Protective Effects of Plant-Derived Compounds Against Traumatic Brain Injury.

Inflammation in the nervous system is one of the key features of many neurodegenerative diseases. It is increasingly being identified as a critical pathophysiological primitive mechanism associated with chronic neurodegenerative diseases following traumatic brain injury (TBI). Phytochemicals have a wide range of clinical properties due to their antioxidant and anti-inflammatory effects. Currently, there are few drugs available for the treatment of neurodegenerative diseases other than symptomatic relief. Numerous studies have shown that plant-derived compounds, in particular polyphenols, protect against various neurodegenerative diseases and are safe for consumption. Polyphenols exert protective effects on TBI via restoration of nuclear factor kappa B (NF-κB), toll-like receptor-4 (TLR4), and Nod-like receptor family proteins (NLRPs) pathways. In addition, these phytochemicals and their derivatives upregulate the phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/AKT) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, which have critical functions in modulating TBI symptoms. There is supporting evidence that medicinal plants and phytochemicals are protective in different TBI models, though future clinical trials are needed to clarify the precise mechanisms and functions of different polyphenolic compounds in TBI.

Raman Spectroscopy Spectral Fingerprints of Biomarkers of Traumatic Brain Injury.

Traumatic brain injury (TBI) affects millions of people of all ages around the globe. TBI is notoriously hard to diagnose at the point of care, resulting in incorrect patient management, avoidable death and disability, long-term neurodegenerative complications, and increased costs. It is vital to develop timely, alternative diagnostics for TBI to assist triage and clinical decision-making, complementary to current techniques such as neuroimaging and cognitive assessment. These could deliver rapid, quantitative TBI detection, by obtaining information on biochemical changes from patient's biofluids. If available, this would reduce mis-triage, save healthcare providers costs (both over- and under-triage are expensive) and improve outcomes by guiding early management. Herein, we utilize Raman spectroscopy-based detection to profile a panel of 18 raw (human, animal, and synthetically derived) TBI-indicative biomarkers (N-acetyl-aspartic acid (NAA), Ganglioside, Glutathione (GSH), Neuron Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase L1 (UCHL1), Cholesterol, D-Serine, Sphingomyelin, Sulfatides, Cardiolipin, Interleukin-6 (IL-6), S100B, Galactocerebroside, Beta-D-(+)-Glucose, Myo-Inositol, Interleukin-18 (IL-18), Neurofilament Light Chain (NFL)) and their aqueous solution. The subsequently derived unique spectral reference library, exploiting four excitation lasers of 514, 633, 785, and 830 nm, will aid the development of rapid, non-destructive, and label-free spectroscopy-based neuro-diagnostic technologies. These biomolecules, released during cellular damage, provide additional means of diagnosing TBI and assessing the severity of injury. The spectroscopic temporal profiles of the studied biofluid neuro-markers are classed according to their acute, sub-acute, and chronic temporal injury phases and we have further generated detailed peak assignment tables for each brain-specific biomolecule within each injury phase. The intensity ratios of significant peaks, yielding the combined unique spectroscopic barcode for each brain-injury marker, are compared to assess variance between lasers, with the smallest variance found for UCHL1 (σ2 = 0.000164) and the highest for sulfatide (σ2 = 0.158). Overall, this work paves the way for defining and setting the most appropriate diagnostic time window for detection following brain injury. Further rapid and specific detection of these biomarkers, from easily accessible biofluids, would not only enable the triage of TBI, predict outcomes, indicate the progress of recovery, and save healthcare providers costs, but also cement the potential of Raman-based spectroscopy as a powerful tool for neurodiagnostics.

Vitamin D Deficiency (VDD) and Benefits of Supplementation in Veterans with IBS-D.

Many veterans deployed to Gulf War areas suffer from persistent chronic diarrhea that is disabling and affects their quality of life. The causes for this condition have eluded investigators until recently and recent literature has shed light on the effect of vitamin D on the brain-gut axis. This study focused on determining clinical causes contributing to diarrhea and assessed whether reversing the identified causes, specifically vitamin D deficiency (VDD), could reduce the incidence of diarrhea in Gulf War veterans (GWVs). All patients completed a workup that included serologies (IBD, celiac), routine laboratory tests (CBC, chemistry panels, TSH, T4, CRP), cultures for enteric pathogens (C diff, bacteria, viruses, small intestinal bacterial overgrowth (SIBO)), and upper and lower endoscopies with histology and a trial of cholestyramine to exclude choleretic diarrhea and rifaximin for dysbiosis. A total of 4221 veterans were screened for chronic diarrhea, yielding 105 GWVs, of which 69 GWVs had irritable bowel syndrome with diarrhea (IBS-D). Paired t-tests demonstrated that all GWVs had VDD (t-11.62, df68 and sig(2-tailed) 0.0001) (defined as a vitamin D level less than 30 ng/mL with normal ranges of 30-100 ng/mL) but no positive serologies, inflammatory markers, abnormal endoscopies, cultures, or histology to explain their persistent diarrhea. There was no correlation with age, BMI, or inflammation. Some zip codes had a higher frequency of GWVs with VDD, but the number of deployments had no impact. Treatment with vitamin D supplementation (3000-5000 units), given in the morning, based on weight, reduced the number of bowel movements per day (p < 0.0001) without causing hypercalcemia. We suggest that VDD is important in the etiology of IBS-D in GWVs and that vitamin D supplementation significantly reduces diarrhea.

A systematic review of heart rate variability (HRV) biofeedback treatment following traumatic brain injury (TBI).

OBJECTIVE: Autonomic nervous system dysregulation is a common consequence of traumatic brain injury (TBI). Heart rate variability (HRV) is a cost-effective measure of autonomic nervous system functioning, with studies suggesting decreased HRV following moderate-to-severe TBI. HRV biofeedback treatment may improve post-TBI autonomic nervous system functioning and post-injury emotional and cognitive functioning. We provide a systematic evidence-based review of the state of the literature and effectiveness of HRV biofeedback following TBI. METHOD: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two coders coded each article and provided quality ratings. Seven papers met inclusion criteria. All studies included a measure of emotional functioning and 5 studies (63%) included neuropsychological outcomes. RESULTS: Participants completed 11 sessions of HRV biofeedback on average (range = 1 to 40). HRV biofeedback was associated with improved HRV following TBI. There was a positive relationship between increased HRV and TBI recovery following biofeedback, including improvements in cognitive and emotional functioning, and physical symptoms such as headaches, dizziness, and sleep problems. CONCLUSION: The literature on HRV biofeedback for TBI is promising, but in its infancy; effectiveness is unclear due to poor-to-fair study quality, and potential publication bias (all studies reported positive results).

Effect of aging on the cerebral metabolic mechanism of electroacupuncture treatment in rats with traumatic brain injury.

Objective: Aging has great influence on the clinical treatment effect of cerebrovascular diseases, and evidence suggests that the effect may be associated with age-related brain plasticity. Electroacupuncture is an effective alternative treatment for traumatic brain injury (TBI). In the present study, we aimed to explore the effect of aging on the cerebral metabolic mechanism of electroacupuncture to provide new evidence for developing age-specific rehabilitation strategies. Methods: Both aged (18 months) and young (8 weeks) rats with TBI were analyzed. Thirty-two aged rats were randomly divided into four groups: aged model, aged electroacupuncture, aged sham electroacupuncture, and aged control group. Similarly, 32 young rats were also divided into four groups: young model, young electroacupuncture, young sham electroacupuncture, and young control group. Electroacupuncture was applied to "Bai hui" (GV20) and "Qu chi" (LI11) for 8 weeks. CatWalk gait analysis was then performed at 3 days pre- and post-TBI, and at 1, 2, 4, and 8 weeks after intervention to observe motor function recovery. Positron emission computed tomography (PET/CT) was performed at 3 days pre- and post-TBI, and at 2, 4, and 8 weeks after intervention to detect cerebral metabolism. Results: Gait analysis showed that electroacupuncture improved the forepaw mean intensity in aged rats after 8 weeks of intervention, but after 4 weeks of intervention in young rats. PET/CT revealed increased metabolism in the left (the injured ipsilateral hemisphere) sensorimotor brain areas of aged rats during the electroacupuncture intervention, and increased metabolism in the right (contralateral to injury hemisphere) sensorimotor brain areas of young rats. Results: This study demonstrated that aged rats required a longer electroacupuncture intervention duration to improve motor function than that of young rats. The influence of aging on the cerebral metabolism of electroacupuncture treatment was mainly focused on a particular hemisphere.

Examining the occurrence and outcomes of concussion and mTBI in mixed martial arts athletes: a systematic review.

INTRODUCTION: Mixed martial arts (MMA) is a sport growing in popularity around the world. However, many individuals participate in the sport with little understanding of the potential short- and long-term consequences of injuries sustained while participating. Specifically, individuals are placed at a high risk of minor traumatic brain injury (mTBI) and concussive episodes as a result of head injuries incurred during training and competition. AIMS: The current review aimed to examine the literature surrounding the occurrence and outcomes of mTBI in MMA athletes to gain a better understanding of these consequences. METHODS: Twenty-five studies were identified within the current review, of which 14 examined occurrence of mTBI within the sport setting, and elevenidentified outcomes of injury. RESULTS: Overall, studies found that MMA athletes experienced mTBI and concussion to a greater extent than athletes in other sports. Deficits in memory, reaction time and processing speed were identified following occurrence of mTBI; however, several gaps in outcome measurement were identified within the current literature, including a lack of focus on speech and language outcomes. CONCLUSION: Future research should examine a wider variety of outcomes to provide a clearer understanding of the consequences of participating in the sport.

Integrated Care Pathways for Black Persons With Traumatic Brain Injury: A Critical Transdisciplinary Scoping Review of the Clinical Care Journey.

Objectives: This novel critical transdisciplinary scoping review examined the literature on integrated care pathways that consider Black people living with traumatic brain injury (TBI). The objectives were to (a) summarize the extent, nature, and range of literature on care pathways that consider Black populations, (b) summarize how Blackness, race, and racism are conceptualized in the literature, (c) determine how Black people come to access care pathways, and (d) identify how care pathways in research consider the mechanism of injury and implications for human occupation. Methods: Six databases were searched systematically identifying 178 articles after removing duplicates. In total, 43 articles on integrated care within the context of Black persons with TBI were included. Narrative synthesis was conducted to analyze the data and was presented as descriptive statistics and as a narrative to tell a story. Findings: All studies were based in the United States where 81% reported racial and ethnic disparities across the care continuum primarily using race as a biological construct. Sex, gender, and race are used as demographic variables where statistical data were stratified in only 9% of studies. Black patients are primarily denied access to care, experience lower rates of protocol treatments, poor quality of care, and lack access to rehabilitation. Racial health disparities are disconnected from racism and are displayed as symptoms of a problem that remains unnamed. Conclusion: The findings illustrate how racism becomes institutionalized in research on TBI care pathways, demonstrating the need to incorporate the voices of Black people, transcend disciplinary boundaries, and adopt an anti-racist lens to research.

The Utility of Melatonin for the Treatment of Sleep Disturbance After Traumatic Brain Injury: A Scoping Review.

OBJECTIVE: To investigate the utility of melatonin supplementation as a treatment option for individuals with sleep disturbance after traumatic brain injury (TBI). DATA SOURCES: A systematic search was conducted in 6 electronic databases (Medline, AMED, CINAHL, Embase, Scopus, and SPORTDiscus) from earliest records to April 2022. STUDY SELECTION: Studies were eligible for inclusion if they met the following criteria: a) human participants with sleep disturbance after TBI, b) melatonin or melatonergic agent used as an intervention to treat sleep disturbance, and c) outcomes of melatonin administration reported. All TBI severity types (mild, moderate, and severe) were eligible. The initial search retrieved a total of 595 articles, with 9 studies meeting the eligibility criteria. DATA EXTRACTION: Two reviewers independently extracted data from eligible studies and assessed methodological quality. Extracted data consisted of participant and injury characteristics, melatonin interventional properties, and sleep outcome. Methodological quality was assessed via the Downs and Black checklist. DATA SYNTHESIS: A total of 251 participants with TBI-induced sleep disturbance (mean age range: 14.0-42.5 years) were included. Melatonin, Circadin (prolonged-release melatonin), or Ramelteon (melatonin receptor agonist) were administered. Dosages and intervention duration ranged from 2 to 10 mg and 3 to 12 weeks, respectively. Eight out of 9 studies reported positive outcomes after melatonin treatment. Significant improvements in subjective sleep quality, objective sleep efficiency, and total sleep time were found with melatonin. Reductions in self-reported fatigue, anxiety, and depressive symptoms were also observed with melatonin treatment. No serious adverse events were reported after melatonin administration. CONCLUSION: Melatonin has good tolerability after short-term use and the potential to be a therapeutic agent for those with sleep disturbance after TBI. Melatonin was shown to be beneficial to sleep quality, sleep duration, and sleep efficiency. Additional clinically relevant outcomes of improved mental health suggest that melatonin use may be a promising treatment option for individuals experiencing co-occurring disorders of mood and sleep disturbance post-injury.

Acupuncture promotes nerve repair through the benign regulation of mTOR-mediated neuronal autophagy in traumatic brain injury rats.

AIMS: Recent investigations have already proved the neuroprotective efficacy of acupuncture in clinical practice in the treatment of neurological diseases, such as traumatic brain injury (TBI). Since growing evidence has suggested that neuronal autophagy was involved in multiple stages of TBI, this study aims to clarify the autophagy mediating mechanism underlying the neuroprotective effect of acupuncture in TBI rats. METHODS: Three experiments were carried out to detect changes in neuronal autophagy and identify the potential molecular mechanism underlying the neuroprotective effect of acupuncture for TBI treatment. Feeney's free-falling epidural impingement method was used to establish the moderate TBI rat model; modified neurological severity scoring (mNSS) was used for neurological recovery evaluation. Nissl and HE staining were used to examine the histopathological changes. Immunofluorescence was used to detect the LC3-positive cell rate. The transmission electron microscope (TEM) was used to investigate the morphology and quantity of autophagosomes. Western blotting was used to determine the protein expressions of LC3, p62, beclin1, mTOR, ULK1, p-mTOR, and p-ULK1. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for gene expressions analysis of LC3 mRNA and p62 mRNA. Co-immunoprecipitation (CO-IP) method was used to identify the protein interaction of mTOR and ULK1. RESULTS: On Day 3 after TBI, acupuncture accelerated the removal of damaged cellular structures by promoting neuronal autophagy; on Day 7 and Day 14 after TBI, acupuncture inhibited neuronal autophagy, preventing excessive autophagy and thus alleviated nerve damage. In addition, the simultaneous treatment with 3-MA or rapamycin at different stages after TBI attenuated the effect of acupuncture. CONCLUSION: Acupuncture has a benign regulatory effect on neuronal autophagy in different stages of TBI, possibly through the mTOR/ULK1 pathway.

Advancing care and research for traumatic brain injury: a roadmap.

Across all segments of society in the United States, millions of adults and children experience a traumatic brain injury (TBI) each year, which may pose lifetime health and financial burdens in the billions of dollars. Efforts have been made to advance research and care with goals to improve awareness of the causes and consequences of TBI, but gaps still remain in understanding TBI and delivering high-quality care to everyone who needs it both in military and civilian life. At the request of the Department of Defense, the National Academies of Sciences, Engineering and Medicine recently convened experts to address existing gaps in brain injury science and systems of care. Although many people who experience a TBI recover fully, others experience long-term physical, emotional, and often financial consequences to the patient and family system, and require ongoing accommodations to support their return to the communities in which they live, learn, and work. A holistic approach within the context of osteopathic medicine may be helpful and enhance contributions within the field. This article will discuss the roadmap to help guide the field, including key conclusions and recommendations for actions to advance progress over the next decade while embracing a comprehensive bio-psycho-socio-ecological model of TBI care bringing in the distinctive osteopathic approach not only to improve care and outcomes, but also to understand patient and family experiences on their TBI journey.

Diet-induced ketosis in adult patients with subacute acquired brain injury: a feasibility study.

Background: Research in animal models on cerebral metabolism after brain injury highlights the potential benefits of ketosis in reducing secondary brain injury, but studies in humans are lacking. Aim: This study aimed to examine if a 6-week ketogenic diet intervention with added medium-chain triglycerides (MCT) was feasible in adult patients with acquired brain injury in the subacute phase, whether ketosis could be achieved and maintained, and to what extent serious adverse reactions, adverse reactions, serious adverse events, and adverse events occured. Methods: Patients ≥18 years of age diagnosed with subacute acquired brain injury and an expectation of hospitalisation ≥6 weeks were included in the intervention group. Patients not included in the intervention group were included in a standard care reference group. The intervention consisted of a ketogenic diet supplemented with MCT to obtain a plasma concentration of ß-hydroxybutyrate (BHB) ≥0.5 mmol/L. Patients who were enterally fed were given KetoCal® 2.5:1 LQ MCT Multi Fiber (Nutricia A/S, Allerød, Denmark), supplemented with Liquigen® (Nutricia A/S, Allerød, Denmark). Patients consuming oral nutrition were given KetoCal® 2.5:1 LQ MCT Multi Fiber supplemented with Liquigen®, in addition to ketogenic meals. Results: During a 13-week inclusion period, 12 of 13 eligible patients (92% [95% CI: 67% to 99%]) were included in the intervention group, and 17 of 18 excluded patients (94% [95% CI: 74% to 99%]) were included in the reference group. Eight patients (67%) completed the 6-week intervention. It took a median of 1 day to achieve ketosis from starting a 100% MCT ketogenic diet, and it was maintained for 97% of the intervention period after ketosis was obtained. There were no serious adverse reactions to the MCT ketogenic diet, and patients experienced adverse reactions not considered serious in 9.5% of days with the intervention. The MCT ketogenic diet was accepted by patients on all intervention days, and in the two patients transitioning from enteral feeding to oral intake, there were no complications related to transitioning. Conclusion: Intervention with MCT ketogenic diet is feasible and tolerated for 6 weeks in hospitalised adult patients with subacute acquired brain injury. Randomised controlled trials are needed to assess the benefits and harms of the MCT ketogenic diet and the effect on patients' recovery.Clinical trial registration: ClinicalTrials.gov, identifier [NCT04308577].

Osteopathy in the Cranial Field as a Method to Enhance Brain Injury Recovery: A Preliminary Study.

The clinical burden of traumatic brain injury (TBI) continues to grow worldwide, with patients often developing chronic neurological, behavorial, and cognitive deficits. Treatment and management strategies remain a key challenge, given that they target the symptoms and not the underlying pathological response. To advance pre-clinical research and therapeutic developments, there is a need to study treatment strategies that improve brain injury recovery. Cranial osteopathic manipulative medicine (cOMM) is a non-invasive and non-pharmacological strategy that has been shown to improve quality of life for several medical conditions and injuries, and may be able to treat TBI and reduce subsequent symptoms. In this study, we aimed to evaluate the neurobiological effect of cOMM on the injury response and its potential to alleviate symptoms. We investigated the ability of cOMM to enhance fluid transport by quantifying fluorescent tracer clearance throughout the brain. Further, using an in vivo TBI model, male rats were exposed to a repeated blast overpressure that was followed by cOMM treatment 24 h later. Our findings indicated that cOMM treatment attenuated acute and subacute anxiety-like behaviors. Post-mortem pathological examination in the hippocampus, pre-frontal, and motor cortices indicated improvements in glial pathology in cOMM-treated animals compared to the untreated injury group. Overall, this is the first study to explore cOMM as a treatment option for brain injury, demonstrating its capability to improve TBI outcomes.

Dietary Supplementation With Branched Chain Amino Acids to Improve Sleep in Veterans With Traumatic Brain Injury: A Randomized Double-Blind Placebo-Controlled Pilot and Feasibility Trial.

Study Objectives: Traumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment. Our prior preclinical work demonstrated dietary supplementation with branched chain amino acids (BCAA: leucine, isoleucine, and valine), precursors to de novo glutamate production, restored impairments in glutamate, orexin/hypocretin neurons, sleep, and memory in rodent models of TBI. This pilot study assessed the feasibility and preliminary efficacy of dietary supplementation with BCAA on sleep and cognition in Veterans with TBI. Methods: Thirty-two Veterans with TBI were prospectively enrolled in a randomized, double-blinded, placebo-controlled trial comparing BCAA (30 g, b.i.d. for 21-days) with one of two placebo arms (microcrystalline cellulose or rice protein, both 30 g, b.i.d. for 21-days). Pre- and post-intervention outcomes included sleep measures (questionnaires, daily sleep/study diaries, and wrist actigraphy), neuropsychological testing, and blood-based biomarkers related to BCAA consumption. Results: Six subjects withdrew from the study (2/group), leaving 26 remaining subjects who were highly adherent to the protocol (BCAA, 93%; rice protein, 96%; microcrystalline, 95%; actigraphy 87%). BCAA were well-tolerated with few side effects and no adverse events. BCAA significantly improved subjective insomnia symptoms and objective sleep latency and wake after sleep onset on actigraphy. Conclusion: Dietary supplementation with BCAA is a mechanism-based, promising intervention that shows feasibility, acceptability, and preliminary efficacy to treat insomnia and objective sleep disruption in Veterans with TBI. A larger scale randomized clinical trial is warranted to further evaluate the efficacy, dosing, and duration of BCAA effects on sleep and other related outcome measures in individuals with TBI. Clinical Trial Registration: [http://clinicaltrials.gov/], identifier [NCT03990909].

Immunomodulatory protein from ganoderma microsporum protects against oxidative damages and cognitive impairments after traumatic brain injury.

A traumatic brain injury (TBI) causes abnormal proliferation of neuroglial cells, and over-release of glutamate induces oxidative stress and inflammation and leads to neuronal death, memory deficits, and even death if the condition is severe. There is currently no effective treatment for TBI. Recent interests have focused on the benefits of supplements or natural products like Ganoderma. Studies have indicated that immunomodulatory protein from Ganoderma microsporum (GMI) inhibits oxidative stress in lung cancer cells A549 and induces cancer cell death by causing intracellular autophagy. However, no evidence has shown the application of GMI on TBI. Thus, this study addressed whether GMI could be used to prevent or treat TBI through its anti-inflammation and antioxidative effects. We used glutamate-induced excitotoxicity as in vitro model and penetrating brain injury as in vivo model of TBI. We found that GMI inhibits the generation of intracellular reactive oxygen species and reduces neuronal death in cortical neurons against glutamate excitotoxicity. In neurite injury assay, GMI promotes neurite regeneration, the length of the regenerated neurite was even longer than that of the control group. The animal data show that GMI alleviates TBI-induced spatial memory deficits, expedites the restoration of the injured areas, induces the secretion of brain-derived neurotrophic factors, increases the superoxide dismutase 1 (SOD-1) and lowers the astroglial proliferation. It is the first paper to apply GMI to brain-injured diseases and confirms that GMI reduces oxidative stress caused by TBI and improves neurocognitive function. Moreover, the effects show that prevention is better than treatment. Thus, this study provides a potential treatment in naturopathy against TBI.

Nano-PSO Administration Attenuates Cognitive and Neuronal Deficits Resulting from Traumatic Brain Injury.

Traumatic Brain Injury (TBI), is one of the most common causes of neurological damage in young populations. It is widely considered as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's (PD) disease. These diseases are characterized in part by the accumulation of disease-specific misfolded proteins and share common pathological features, such as neuronal death, as well as inflammatory and oxidative damage. Nano formulation of Pomegranate seed oil [Nano-PSO (Granagard TM)] has been shown to target its active ingredient to the brain and thereafter inhibit memory decline and neuronal death in mice models of AD and genetic Creutzfeldt Jacob disease. In this study, we show that administration of Nano-PSO to mice before or after TBI application prevents cognitive and behavioral decline. In addition, immuno-histochemical staining of the brain indicates that preventive Nano-PSO treatment significantly decreased neuronal death, reduced gliosis and prevented mitochondrial damage in the affected cells. Finally, we examined levels of Sirtuin1 (SIRT1) and Synaptophysin (SYP) in the cortex using Western blotting. Nano-PSO consumption led to higher levels of SIRT1 and SYP protein postinjury. Taken together, our results indicate that Nano-PSO, as a natural brain-targeted antioxidant, can prevent part of TBI-induced damage.

Prophylactic zinc supplementation modulates hippocampal ionic zinc and partially remediates neurological recovery following repetitive mild head injury in mice.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition caused by repetitive mild traumatic brain injury (TBI) that leads to impaired executive functioning, emotional disturbances, and disordered memory, warranting both basic and translational research of potential therapeutic targets. One area of research concerns prophylactic zinc (Zn) supplementation; however, Zn supplementation remains poorly understood. This study explored the effects of Zn supplementation in a mouse model of repetitive mild TBI. Four-week-old male (n = 50) and female (n = 50) C57BL/6J mice consumed tap water or 10 parts per million Zn-supplemented water for eight weeks prior to injury. At 12 weeks of age, mice underwent either five sham procedures or five closed-head injuries spaced apart by 48 h after which they completed behavioral tests. Zinc-supplemented injured mice righted themselves and regained normal ambulatory function as fast as non-injured mice across four out of the five injury days. In contrast, non-supplemented injured mice exhibited impairment in normal ambulation by days 4 and 5. Injury also reduced free, ionic Zn in the dentate gyrus and CA3 region of the hippocampus and Zn supplementation partially remediated this reduction but not to the levels of non-injured mice. There were no structural differences in cortex, hippocampus, striatum, and corpus callosum, suggesting that Zn reduction was not due to macroscopic abnormalities. Overall, these results suggest that Zn may improve short-term and physical neurological recovery, but it may not be sufficient as a single pre-treatment for consequences of repetitive mild TBI such as cognitive impairment. These results further demonstrate the need for additional research documenting the underlying mechanisms of Zn in TBI-related neuropathology.

Neurological Music Therapy Rebuilds Structural Connectome after Traumatic Brain Injury: Secondary Analysis from a Randomized Controlled Trial.

BACKGROUND: Traumatic brain injury (TBI) is a common and devastating neurological condition, associated often with poor functional outcome and deficits in executive function. Due to the neuropathology of TBI, neuroimaging plays a crucial role in its assessment, and while diffusion MRI has been proposed as a sensitive biomarker, longitudinal studies evaluating treatment-related diffusion MRI changes are scarce. Recent evidence suggests that neurological music therapy can improve executive functions in patients with TBI and that these effects are underpinned by neuroplasticity changes in the brain. However, studies evaluating music therapy induced structural connectome changes in patients with TBI are lacking. DESIGN: Single-blind crossover (AB/BA) randomized controlled trial (NCT01956136). OBJECTIVE: Here, we report secondary outcomes of the trial and set out to assess the effect of neurological music therapy on structural white matter connectome changes and their association with improved execute function in patients with TBI. METHODS: Using an AB/BA design, 25 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 16) or second (BA, n = 9) half of a 6-month follow-up period. Neuropsychological testing and diffusion MRI scans were performed at baseline and at the 3-month and 6-month stage. FINDINGS: Compared to the control group, the music therapy group increased quantitative anisotropy (QA) in the right dorsal pathways (arcuate fasciculus, superior longitudinal fasciculus) and in the corpus callosum and the right frontal aslant tract, thalamic radiation and corticostriatal tracts. The mean increased QA in this network of results correlated with improved executive function. CONCLUSIONS: This study shows that music therapy can induce structural white matter neuroplasticity in the post-TBI brain that underpins improved executive function.

Boswellia serrata extract shows cognitive benefits in a double-blind, randomized, placebo-controlled pilot clinical trial in individuals who suffered traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. TBI can result in neuropsychiatric and cognitive problems as well as neurodegenerative pathologies that can appear right after or develop and persist years after injury. METHOD: We conducted a double-blind, randomized, placebo-controlled clinical trial on patients who suffered from TBI three months to three years ago. The patients were randomized to placebo (n = 34) or K-Vie™ group (n = 46) for a treatment period of 3 months. The main primary outcomes include cognitive assessment in the Rey Auditory Verbal Learning Test-Recognition Test (RAVLT), Wechsler adult intelligence Digit Symbol Substitution Test (DSST) and trail-making test part B (TMT-B). Assessments were performed at baseline and at the month 3 follow-up visit. Linear mixed models were carried out to evaluate cognitive changes from baseline across all cognitive assessment tests. RESULT: The current study showed significant (p < 0.05) improvement in cognitive function of patients who were given K-Vie™ compared with placebo across the RAVLT, DSST and TMT-B performance assessments. A larger cohort would be beneficial to further confirm the clinical utility of K-Vie™ and assess its effects in acute phases of TBI.

Department of Defense positions on alternative uses of hyperbaric oxygen therapy.

Hyperbaric oxygen therapy is an existing and approved treatment to address multiple medical conditions, including decompression sickness, air or gas embolism, carbon monoxide poisoning, and profound blood loss when transfusion cannot be accomplished. However, recent efforts have emerged to promote hyperbaric oxygen therapy for other purposes. The most controversial applications have been utilizing this therapy as a treatment for mild traumatic brain injury and post-traumatic stress disorder. As evidence accumulates and the debate continues about whether published studies have satisfied the threshold of clinical significance, a common issue is raised regarding current clinical practices and health insurance coverage as allowed or recommended by the Department of Defense and other federal agencies. This review describes the current federal policies regarding medical insurance issues for providers and clinical practice guidelines as they pertain to alternative uses of hyperbaric oxygen therapy. First, the current policies are explored for what is reimbursable under federal insurance as approved clinical or research usages. Second, these policies are compared to the clinical practice guidelines to determine what might be clinical best practice versus exploratory research. Third, the evidence from government reports is reviewed as supporting documentation for these positions. As such, the current discussion addresses what can and cannot be covered under health insurance and where various federal health care organizations stand currently on using hyperbaric oxygen therapy as an alternative therapeutic technique. The primary goal is informing military healthcare practitioners and prospective patients about the treatment options available to them under current federal guidelines.

Injury to thalamocortical projections following traumatic brain injury results in attractor dynamics for cortical networks.

Major theories of consciousness predict that complex electroencephalographic (EEG) activity is required for consciousness, yet it is not clear how such activity arises in the corticothalamic system. The thalamus is well-known to control cortical excitability via interlaminar projections, but whether thalamic input is needed for complexity is not known. We hypothesized that the thalamus facilitates complex activity by adjusting synaptic connectivity, thereby increasing the availability of different configurations of cortical neurons (cortical "states"), as well as the probability of state transitions. To test this hypothesis, we characterized EEG activity from prefrontal cortex (PFC) in traumatic brain injury (TBI) patients with and without injuries to thalamocortical projections, measured with diffusion tensor imaging (DTI). We found that injury to thalamic projections (especially from the mediodorsal thalamus) was strongly associated with unconsciousness and delta-band EEG activity. Using advanced signal processing techniques, we found that lack of thalamic input led to 1.) attractor dynamics for cortical networks with a tendency to visit the same states, 2.) a reduced repertoire of possible states, and 3.) high predictability of transitions between states. These results imply that complex PFC activity associated with consciousness depends on thalamic input. Our model implies that restoration of cortical connectivity is a critical function of the thalamus after brain injury. We draw a critical connection between thalamic input and complex cortical activity associated with consciousness.