.39-2.71]) but not for injury severity. We observed evidence of stronger associations between head injury and more severe stroke (National Institutes of Health Stroke Scale score ≤5: HR, 1.31 [95% CI, 1.04-1.64]; National Institutes of Health Stroke Scale score 6-10: HR, 1.64 [95% CI, 1.06-2.52]; National Institutes of Health Stroke Scale score ≥11: HR, 1.80 [95% CI, 1.18-2.76]). Results were similar across stroke mechanism and within strata of race, sex, and age. In this community-based cohort, head injury was associated with subsequent ischemic stroke. These results suggest the importance of public health interventions aimed at preventing head injuries and primary stroke prevention among individuals with prior traumatic brain injuries.

Modified Mouse Model of Repetitive Mild Traumatic Brain Injury Incorporating Thinned-Skull Window and Fluid Percussion.

Mild traumatic brain injury is a clinically highly heterogeneous neurological disorder. Highly reproducible traumatic brain injury (TBI) animal models with well-defined pathologies are urgently needed for studying the mechanisms of neuropathology after mild TBI and testing therapeutics. Replicating the entire sequelae of TBI in animal models has proven to be a challenge. Therefore, the availability of multiple animal models of TBI is necessary to account for the diverse aspects and severities seen in TBI patients. CHI is one of the most common methods for fabricating rodent models of rmTBI. However, this method is susceptible to many factors, including the impact method used, the thickness and shape of the skull bone, animal apnea, and the type of head support and immobilization utilized. The aim of this protocol is to demonstrate a combination of the thinned-skull window and fluid percussion injury (FPI) methods to produce a precise mouse model of CHI-associated rmTBI. The primary objective of this protocol is to minimize factors that could impact the accuracy and consistency of CHI and FPI modeling, including skull bone thickness, shape, and head support. By utilizing a thinned-skull window method, potential inflammation due to craniotomy and FPI is minimized, resulting in an improved mouse model that replicates the clinical features observed in patients with mild TBI. Results from behavior and histological analysis using hematoxylin and eosin (HE) staining suggest that rmTBI can lead to a cumulative injury that produces changes in both behavior and gross morphology of the brain. Overall, the modified CHI-associated rmTBI presents a useful tool for researchers to explore the underlying mechanisms that contribute to focal and diffuse pathophysiological changes in rmTBI.

An overview of preclinical models of traumatic brain injury (TBI): relevance to pathophysiological mechanisms.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, affecting millions annually worldwide. Although the majority of TBI patients return to premorbid baseline, a subset of patient can develop persistent and often debilitating neurocognitive and behavioral changes. The etiology of TBI within the clinical setting is inherently heterogenous, ranging from sport related injuries, fall related injuries and motor vehicle accidents in the civilian setting, to blast injuries in the military setting. Animal models of TBI, offer the distinct advantage of controlling for injury modality, duration and severity. Furthermore, preclinical models of TBI have provided the necessary temporal opportunity to study the chronic neuropathological sequelae of TBI, including neurodegenerative sequelae such as tauopathy and neuroinflammation within the finite experimental timeline. Despite the high prevalence of TBI, there are currently no disease modifying regimen for TBI, and the current clinical treatments remain largely symptom based. The preclinical models have provided the necessary biological substrate to examine the disease modifying effect of various pharmacological agents and have imperative translational value. The current review will include a comprehensive survey of well-established preclinical models, including classic preclinical models including weight drop, blast injury, fluid percussion injury, controlled cortical impact injury, as well as more novel injury models including closed-head impact model of engineered rotational acceleration (CHIMERA) models and closed-head projectile concussive impact model (PCI). In addition to rodent preclinical models, the review will include an overview of other species including large animal models and Drosophila. There are major neuropathological perturbations post TBI captured in various preclinical models, which include neuroinflammation, calcium dysregulation, tauopathy, mitochondrial dysfunction and oxidative stress, axonopathy, as well as glymphatic system disruption. The preclinical models of TBI continue to offer valuable translational insight, as well as essential neurobiological basis to examine specific disease modifying therapeutic regimen.

Women Report Worse Neurobehavioral Symptoms than Men following Mild Traumatic Brain Injury in U.S. Military Service Members.

Women are more directly involved in combat operations today than ever before, currently making up 18.6% of officers and 16.8% of enlisted personnel in the US military. However, women continue to be underrepresented in military research. Studies which do consider gender differences in traumatic brain injury (TBI) outcomes have shown that women report significantly more post-concussive symptoms compared to men. Conclusions for true gender differences related to TBI is hard to make without controlling for non-TBI factors. The objective of this study was to examine the effects of gender specific to mild TBI (MTBI) sequelae from injured and non-injured control groups and investigate the role of PTSD in symptom reporting. It should be noted that the terms gender and men/women are used in this paper in place of sex or males/females given we are not discussing biological attributes. A total of 966 U.S. military service members and veterans where include in the study. Of the total sample, 455 men and 46 women where in the MTBI group, 285 men and 31 women in the Injured Controls group (IC), 111 men and 38 women in the Non-injured Controls group (NIC). Postconcussive and quality of life symptoms were compared for men and women while controlling for combat exposure. MTBI and IC groups were also stratified by PTSD presentation. Measures used included the Neurobehavioral Symptom Inventory (NSI), PTSD Checklist (PCL-C), Traumatic Brain Injury Quality of Life (TBI-QOL), and Combat Exposure Scale. In the MTBI group, women had worse scores on NSI total, NSI Somatosensory and Affective clusters; and the TBI-QOL Anxiety, Fatigue, and Headache scales (n2=.018 to .032, small to small-medium effect sizes). When PTSD was present, women had worse scores on the NSI Somatosensory cluster only (n2=.029, small-medium effect size). In contrast, when PTSD was absent, women had worse scores on the NSI Somatosensory and Affective clusters, and the TBI-QOL Anxiety and Headache scales compared to men (n2=.032 to .063, small to medium effect sizes). In the IC group, women had worse scores on the NSI Cognitive cluster and the TBI-QOL Fatigue and Pain Interference scales (n2=.024 to .042, small to small-medium effect sizes). However, group differences were no longer found when stratified by PTSD sub-groups. In the NIC group, there were no significant group differences for all analyses. We were able to identify symptoms unique to women recovering from MTBI which were not present following other forms of physical injury or healthy controls. However, the impact of PTSD exacerbates the symptom profile and its comorbidity with MTBI equates most of the noted gender differences.

Analysis of middle meningeal artery embolization for the treatment of chronic, acute on chronic, and subacute subdural hematomas.

Chronic subdural hematoma (cSDH) is a common sequela of traumatic brain injury. Middle meningeal artery embolization (MMAE) has shown promising results as an emerging minimally invasive alternative treatment. The purpose of this study is to examine the safety and efficacy of MMAE performed in patients with cSDH, acute-on-chronic, and subacute SDH with a traumatic etiology. This retrospective study included cases performed at a Level II Trauma Center between January 2019 and December 2020 for MMAE of cSDHs. Data collected included patient demographic characteristics and comorbidities, SDH characteristics, complications, and efficacy outcomes. The lesion measurements were collected before the procedure, 4-6 weeks and 3-6 months post-procedure. In our patient population, 78% (39) either had lesions improve or completely resolved. The sample included 50 patients with a mean age of 74 years old. Statistically significant reductions in lesion size were found from pre- to post-procedure in the left lesions, right lesions, and midline shifts. The left lesions decreased from 13.88 ± 5.70 mm to 3.19 ± 4.89 mm at 3-6 months with P < 0.001. The right lesions decreased from 13.74 ± 5.28 mm to 4.93 ± 7.46 mm at 3-6 months with P = 0.02. Midline shifts decreased from 3.78 ± 3.98 mm to 0.48 ± 1.31 mm at 3-6 months with P = 0.02. No complications were experienced for bleeding, hematoma, worsening SDH, pseudoaneurysm, or stroke. Our pilot study from a single center utilizing MMAE demonstrates that MMAE is successful without increasing treatment-related complications not only for cSDH but also in acute-on-cSDH and SDH with a subacute component.

Tracing the path of disruption: 13C isotope applications in traumatic brain injury-induced metabolic dysfunction.

Cerebral metabolic dysfunction is a critical pathological hallmark observed in the aftermath of traumatic brain injury (TBI), as extensively documented in clinical investigations and experimental models. An in-depth understanding of the bioenergetic disturbances that occurfollowing TBI promises to reveal novel therapeutic targets, paving the way for the timely development ofinterventions to improve patient outcomes. The 13C isotope tracing technique represents a robust methodological advance, harnessing biochemical quantification to delineate the metabolic trajectories of isotopically labeled substrates. This nuanced approach enables real-time mapping of metabolic fluxes, providing a window into the cellular energetic state and elucidating the perturbations in key metabolic circuits. By applying this sophisticated tool, researchers can dissect the complexities of bioenergetic networks within the central nervous system, offering insights into the metabolic derangements specific to TBI pathology. Embraced by both animal studies and clinical research, 13C isotope tracing has bolstered our understanding of TBI-induced metabolic dysregulation. This review synthesizes current applications of isotope tracing and its transformative potential in evaluating and addressing the metabolic sequelae of TBI.

Caregiver report of social-emotional functioning in infants and young children after inflicted traumatic brain injury

ABSTRACT Social-emotional difficulties are common sequelae of traumatic brain injury (TBI). Children who have experienced inflicted TBI (iTBI) may be at increased risk for social-emotional problems due to the risk factors associated with both early neurologic injury and with child maltreatment. We characterized the associations among injury severity, caregiver type (i.e., biological parents, non-kinship, kinship), and child social-emotional functioning in 41 infants and young children who had sustained iTBI and were seen in a large, regional children’s hospital. This study was a retrospective analysis, utilizing data collected from the medical record as part of routine clinical care. Social-emotional functioning was assessed with the Bayley Scales of Infant and Toddler Development-Third Edition. Children with more severe injuries were rated as having worse social-emotional functioning. Caregiver type was associated with child social-emotional scores, above and beyond injury and demographic predictors. Biological parents were more likely to report better social-emotional skills than non-kinship caregivers, with the pattern of results suggesting that rater bias plays a role in this difference. In order to ensure that children are accurately identified for supports, these relationships should be considered when interpreting caregiver report of social-emotional skills.

Coverage of education and training of traumatic brain injury-induced growth hormone deficiency in US residency and fellowship programs: a cross-sectional study

BackgroundHypopituitarism, including growth hormone deficiency (GHD), is a common sequela of traumatic brain injury (TBI). This study explored the coverage of education and training of TBI-induced hypopituitarism in general and GHD in particular, in postgraduate program curricula to identify knowledge gaps and opportunities.MethodsAn online survey and qualitative interviews (focus groups) were conducted among endocrinology, neurology, and physiatry postgraduate program directors in the United States (US). The study received an IRB exemption.ResultsA total of 419 fellowship and residency programs were invited to participate; 60 program directors completed the survey and 11 of these participated in the focus groups. About half of the respondents considered TBI-induced hypopituitarism important or fairly important to include in the curriculum, and nearly two-thirds considered it an appropriate training component. Neurology program directors considered education regarding hypopituitarism following TBI less important and relevant for their curricula compared with endocrinology and physiatry program directors. About half (53%) of the programs responded that they included TBI-induced pituitary disorders in their curricula. About two-thirds (68%) of endocrinology programs, compared with only one-quarter (25%) of neurology programs, covered TBI-induced pituitary disorders. Respondents identified multiple barriers to expanding hypopituitarism following TBI in the curriculum, including the rarity of condition and lack of time/room in the curriculum. Respondents reported that consensus clinical guidelines and the availability of more data on TBI-induced hypopituitarism, including GHD, would greatly impact the development of educational curricula on this topic.ConclusionsTo improve the management of TBI-induced hypopituitarism, education and training should be expanded in US fellowship and residency programs to prepare trainees to effectively screen, diagnose, and treat TBI-induced hypopituitarism, including GHD.

Pseudobulbar affect - an often overlooked and under-diagnosed debilitating sequelae of traumatic brain injury: A case report

Pseudobulbar affect - an often overlooked and under-diagnosed debilitating sequelae of traumatic brain injury: A case report

Serum amyloid P component accumulates and persists in neurones following traumatic brain injury.

The mechanisms underlying neurodegenerative sequelae of traumatic brain injury (TBI) are poorly understood. The normal plasma protein, serum amyloid P component (SAP), which is normally rigorously excluded from the brain, is directly neurocytotoxic for cerebral neurones and also binds to Aβ amyloid fibrils and neurofibrillary tangles, promoting formation and persistence of Aβ fibrils. Increased brain exposure to SAP is common to many risk factors for dementia, including TBI, and dementia at death in the elderly is significantly associated with neocortical SAP content. Here, in 18 of 30 severe TBI cases, we report immunohistochemical staining for SAP in contused brain tissue with blood-brain barrier disruption. The SAP was localized to neurofilaments in a subset of neurones and their processes, particularly damaged axons and cell bodies, and was present regardless of the time after injury. No SAP was detected on astrocytes, microglia, cerebral capillaries or serotoninergic neurones and was absent from undamaged brain. C-reactive protein, the control plasma protein most closely similar to SAP, was only detected within capillary lumina. The appearance of neurocytotoxic SAP in the brain after TBI, and its persistent, selective deposition in cerebral neurones, are consistent with a potential contribution to subsequent neurodegeneration.

3 The Menopause Transition in Women with Traumatic Brain Injury

Objective:All premenopausal women who survive traumatic brain injury (TBI) will eventually experience menopause. Challenges experienced by women with TBI are superimposed on challenges associated with hormonal changes in midlife. Some women with stressful life contexts such as TBI are more vulnerable to the added burdens of the menopause transition, potentiating its effects. Although it may be argued that TBI research correctly overrepresents the male experience given disparities in injury rates (4:1), there are important differences in how females and males age, their specific health needs, and the psychosocial context of midlife. Development of evidence-based interventions begins with understanding the experience of menopause after TBI, including where and when key problems may emerge.Participants and Methods:All participants were women 40-60 years old, not taking hormones (i.e., replacement therapy or other systematic hormones), with intact ovaries. Women with TBI were &gt; 2 years post injury, whose menstrual period returned after injury, and were living in the community. Severity of injury ranged from complicated-mild to severe TBI. Pre/peri and postmenopausal status was determined by presence/absence of menstrual period in previous 6 months, respectively. Eighteen common menopause symptoms (vasomotor, somatic, psychological, and cognitive) were assessed for presence and frequency (rarely-always), along with Quality of Life in Neurological Disorders (Neuro-QOL) Sleep Disturbance and Traumatic Brain Injury Quality of Life (TBIQOL) Anxiety, Depression, and Fatigue scales.Results:Overall, women with TBI (n = 68) showed greater presence and frequency of symptoms than women without TBI (n = 153), with fewer within-group differences by menopausal status. Among pre/peri-menopausal women, TBI and non-TBI groups did not significantly differ and showed small effect sizes on symptoms associated with changes in estrogen during menopause, including hot flashes, night sweats, bowel and bladder sequelae, and breast tenderness. However, pre/peri-menopausal women with TBI also endorsed body aches and headaches, as well as troubles with memory, focus, fatigue, cognitive concerns, sleep, and anxiety significantly more than their pre/peri-menopausal counterparts (all medium effect sizes). Among postmenopausal women, those with TBI had significantly greater frequency of hot flashes, crying spells, poor memory, worry, moodiness, panic attacks, sleep disturbance, and anxiety than women without TBI. Within TBI, only hot flashes and breast tenderness were greater in postmenopausal versus pre/peri-menopausal women. Within non-TBI, postmenopausal status was associated with significantly greater hot flashes, night sweats, restlessness, poor memory, irritability, sleep disturbance, and anxiety, with greater fatigue but not significantly.Conclusions:The findings support a model of TBI and menopause in which symptoms most closely associated with estrogen decline in pre/peri-menopause are generally similar between women with and without TBI, and symptoms that overlap with common TBI sequelae were generally more often present and frequently experienced among women with TBI versus non-TBI. We did not observe a synergistic or potentiating effect of TBI on menopause symptoms in post-menopause. These findings offer insight that contextualizes the experience of menopause symptoms among women with TBI. Such insights are essential for the development of treatment approaches that maximize health and wellbeing during the menopause transition for women with TBI.

The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) affects more than 2.5 million people in the U.S. each year and is the leading cause of death and disability in children and adults ages 1 to 44. Approximately 90% of TBI cases are classified as mild but may still lead to acute detrimental effects such as impaired cerebral blood flow (CBF) that result in prolonged impacts on brain function and quality of life in up to 15% of patients. We previously reported that nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonism reversed mild blast TBI-induced vestibulomotor deficits and prevented hypoxia. To explore mechanisms by which the NOP receptor-N/OFQ pathway modulates hypoxia and other TBI sequelae, the ability of the NOP antagonist, SB-612111 (SB), to reverse TBI-induced CBF and associated injury marker changes were tested in this study. Male Wistar rats randomly received sham craniotomy or craniotomy + TBI via controlled cortical impact. Injury severity was assessed after 1h (modified neurological severity score (mNSS). Changes in CBF were assessed 2h post-injury above the exposed cortex using laser speckle contrast imaging in response to the direct application of increasing concentrations of vehicle or SB (1, 10, and 100µM) to the brain surface. TBI increased mNSS scores compared to baseline and confirmed mild TBI (mTBI) severity. CBF was significantly impaired on the ipsilateral side of the brain following mTBI, compared to contralateral side and to sham rats. SB dose-dependently improved CBF on the ipsilateral side after mTBI compared to SB effects on the respective ipsilateral side of sham rats but had no effect on contralateral CBF or in uninjured rats. N/OFQ levels increased in the cerebral spinal fluid (CSF) following mTBI, which correlated with the percent decrease in ipsilateral CBF. TBI also activated ERK and cofilin within 3h post-TBI; ERK activation correlated with increased CSF N/OFQ. In conclusion, this study reveals a significant contribution of the N/OFQ-NOP receptor system to TBI-induced dysregulation of cerebral vasculature and suggests that the NOP receptor should be considered as a potential therapeutic target for TBI.

Efficacy of a music-based intervention in a preclinical model of traumatic brain injury: An initial foray into a novel and non-pharmacological rehabilitative therapy

Traumatic brain injury (TBI) causes neurobehavioral and cognitive impairments that negatively impact life quality for millions of individuals. Because of its pernicious effects, numerous pharmacological interventions have been evaluated to attenuate the TBI-induced deficits or to reinstate function. While many such pharmacotherapies have conferred benefits in the laboratory, successful translation to the clinic has yet to be achieved. Given the individual, medical, and societal burden of TBI, there is an urgent need for alternative approaches to attenuate TBI sequelae and promote recovery. Music based interventions (MBIs) may hold untapped potential for improving neurobehavioral and cognitive recovery after TBI as data in normal, non-TBI, rats show plasticity and augmented cognition. Hence, the aim of this study was to test the hypothesis that providing a MBI to adult rats after TBI would improve cognition, neurobehavior, and histological endpoints. Adult male rats received a moderate-to-severe controlled cortical impact injury (2.8 mm impact at 4 m/s) or sham surgery (n = 10–12 per group) and 24 h later were randomized to classical Music or No Music (i.e., ambient room noise) for 3 h/day from 19:00 to 22:00 h for 30 days (last day of behavior). Motor (beam-walk), cognitive (acquisition of spatial learning and memory), anxiety-like behavior (open field), coping (shock probe defensive burying), as well as histopathology (lesion volume), neuroplasticity (BDNF), and neuroinflammation (Iba1, and CD163) were assessed. The data showed that the MBI improved motor, cognitive, and anxiety-like behavior vs. No Music (p's < 0.05). Music also reduced cortical lesion volume and activated microglia but increased resting microglia and hippocampal BDNF expression. These findings support the hypothesis and provide a compelling impetus for additional preclinical studies utilizing MBIs as a potential efficacious rehabilitative therapy for TBI.

Psychiatric sequelae of traumatic brain injury - future directions in research.

Despite growing appreciation that traumatic brain injury (TBI) is an important public health burden, our understanding of the psychiatric and behavioural consequences of TBI remains limited. These changes are particularly detrimental to a person's sense of self, their relationships and theirparticipation in the wider community, and they continue to have devastating individual and cumulative effects long after TBI. This Review relates specifically to TBIs that confer objective clinical or biomarker evidence of structural brain injury; symptomatic head injuries without such evidence are outside the scope of this article. Common psychiatric, affective and behavioural sequelae of TBI and their proposed underlying mechanisms are outlined, along with a brief overview of current treatments. Suggestions for how scientists and clinicians can work together in the future to address the chasms in clinical care and knowledge are discussed in depth.

SLEEP DISTURBANCE AFTER TRAUMATIC BRAIN INJURY: NEW INSIGHT

Disruptions in sleep-wake cycles are particularly prevalent after a Traumatic Brain Injury (TBI). Sleep disruptions may occur as a main impact of brain damage or as a result of other neuropsychiatric sequelae of TBI, such as anxiety disorder, depressive disorders, substance abuse, chronic pain, and/or medication consumption. Chronic discomfort (headache and broad pain, presumably of central origin) and/or sleep difficulties (insomnia, disturbed breathing, periodic limb movements) occur in about one in five people with TBI. Disruptions in sleep-wake cycles linked with TBI need therapy. Although data specific to individuals with TBI is currently limited, cognitive-behavioral treatment and medication may be beneficial in alleviating sleep-wake problems in people who have sustained a TBI. This article aims to raise awareness of sleep disturbance after TBI to enhance diagnosis, assessment, and therapy and disclose new research opportunities.

Exploring medical cannabis use in individuals with a traumatic brain injury

Aim: Traumatic brain injury (TBI) is a common neurological condition, which can present with a wide range of neuropsychological symptoms. Treating this broad spectrum of symptoms represents a significant medical challenge. In part because of this, there is growing interest in the use of medical cannabis to treat the sequelae of TBI, as medical cannabis has been used to treat multiple associated conditions, such as pain. However, medical cannabis represents a heterogeneous collection of therapies, and relatively little is known about their effectiveness in treating TBI symptoms. The aim of the present study was therefore to assess medical cannabis use in patients with TBI. Methods: In the present study, a retrospective chart review was conducted of patterns of cannabis use and TBI symptoms in individuals who used medical cannabis to treat TBI-related symptoms. All subjects were recruited from a medical cannabis clinic, where cannabis was authorized by physicians, using licensed cannabis products. A total of 53 subjects provided written consent to have their charts reviewed. Results: Neuropsychiatric conditions, including depression, pain, and anxiety were frequent in this group. The most common forms of medical cannabis consumption at intake included smoking, vaping, and oral ingestion. Patients used a combination of high tetrahydrocannabinol (THC)/low cannabidiol (CBD) and low THC/high CBD products, typically 1–3 times per day. Medical cannabis appeared to be relatively well-tolerated in subjects, with few serious side effects. At follow-up, subjects self-reported improvements in TBI symptoms, although these were not statistically significant when assessed using validated questionnaires. Conclusions: Overall findings indicate modest potential benefits of medical cannabis for TBI, but further research will be required to validate these results.

Psychosis Secondary to Traumatic Brain Injury: Critical Literature Review and Illustrative Case Study

Psychosis secondary to traumatic brain injury (PSTBI) is rare yet a serious sequela of traumatic brain injury (TBI).We provide a critical literature review on PSTBI, outlining clinical features and approach to the diagnosis and treatment. Finally, we illustrate a case description, to discuss its conceptual framework. Conceptualizing PSTBI as a neurobiological syndrome has clinical relevance, insofar as, it facilitates a rational scheme, by which specific diagnostic dilemmas should be tackled in the workup, to provide a tailored treatment. Additionally, it may shed light on the understanding of psychotic disorders by integrating data on primary and secondary psychosis. TBI can contribute to the emergence of psychotic symptoms in various manners. It may precipitate psychosis in susceptible individuals, occur in a direct relationship to post‐traumatic epilepsy, or develop directly due to brain injury. It is this last clinical entity that we focus on in this article. Its neurobiological underpinnings comprise the following mechanisms: damage to frontal and temporal lobes (primary injury); structural and/or functional dysconnectivity in sensory‐ and other information‐ ‐processing networks, such as the Default‐Mode network, which stem from diffuse axonal injury (DAI) (primary injury); neuroinflammation and neurodegeneration (secondary injury). The clinical presentation may take two forms: delusional disorder or schizophrenia‐like psychosis. Both subtypesare often preceded by a prodromal phase superimposed on other sequelae, namely affective instability, social and occupational functional decline. In comparison to primary schizophrenia, PSTBI has a lower genetic load, fewer negative symptoms, more neurocognitive symptoms, which may be intertwined with frontal‐subcortical system dysfunction/ frontal syndromes and are more likely to present findings on neuroimaging and electroencephalographic studies. PSTBI has a bimodal distribution of onset. Latencies of under a year (early‐onset) have been associated with DAI and delusional disorder subtype. Schizophrenia‐like psychosis subtype usually develops after a latency of 1‐5 years (late‐onset), and has been more associated with epilepsy, focal brain lesions and a chronic course. Antipsychotics should be used cautiously considering the increased sensitivity to the sedating, anticholinergic, and seizure threshold‐lowering side effects. Late‐onset PSTBI might benefit from anticonvulsants, by virtue of its anti‐ ‐kindling properties. Additionally, further pharmacological approaches may be used to address cognitive, emotional, and behavioural issues.

Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort.

Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Hyperbaric Oxygen Therapy for the Management of Mild and Moderate Traumatic Brain Injury: A Single-Center Experience

Hyperbaric oxygen therapy (HBOT) has been shown to be an effective modality in the management of a variety of conditions. However, its role in the treatment of traumatic brain injury (TBI) remains an area of controversy. This study aims to evaluate the safety and outcomes of HBOT in managing the long-term sequelae of TBI. The records of TBI patients who underwent increments of 40 sessions of HBOT at 1.5 atmosphere absolute at a single medical center were reviewed. The outcome measures included physical, cognitive (i.e., Trail Making Test, parts A and B; U.S. Department of Veterans Affairs' Evaluation of Cognitive Impairment and Subjective Symptoms tool), and single-photon emission computed tomography findings. The complications and withdrawals were recorded. During the study period, 17 patients underwent HBOT to manage the long-term sequelae of their TBI. Of the 17 patients, 12 (70.6%) completed 120 HBOT sessions and were evaluated 3 months after treatment. All 12 patients had statistically significant improvements in their Trail Making Test, parts A and B, and U.S. Department of Veterans Affairs' Evaluation of Cognitive Impairment and Subjective Symptoms scores (P < 0.05). Additionally, single-photon emission computed tomography depicted increased cerebral blood flow and oxygen metabolism among studied subjects compared with the baseline values. A total of 5 patients withdrew from the study, which was related to new-onset headaches associated with HBOT for 1 patient. HBOT using 1.5 atmosphere absolute in increments of 40 sessions was found to be a safe and effective modality in the management of the long-term sequelae of TBI. HBOT should be considered in the management of this patient population.

Alpha-methyltyrosine reduces the acute cardiovascular and behavioral sequelae in a murine model of traumatic brain injury.

Increased catecholamines contribute to heightened cardiovascular reactivity and behavioral deficits after traumatic brain injury (TBI); adrenergic receptor blockade has limited success in reducing adverse sequelae of TBI. Injury-induced increases in the synthesis of catecholamines could contribute to adverse outcomes in TBI. Inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) could offer a benefit after TBI. Original research trial in mice randomized to αMT (50 mg·kg -1 ·d -1 ) or vehicle for 1 week after TBI induced by controlled cortical impact. Primary outcomes of cardiovascular reactivity and behavioral deficits were assessed after 1 week. Secondary outcomes included blood brain barrier permeability and quantification of gene transcription whose products determine intraneuronal chloride concentrations, the release of catecholamines, and activation of the sympathetic nervous system. These genes were the alpha-2 adrenergic receptor ("Adra2c"), the sodium-potassium-chloride cotransporter ("Nkcc1"), and the potassium chloride cotransporter ("Kcc2"). We also assessed the effect of TBI and αMT on the neuronal chloride/bicarbonate exchanger ("Ae3"). Traumatic brain injury-induced increases in blood pressure and cardiac reactivity were blocked by αMT. Inhibition of catecholamine synthesis decreased blood brain barrier leakage and improved behavioral outcomes after TBI. Traumatic brain injury diminished the transcription of Adra2c and enhanced expression of Nkcc1 while reducing Kcc2 transcription; αMT prevented the induction of the Nkcc1 by TBI without reversing the effects of TBI on Kcc2 expression; αMT also diminished Ae3 transcription. Traumatic brain injury acutely increases cardiovascular reactivity and induces behavioral deficits in an αMT-sensitive manner, most likely by inducing Nkcc1 gene transcription. Alpha-methyltyrosine may prove salutary in the treatment of TBI by attenuating the enhanced expression of Nkcc1, minimizing blood brain barrier leakage, and diminishing central catecholamine and sympathetic output. We also found an unreported relationship between Kcc2 and the chloride/bicarbonate exchanger, which should be considered in the design of trials planned to manipulate central intraneuronal chloride concentrations following acute brain injury.