Traumatic brain injury and the pathways to cerebral tau accumulation.

Tau is a protein that has received national mainstream recognition for its potential negative impact to the brain. This review succinctly provides information on the structure of tau and its normal physiological functions, including in hibernation and changes throughout the estrus cycle. There are many pathways involved in phosphorylating tau including diabetes, stroke, Alzheimer's disease (AD), brain injury, aging, and drug use. The common mechanisms for these processes are put into context with changes observed in mild and repetitive mild traumatic brain injury (TBI). The phosphorylation of tau is a part of the progression to pathology, but the ability for tau to aggregate and propagate is also addressed. Summarizing both the functional and dysfunctional roles of tau can help advance our understanding of this complex protein, improve our care for individuals with a history of TBI, and lead to development of therapeutic interventions to prevent or reverse tau-mediated neurodegeneration.

Rodent Estrous Cycle Monitoring Utilizing Vaginal Lavage: No Such Thing As a Normal Cycle.

The current methodology establishes a reproducible, standardized, and cost-effective approach to monitoring the estrous cycle of female Sprague Dawley (SD) adolescent rats. This study demonstrates the complexity of hormonal cycles and the broad spectrum of understanding required to construct a reliable and valid monitoring technique. Through an in-depth examination of principal experimental design and procedural elements, this description of the cycle and its fundamental principles provides a framework for further understanding and deconstructs misconceptions for future replication. Along with an outline of the sample collection process employing vaginal lavage, the procedure describes the mechanism of data categorization into the four-stage model of proestrus, estrus, metestrus, and diestrus. These stages are characterized by a new proposed approach, utilizing the 4 categorizing determinants of vaginal fluid condition, cell type(s) present, cell arrangement, and cell quantity at the time of collection. Variations of each stage, favorable and unfavorable samples, the distinction between cyclicity and acyclicity, and graphic depictions of the collected categorizing components are presented alongside effective interpretive and organizational practices of the data. Overall, these tools allow for the publication of quantifiable data ranges for the first time, leading to the standardization of categorization factors upon replication.

Pathophysiology of Pediatric Traumatic Brain Injury.

The national incidence of traumatic brain injury (TBI) exceeds that of any other disease in the pediatric population. In the United States the Centers for Disease Control and Prevention (CDC) reports 697,347 annual TBIs in children ages 0-19 that result in emergency room visits, hospitalization or deaths. There is a bimodal distribution within the pediatric TBI population, with peaks in both toddlers and adolescents. Preclinical TBI research provides evidence for age differences in acute pathophysiology that likely contribute to long-term outcome differences between age groups. This review will examine the timecourse of acute pathophysiological processes during cerebral maturation, including calcium accumulation, glucose metabolism and cerebral blood flow. Consequences of pediatric TBI are complicated by the ongoing maturational changes allowing for substantial plasticity and windows of vulnerabilities. This review will also examine the timecourse of later outcomes after mild, repeat mild and more severe TBI to establish developmental windows of susceptibility and altered maturational trajectories. Research progress for pediatric TBI is critically important to reveal age-associated mechanisms and to determine knowledge gaps for future studies.

Sex Differences in Neurophysiological Changes Following Voluntary Exercise in Adolescent Rats.

Background: Adolescence is a period of time characterized by the onset of puberty and is marked by cognitive and social developments and gross physical changes that can play a role in athletic performance. Sex differences are present with differences in body size, height, physiology and behavior which contribute to differences in athletic performance as well. Pre-clinical studies representing this active group are lacking. Methods: Acute and chronic effects of exercise were evaluated. Male and female adolescent rats were given voluntary access to a running wheel for 10 consecutive days. Running behavior (males and females) and estrous cycling (females only) were analyzed daily. A second group was given 10 days of voluntary access to a running wheel, then rested for 10 days to determine the long-term effects of exercise on the adolescent brain. Brain and muscle tissue were harvested at 10 and 20 day time points to understand exercise-dependent changes in mitochondrial activity and neuroplasticity. Animal cohorts were carried out at two different sites: University of California Los Angeles and Pepperdine University. Results: On average, running distance, intensity of run, and length of running bout increased for both male and female rats across the 10 days measured. Females ran significantly further and for longer intervals compared to males. Cortical and muscle expression of PGC1α showed similar levels at 10 days regardless of sex and exercise. There was a significant increase in expression at 20 days in all groups correlating with body size (p's < 0.05). Cortical and hippocampal levels of BDNF were similar across all groups, however, BDNF was significantly higher in exercised females at the acute compared to long-term time point. Discussion: Adolescent rats allowed 10 days of exercise show changes in physiologic function. There are sex differences in running behavior not impacted by sex hormones. These results are important to further our understanding of how exercise impacts the adolescent brain.

Alternative substrate metabolism depends on cerebral metabolic state following traumatic brain injury.

Decreases in energy metabolism following traumatic brain injury (TBI) are attributed to impairment of glycolytic flux and oxidative phosphorylation. Glucose utilization post-TBI is decreased while administration of alternative substrates has been shown to be neuroprotective. Changes in energy metabolism following TBI happens in two phases; a period of hyper-metabolism followed by prolonged hypo-metabolism. It is not understood how different cerebral metabolic states may impact substrate metabolism and ultimately mitochondrial function. Adult male or female Sprague Dawley rats were given sham surgery or controlled cortical impact (CCI) and were assigned one of two administration schemes. Glucose, lactate or beta-hydroxybutyrate (BHB) were infused i.v. either starting immediately after injury or beginning 6 h post-injury for 3 h to reflect the hyper- and hypo-metabolic stages. Animals were euthanized 24 h post-injury. The peri-contusional cortex was collected and assayed for mitochondrial respiration peroxide production, and citrate synthase activity. Tissue acetyl-CoA, ATP, glycogen and HMGB1 were also quantified. Sex differences were observed in injury pattern. Administration based on cerebral metabolic state identified that only early lactate and late BHB improved mitochondrial function and peroxide production and TCA cycle intermediates in males. In contrast, both early and late BHB had deleterious effects on all aspects of metabolic measurements in females. These data stress there is no one optimal alternative substrate, but rather the fuel type used should be guided by both cerebral metabolic state and sex.

The Prehospital Evaluation and Care of Moderate/Severe TBI in the Austere Environment.

Increased resource constraints secondary to a smaller medical footprint, prolonged evacuation times, or overwhelming casualty volumes all increase the challenges of effective management of traumatic brain injury (TBI) in the austere environment. Prehospital providers are responsible for the battlefield recognition and initial management of TBI. As such, targeted education is critical to efficient injury recognition, promoting both provider readiness and improved patient outcomes. When austere conditions limit or prevent definitive treatment, a comprehensive understanding of TBI pathophysiology can help inform acute care and enhance prevention of secondary brain injury. Field deployable, noninvasive TBI assessment and monitoring devices are urgently needed and are currently undergoing clinical evaluation. Evidence shows that the assessment, monitoring, and treatment in the first few hours and days after injury should focus on the preservation of cerebral perfusion and oxygenation. For cases where medical management is inadequate (eg, evidence of an enlarging intracranial hematoma), guidelines have been developed for the performance of cranial surgery by nonneurosurgeons. TBI management in the austere environment will continue to be a challenge, but research focused on improving evidence-based monitoring and therapeutic interventions can help to mitigate some of these challenges and improve patient outcomes.

Recovery From Repeat Mild Traumatic Brain Injury in Adolescent Rats Is Dependent on Pre-injury Activity State.

Adolescents and young adults have the highest incidence of mild traumatic brain injury (mTBI); sport-related activities are a major contributor. Roughly a third of these patients diagnosed with mTBI are estimated to have received a subsequent repeat mTBI (rTBI). Previously, animal studies have only modeled mTBI in sedentary animals. This study utilizes physical activity as a dependent variable prior to rTBI in adolescent rats by allowing voluntary exercise in males, establishing the rat athlete (rathlete). Rats were given access to locked or functional running wheels for 10 d prior to sham or rTBI injury. Following rTBI, rathletes were allowed voluntary access to running wheels beginning on different days post-injury: no run (rTBI+no run), immediate run (rTBI+Immed), or 3 day delay (rTBI+3dd). Rats were tested for motor and cognitive-behavioral (anxiety, social, memory) and mechanosensory (allodynia) dysfunction using a novel rat standardized concussion assessment tool on post-injury days 1,3,5,7, and 10. Protein expression of brain derived neurotrophic factor (BDNF) and proliferator-activated gamma coactivator 1-alpha (PGC1α) was measured in the parietal cortex, hippocampus, and gastrocnemius muscle. Sedentary shams displayed lower anxiety-like behaviors compared to rathlete shams on all testing days. BDNF and PGC1α levels increased in the parietal cortex and hippocampus with voluntary exercise. In rTBI rathletes, the rTBI+Immed group showed impaired social behavior, memory impairment in novel object recognition, and increased immobility compared to rathlete shams. All rats showed greater neuropathic mechanosensory sensitivity than previously published uninjured adults, with rTBI+3dd showing greatest sensitivity. These results demonstrate that voluntary exercise changes baseline functioning of the brain, and that among rTBI rathletes, delayed return to activity improved cognitive recovery.

Bridging the gap: Mechanisms of plasticity and repair after pediatric TBI.

Traumatic brain injury is the leading cause of death and disability in the United States, and may be associated with long lasting impairments into adulthood. The multitude of ongoing neurobiological processes that occur during brain maturation confer both considerable vulnerability to TBI but may also provide adaptability and potential for recovery. This review will examine and synthesize our current understanding of developmental neurobiology in the context of pediatric TBI. Delineating this biology will facilitate more targeted initial care, mechanism-based therapeutic interventions and better long-term prognostication and follow-up.

How to Translate Time: The Temporal Aspects of Rodent and Human Pathobiological Processes in Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers multiple pathobiological responses with differing onsets, magnitudes, and durations. Identifying the therapeutic window of individual pathologies is critical for successful pharmacological treatment. Dozens of experimental pharmacotherapies have been successfully tested in rodent models, yet all of them (to date) have failed in clinical trials. The differing time scales of rodent and human biological and pathological processes may have contributed to these failures. We compared rodent versus human time scales of TBI-induced changes in cerebral glucose metabolism, inflammatory processes, axonal integrity, and water homeostasis based on published data. We found that the trajectories of these pathologies run on different timescales in the two species, and it appears that there is no universal "conversion rate" between rodent and human pathophysiological processes. For example, the inflammatory process appears to have an abbreviated time scale in rodents versus humans relative to cerebral glucose metabolism or axonal pathologies. Limitations toward determining conversion rates for various pathobiological processes include the use of differing outcome measures in experimental and clinical TBI studies and the rarity of longitudinal studies. In order to better translate time and close the translational gap, we suggest 1) using clinically relevant outcome measures, primarily in vivo imaging and blood-based proteomics, in experimental TBI studies and 2) collecting data at multiple post-injury time points with a frequency exceeding the expected information content by two or three times. Combined with a big data approach, we believe these measures will facilitate the translation of promising experimental treatments into clinical use.

Concussion: pathophysiology and clinical translation.

The majority of the 3.8 million estimated annual traumatic brain injuries (TBI) in the United States are mild TBIs, or concussions, and they occur primarily in adolescents and young adults. A concussion is a brain injury associated with rapid brain movement and characteristic clinical symptoms, with no associated objective biomarkers or overt pathologic brain changes, thereby making it difficult to diagnose by neuroimaging or other objective diagnostic tests. Most concussion symptoms are transient and resolve within 1-2 weeks. Concussions share similar acute pathophysiologic perturbations to more severe TBI: there is a rapid release of neurotransmitters, which causes ionic disequilibrium across neuronal membranes. Re-establishing ionic homeostasis consumes energy and leads to dynamic changes in cerebral glucose uptake. The magnitude and duration of these changes are related to injury severity, with milder injuries showing faster normalization. Cerebral sex differences add further variation to concussion manifestation. Relative to the male brain, the female brain has higher overall cerebral blood flow, and demonstrates regional differences in glucose metabolism, inflammatory responses, and connectivity. Understanding the pathophysiology and clinical translation of concussion can move research towards management paradigms that will minimize the risk for prolonged recovery and repeat injury.

Repeat Mild Traumatic Brain Injury in Adolescent Rats Increases Subsequent ß-Amyloid Pathogenesis.

Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurodegenerative disease by facilitating ß-amyloid (Aß) deposition. However, the chronic effects on Aß pathogenesis of repetitive mild TBIs (rTBI), which are common in adolescents and young adults, remain uncertain. We examined the effects of rTBI sustained during adolescence on subsequent deposition of Aß pathology in a transgenic APP/PS1 rat model. Transgenic rats received sham or four individual mild TBIs (rTBIs) separated by either 24- or 72-h intervals at post-natal day 35 (before Aß plaque deposition). Animals were euthanized at 12 months of age and underwent immunohistochemical analyses of Aß plaque deposition. Significantly greater hippocampal Aß plaque deposition was observed after rTBI separated by 24 h relative to rTBI separated by 72 h or sham injuries. These increases in hippocampal Aß plaque load were driven by increases in both plaque number and size. Similar, though less-pronounced, effects were observed in extrahippocampal regions. Increases in Aß plaque deposition were observed both ipsilaterally and contralaterally to the injury site and in both males and females. rTBIs sustained in adolescence can increase subsequent deposition of Aß pathology, and these effects are critically dependent on interinjury interval.

Glucose metabolism in pediatric traumatic brain injury.

Traumatic brain injury is the number one cause of death and disability among the pediatric population in the USA. The heterogeneity of the pediatric population is reflected by both the normal cerebral maturation and the age differences in the causes of TBI, which generate unique age-related pathophysiology responses and recovery profiles. This review will address the normal changes in cerebral glucose metabolism throughout developmental phases and how TBI alters glucose metabolism. Evidence has shown that TBI disrupts the biochemical processing of glucose to energy. This brings to question, "What is the optimal substrate to manage a pediatric TBI patient?" Issues related to glycemic control and alternative substrate metabolism are addressed specifically in regard to pediatric TBI. Research into pediatric glucose metabolism after TBI is limited, and understanding these age-related differences within the pediatric population have great potential to improve support for the injured younger brain.

It's Not All Fun and Games: Sports, Concussions, and Neuroscience.

Few items grab the public's attention like sports, from extremes of great victory to injury and defeat. No injury currently arouses stronger interest than concussion. Giza et al., discuss how neuroscience can provide balance between physical activity and TBI, and guide thoughtful discourse and policy.

What is the physiological time to recovery after concussion? A systematic review.

AIM OR OBJECTIVE: The aim of this study is to consolidate studies of physiological measures following sport-related concussion (SRC) to determine if a time course of postinjury altered neurobiology can be outlined. This biological time course was considered with respect to clinically relevant outcomes such as vulnerability to repeat injury and safe timing of return to physical contact risk. DESIGN: Systematic review. DATA SOURCES: PubMed, CINAHL, Cochrane Central, PsychINFO. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they reported original research on physiological or neurobiological changes after SRC. Excluded were cases series <5 subjects, reviews, meta-analyses, editorials, animal research and research not pertaining to SRC. RESULTS: A total of 5834 articles were identified, of which 80 were included for full-text data extraction and review. Relatively few longitudinal studies exist that follow both physiological dysfunction and clinical measures to recovery. SUMMARY/CONCLUSIONS: Modalities of measuring physiological change after SRC were categorised into the following: functional MRI, diffusion tensor imaging, magnetic resonance spectroscopy, cerebral blood flow, electrophysiology, heart rate, exercise, fluid biomarkers and transcranial magnetic stimulation. Due to differences in modalities, time course, study design and outcomes, it is not possible to define a single 'physiological time window' for SRC recovery. Multiple studies suggest physiological dysfunction may outlast current clinical measures of recovery, supporting a buffer zone of gradually increasing activity before full contact risk. Future studies need to use generalisable populations, longitudinal designs following to physiological and clinical recovery and careful correlation of neurobiological modalities with clinical measures.

Influence of Glycemic Control on Endogenous Circulating Ketone Concentrations in Adults Following Traumatic Brain Injury.

BACKGROUND: The objective was to investigate the impact of targeting tight glycemic control (4.4-6.1 mM) on endogenous ketogenesis in severely head-injured adults. METHODS: The data were prospectively collected during a randomized, within-patient crossover study comparing tight to loose glycemic control, defined as 6.7-8.3 mM. Blood was collected periodically during both tight and loose glycemic control epochs. Post hoc analysis of insulin dose and total nutritional provision was performed. RESULTS: Fifteen patients completed the crossover study. Total ketones were increased 81 µM ([38 135], p < 0.001) when blood glucose was targeted to tight (4.4-6.1 mM) compared with loose glycemic control (6.7-8.3 mM), corresponding to a 60 % increase. There was a significant decrease in total nutritional provisions (p = 0.006) and a significant increase in insulin dose (p = 0.008). CONCLUSIONS: Permissive underfeeding was tolerated when targeting tight glycemic control, but total nutritional support is an important factor when treating hyperglycemia.

Metabolic crisis occurs with seizures and periodic discharges after brain trauma.

OBJECTIVE: Traumatic brain injury (TBI) results in persistent disruption of brain metabolism that has yet to be mechanistically defined. Early post-traumatic seizures are one potential mechanism for metabolic crisis and hence could be a therapeutic target. We hypothesized that seizures and pseudoperiodic discharges (PDs) may be mechanistically linked to metabolic crisis as measured by cerebral microdialysis. METHODS: A prospective multicenter study of surface and intracortical depth electroencephalography (EEG) was performed in conjunction with cerebral microdialysis in a cohort of severe TBI patients with time-locked analysis of the neurochemical response to seizures and pseudoperiodic discharges. RESULTS: Seizures or PDs occurred in 61% of 34 subjects, with 42.9% of these seizures noted only on intracortical depth EEG and in some cases lasting for many hours. Metabolic crisis as measured by elevated cerebral microdialysis lactate/pyruvate ratio occurred during seizures or PDs but not during electrically nonepileptic epochs. INTERPRETATION: In TBI patients, seizures and periodic discharges are one mechanism for metabolic crisis, and hence represent a therapeutic target for future study.

Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity.

Cerebral metabolism of ketones after traumatic brain injury (TBI) improves neuropathology and behavior in an age-dependent manner. Neuroprotection is attributed to improved cellular energetics, although other properties contribute to the beneficial effects. Oxidative stress is responsible for mitochondrial dysfunction after TBI. Ketones decrease oxidative stress, increase antioxidants and scavenge free radicals. It is hypothesized that ketogenic diet (KD) will decrease post-TBI oxidative stress and improve mitochondria. Postnatal day 35 (PND35) male rats were given sham or controlled cortical impact (CCI) injury and placed on standard (STD) or KD. Ipsilateral cortex homogenates and mitochondria were assayed for markers of oxidative stress, antioxidant expression and mitochondrial function. Oxidative stress was significantly increased at 6 and 24 h post-injury and attenuated by KD while inducing protein expression of antioxidants, NAD(P)H dehydrogenase quinone 1 (NQO1) and superoxide dismutase (SOD1/2). Complex I activity was inhibited in STD and KD groups at 6 h and normalized by 24 h. KD significantly improved Complex II-III activity that was reduced in STD at 6 h. Activity remained reduced at 24 h in STD and unchanged in KD animals. These results strongly suggest that ketones improve post-TBI cerebral metabolism by providing alternative substrates and through antioxidant properties, preventing oxidative stress-mediated mitochondrial dysfunction.

Metabolic Response of Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) in the pediatric brain presents unique challenges as the complex cascades of metabolic and biochemical responses to TBI are further complicated ongoing maturational changes of the developing brain. TBIs of all severities have been shown to significantly alter metabolism and hormones which impair the ability of the brain to process glucose for cellular energy. Under these conditions, the brain's primary fuel (glucose) becomes a less favorable fuel and the ability of the younger brain to revert to ketone metabolism can an advantage. This review addresses the potential of alternative substrate metabolic intervention as a logical pediatric TBI neuroprotective strategy.