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Cognitive impairments and emotional lability are common long-term consequences of traumatic brain injury (TBI). How TBI affects interactions between sensory, cognitive, and emotional systems may reveal mechanisms that underlie chronic mental health comorbidities. Previously, we reported changes in auditory-emotional network activity and enhanced fear learning early after TBI. In the current study, we asked whether TBI has long-term effects on fear learning and responses to novel stimuli. Four weeks following lateral fluid percussion injury (FPI) or sham surgery, adult male rats were fear conditioned to either white noise-shock or tone-shock pairing, or shock-only control and subsequently were tested for freezing to context and to the trained or novel auditory cues in a new context. FPI groups showed greater freezing to their trained auditory cue, indicating long-term TBI enhanced fear. Interestingly, FPI-Noise Shock animals displayed robust fear to the novel, untrained tone compared with Sham-Noise Shock across both experiments. Shock Only groups did not differ in freezing to either auditory stimulus. These findings suggest that TBI precipitates maladaptive associative fear generalization rather than non-associative sensitization. Basolateral amygdala (BLA) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr) subunits GluA1 and GluA2 levels were analyzed and the FPI-Noise Shock group had increased GluA1 (but not GluA2) levels that correlated with the level of tone fear generalization. This study illustrates a unique chronic TBI phenotype with both a cognitive impairment and increased fear and possibly altered synaptic transmission in the amygdala long after TBI, where stimulus generalization may underlie maladaptive fear and hyperarousal.

Traumatic brain injury (TBI)-induced disruptions in synaptic function within brain regions and across networks in the limbic system may underlie a vulnerability for maladaptive plasticity and contribute to behavioral comorbidities. In this study we measured how synaptic proteins respond to lateral fluid percussion injury (FPI) brain regions known to regulate emotion and memory, including the basolateral amygdala (BLA), dorsal and ventral hippocampus (DH, VH), and medial prefrontal cortex (PFC). We investigated proteins involved in regulating plasticity, including synaptic glutamatergic a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA; GluA1, GluA2) and N- methyl-D-aspartate (NMDA; NR1, NR2A, NR2B) receptor subunits as well as inhibitory gamma-aminobutyric acid (GABA) synthetic enzymes (GAD67, GAD65) via western blot. Adult male rats received a mild-moderate lateral FPI or sham surgery and ipsi- and contralateral BLA, DH, VH, and PFC were collected 6 h, 24 h, 48 h, and 7 days post-injury. In the ipsilateral BLA, there was a significant decrease in NR1 and GluA2 24 h after injury, whereas NR2A and NR2B were increased in the contralateral BLA at 48 h compared with sham. GAD67 was increased ipsilaterally at 24 h, but decreased contralaterally at 48 h in the BLA. In the DH, both NMDA (NR2A, NR2B) and GABA-synthetic (GAD65, GAD67) proteins were increased acutely at 6 h compared with sham. GAD67 was also robustly increased in the ipsilateral VH at 6 h. In the contralateral VH, NR2A significantly increased between 6 h and 24 h after FPI, whereas GAD65 was decreased across the same time-points in the contralateral VH. In the medial PFC at 24 h we saw bilateral increases in GAD67 and a contralateral decrease in GluA1. Later, there was a significant decrease in GAD67 in contralateral PFC from 48 h to 7 days post-injury. Collectively, these data suggest that lateral FPI causes a dynamic homeostatic response across limbic networks, leading to an imbalance of the proteins involved in plasticity in neural systems underlying cognitive and emotional regulation., Competing Interests: M.S.F. is director of research for Neurovation Labs. C.C.G. has research grants funded by the National Collegiate Athletic Association (NCAA) and the U.S. Department of Defense; is a clinical consultant for the National Football League (NFL)-Neurological Care Program, the National Hockey League Players' Association (NHLPA), and the LA Lakers; serves on advisory panels for Major League Soccer, the National Basketball Association (NBA), the U.S. Soccer Federation, and Highmark Interactive; has stock options from Highmark Interactive; and has received book royalties from Blackwell/Wiley Publishing (Prioritized Neurological Differential Diagnosis)., (© Ann N. Hoffman et al., 2021; Published by Mary Ann Liebert, Inc.)

Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods : We sought to determine memory differences between persons with RC/SCI, moderate-to-severe single-impact traumatic brain injury (SI-TBI), and healthy controls. MRI scans from a subsample of participants with SI-TBI were used to identify the neuroanatomical correlates of observed memory process differences between the brain injury groups. Results : Both brain injury groups evidenced worse learning and recall in contrast to controls, although SI-TBI group had poorer memory than the RC/SCI group. Regarding memory process differences, in contrast to controls, the SI-TBI group evidenced difficulties with encoding, consolidation, and retrieval, while the RC/SCI group showed deficits in consolidation and retrieval. Delayed recall was predicted by encoding, with consolidation as a secondary predictor in the SI-TBI group. In the RC/SCI group, delayed recall was only predicted by consolidation. MRI data showed that the consolidation index we used mapped onto hippocampal atrophy. Conclusions : RC/SCI is primarily associated with consolidation deficits, which differs from SI-TBI. Given the role of the hippocampus in memory consolidation and the fact that hyperphosphorylated tau tends to accumulate in the medial temporal lobe in RC/SCI, consolidation deficits may be a cognitive marker of chronic traumatic encephalopathy in athletes.

Traumatic brain injury (TBI) is one of the most common injuries to military personnel, a population often exposed to stressful stimuli and emotional trauma. Changes in sensory processing after TBI might contribute to TBI-post traumatic stress disorder (PTSD) comorbidity. Combining an animal model of TBI with an animal model of emotional trauma, we reveal an interaction between auditory sensitivity after TBI and fear conditioning where 75 dB white noise alone evokes a phonophobia-like phenotype and when paired with footshocks, fear is robustly enhanced. TBI reduced neuronal activity in the hippocampus but increased activity in the ipsilateral lateral amygdala (LA) when exposed to white noise. The white noise effect in LA was driven by increased activity in neurons projecting from ipsilateral auditory thalamus (medial geniculate nucleus). These data suggest that altered sensory processing within subcortical sensory-emotional circuitry after TBI results in neutral stimuli adopting aversive properties with a corresponding impact on facilitating trauma memories and may contribute to TBI-PTSD comorbidity.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cerebral acidosis is a consequence of secondary injury mechanisms following traumatic brain injury (TBI), including excitotoxicity and ischemia, with potentially significant clinical implications. However, there remains an unmet clinical need for technology for non-invasive, high resolution pH imaging of human TBI for studying metabolic changes following injury. The current study examined 17 patients with TBI and 20 healthy controls using amine chemical exchange saturation transfer echoplanar imaging (CEST EPI), a novel pH-weighted molecular MR imaging technique, on a clinical 3T MR scanner. Results showed significantly elevated pH-weighted image contrast (MTR asym at 3 ppm) in areas of T2 hyperintensity or edema (P < 0.0001), and a strong negative correlation with Glasgow Coma Scale (GCS) at the time of the MRI exam (R 2  = 0.4777, P = 0.0021), Glasgow Outcome Scale - Extended (GOSE) at 6 months from injury (R 2  = 0.5334, P = 0.0107), and a non-linear correlation with the time from injury to MRI exam (R 2  = 0.6317, P = 0.0004). This evidence suggests clinical feasibility and potential value of pH-weighted amine CEST EPI as a high-resolution imaging tool for identifying tissue most at risk for long-term damage due to cerebral acidosis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Experimental models have been proven to be valuable tools to understand downstream cellular mechanisms of Traumatic Brain Injury (TBI). The models allow for reduction of confounding variables and tighter control of varying parameters. It has been recently reported that craniectomy induces pro-inflammatory responses, which therefore needs to be properly addressed given the fact that craniectomy is often considered a control procedure for experimental TBI models. The current study aims to determine whether a craniectomy induces alterations in Resting State Network (RSN) in a developmental rodent model. Functional Magnetic Resonance Imaging (fMRI) data-driven RSN show clusters of peak differences (left caudate putamen, somatosensory cortex, amygdala and piriform cortex) between craniectomy and control group, four days post-craniectomy. In addition, the Novel Object Recognition (NOR) task revealed impaired working memory in the craniectomy group. This evidence supports craniectomy-induced neurological changes which need to be carefully addressed, considering the frequent use of craniectomy as a control procedure for experimental models of TBI.

Traumatic brain injury (TBI) is associated with acute cerebral metabolic crisis (ACMC). ACMC-related atrophy appears to be prominent in frontal and temporal lobes following moderate-to-severe TBI. This atrophy is correlated with poorer cognitive outcomes in TBI. The current study investigated ability of acute glucose and lactate metabolism to predict long-term recovery of frontal-temporal cognitive function in participants with moderate-to-severe TBI. Cerebral metabolic rate of glucose and lactate were measured by the Kety-Schmidt method on days 0-7 post-injury. Indices of frontal-temporal cognitive processing were calculated for six months post-injury; 12 months post-injury; and recovery (the difference between the six- and 12-month scores). Glucose and lactate metabolism were included in separate regression models, as they were highly intercorrelated. Also, glucose and lactate values were centered and averaged and included in a final regression model. Models for the prediction frontal-temporal cognition at six and 12 months post-injury were not significant. However, average glucose and lactate metabolism predicted recovery of frontal-temporal cognition, accounting for 23% and 22% of the variance, respectively. Also, maximum glucose metabolism, but not maximum lactate metabolism, was an inverse predictor in the recovery of frontal-temporal cognition, accounting for 23% of the variance. Finally, the average of glucose and lactate metabolism predicted frontal-temporal cognitive recovery, accounting for 22% of the variance. These data indicate that acute glucose and lactate metabolism both support cognitive recovery from TBI. Also, our data suggest that control of endogenous fuels and/or supplementation with exogenous fuels may have therapeutic potential for cognitive recovery from TBI., (© 2017 Wiley Periodicals, Inc.)

Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP-BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP-BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury-defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) in children can cause persisting cognitive and behavioral dysfunction, and inevitably raises concerns about lost potential in these injured youth. Lateral fluid percussion injury (FPI) in weanling rats pathologically affects hippocampal N-methyl-d-aspartate receptor (NMDAR)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated glutamatergic neurotransmission subacutely within the first post-injury week. FPI to weanling rats has also been shown to impair enriched-environment (EE) induced enhancement of Morris water maze (MWM) learning and memory in adulthood. Recently, improved outcomes can be achieved using agents that enhance NMDAR function. We hypothesized that administering D-cycloserine (DCS), an NMDAR co-agonist, every 12 h (i.p.) would restore subacute glutamatergic neurotransmission and reinstate experience-dependent plasticity. Postnatal day 19 (P19) rats received either a sham or FPI. On post-injury day (PID) 1-3, animals were randomized to saline (Sal) or DCS. Firstly, immunoblotting of hippocampal NMDAR and AMPAR proteins were measured on PID4. Second, PID4 novel object recognition, an NMDAR- and hippocampal- mediated working memory task, was assessed. Third, P19 rats were placed in an EE (17 days), and MWM performance was measured, starting on PID30. On PID4, DCS restored reduced NR2A and increased GluR2 by 54%, and also restored diminished recognition memory in FPI pups. EE significantly improved MWM performance in shams, regardless of treatment. In contrast, FPI-EE-Sal animals only performed to the level of standard housed animals, whereas FPI-EE-DCS animals were comparable with sham-EE counterparts. This study shows that NMDAR agonist use during reduced glutamatergic transmission after developmental TBI can reinstate early molecular and behavioral responses that subsequently manifest in experience-dependent plasticity and rescued potential.

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.

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., (© The Author(s) 2015.)

Experimental traumatic brain injury (TBI) is known to produce an acute increase in cerebral glucose utilization, followed rapidly by a generalized cerebral metabolic depression. The current studies determined effects of single or multiple treatments with sodium pyruvate (SP; 1000mg/kg, i.p.) or ethyl pyruvate (EP; 40mg/kg, i.p.) on cerebral glucose metabolism and neuronal injury in rats with unilateral controlled cortical impact (CCI) injury. In Experiment 1 a single treatment was given immediately after CCI. SP significantly improved glucose metabolism in 3 of 13 brain regions while EP improved metabolism in 7 regions compared to saline-treated controls at 24h post-injury. Both SP and EP produced equivalent and significant reductions in dead/dying neurons in cortex and hippocampus at 24h post-CCI. In Experiment 2 SP or EP were administered immediately (time 0) and at 1, 3 and 6h post-CCI. Multiple SP treatments also significantly attenuated TBI-induced reductions in cerebral glucose metabolism (in 4 brain regions) 24h post-CCI, as did multiple injections of EP (in 4 regions). The four pyruvate treatments produced significant neuroprotection in cortex and hippocampus 1day after CCI, similar to that found with a single SP or EP treatment. Thus, early administration of pyruvate compounds enhanced cerebral glucose metabolism and neuronal survival, with 40mg/kg of EP being as effective as 1000mg/kg of SP, and multiple treatments within 6h of injury did not improve upon outcomes seen following a single treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Concussion, or mild traumatic brain injury (TBI), affects millions of patients worldwide. Understanding the pathophysiology of TBI can help manage its repercussions. The brain is significantly altered immediately following mild TBI because of metabolic, hemodynamic, structural, and electrophysiologic changes. This process affects cognition and behavior and can leave the brain vulnerable for worse injury in the setting of repeat insult. This article is an update of our previously published review, reporting relevant and current studies from the bench to the bedside of mild TBI. Understanding the pathobiology can help prevent and treat mild TBI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, placing a significant financial burden on the healthcare system worldwide. Non-invasive neuroimaging technologies have been playing a pivotal role in the study of TBI, providing important information for surgical planning and patient management. Advances in understanding the basic mechanisms and pathophysiology of the brain following TBI are hindered by a lack of reliable image analysis methods for accurate quantitative assessment of TBI-induced structural and pathophysiological changes seen on anatomical and functional images obtained from multiple imaging modalities. Conventional region-of-interest (ROI) analysis based on manual labeling of brain regions is time-consuming and the results could be inconsistent within and among investigators. In this study, we propose a workflow solution framework that combined the use of non-linear spatial normalization of structural brain images and template-based anatomical labeling to automate the ROI analysis process. The proposed workflow solution is applied to dynamic PET scanning with 15 O-water (0-10 min) and 18 F-FDDNP (0-6 min) for measuring cerebral blood flow in patients with TBI., Competing Interests: J.R.B. and S.-C.H. are co-inventors of the 18F-FDDNP PET technology that is covered under University of California, Los Angeles patents and licensed to TauMark, LLC. J.R.B. has a financial interest in TauMark, LLC. K.-P.W., M.B., T.C.G., V.K., D.A.H., and P.M.V. have no financial conflicts of interest.

The impact of hyperglycemia after traumatic brain injury (TBI), and even the administration of glucose-containing solutions to head injured patients, remains controversial. In the current study adult male Sprague-Dawley rats were tested on behavioral tasks and then underwent surgery to induce sham injury or unilateral controlled cortical impact (CCI) injury followed by injections (i.p.) with either a 50% glucose solution (Glc; 2g/kg) or an equivalent volume of either 0.9% or 8% saline (Sal) at 0, 1, 3 and 6h post-injury. The type of saline treatment did not significantly affect any outcome measures, so these data were combined. Rats with CCI had significant deficits in beam-walking traversal time and rating scores (p's < 0.001 versus sham) that recovered over test sessions from 1 to 13 days post-injury (p's < 0.001), but these beam-walking deficits were not affected by Glc versus Sal treatments. Persistent post-CCI deficits in forelimb contraflexion scores and forelimb tactile placing ability were also not differentially affected by Glc or Sal treatments. However, deficits in latency to retract the right hind limb after limb extension were significantly attenuated in the CCI-Glc group (p < 0.05 versus CCI-Sal). Both CCI groups were significantly impaired in a plus maze test of spatial working memory on days 4, 9 and 14 post-surgery (p < 0.001 versus sham), and there was no effect of Glc versus Sal on this cognitive outcome measure. At 15 days post-surgery the loss of cortical tissue volume (p < 0.001 versus sham) was significantly less in the CCI-Glc group (30.0%; p < 0.05) compared to the CCI-Sal group (35.7%). Counts of surviving hippocampal hilar neurons revealed a significant (~40%) loss ipsilateral to CCI (p < 0.001 versus sham), but neuronal loss in the hippocampus was not different in the CCI-Sal and CCI-Glc groups. Taken together, these results indicate that an early elevation of blood glucose may improve some neurological outcomes and, importantly, the induction of hyperglycemia after isolated TBI did not adversely affect any sensorimotor, cognitive or histological outcomes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.

We evaluated the hypothesis that lactate shuttling helps support the nutritive needs of injured brains. To that end, we utilized dual isotope tracer [6,6-(2)H2]glucose, that is, D2-glucose, and [3-(13)C]lactate techniques involving arm vein tracer infusion along with simultaneous cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Traumatic brain injury (TBI) patients with nonpenetrating brain injuries (n=12) were entered into the study following consent of patients' legal representatives. Written and informed consent was obtained from control volunteers (n=6). Patients were studied 5.7±2.2 (mean±SD) days post-injury; during periods when arterial glucose concentration tended to be higher in TBI patients. As in previous investigations, the cerebral metabolic rate for glucose (CMRgluc, i.e., net glucose uptake) was significantly suppressed following TBI (p<0.001). However, lactate fractional extraction, an index of cerebral lactate uptake related to systemic lactate supply, approximated 11% in both healthy control subjects and TBI patients. Further, neither the CMR for lactate (CMRlac, i.e., net lactate release), nor the tracer-measured cerebral lactate uptake differed between healthy controls and TBI patients. The percentages of lactate tracer taken up and released as (13)CO2 into the JB accounted for 92% and 91% for control and TBI conditions, respectively, suggesting that most cerebral lactate uptake was oxidized following TBI. Comparisons of isotopic enrichments of lactate oxidation from infused [3-(13)C]lactate tracer and (13)C-glucose produced during hepatic and renal gluconeogenesis (GNG) showed that 75-80% of (13)CO2 released into the JB was from lactate and that the remainder was from the oxidation of glucose secondarily labeled from lactate. Hence, either directly as lactate uptake, or indirectly via GNG, peripheral lactate production accounted for ∼70% of carbohydrate (direct lactate uptake+uptake of glucose from lactate) consumed by the injured brain. Undiminished cerebral lactate fractional extraction and uptake suggest that arterial lactate supplementation may be used to compensate for decreased CMRgluc following TBI.

Adolescents are at greatest risk for traumatic brain injury (TBI) and repeat TBI (RTBI). TBI-induced hypopituitarism has been documented in both adults and juveniles and despite the necessity of pituitary function for normal physical and brain development, it is still unrecognized and untreated in adolescents following TBI. TBI induced hormonal dysfunction during a critical developmental window has the potential to cause long-term cognitive and behavioral deficits and the topic currently remains unaddressed. The purpose of this study was to determine if four mild TBIs delivered to adolescent male rats disrupts testosterone production and adult behavioral outcomes. Plasma testosterone was quantified from 72 hrs preinjury to 3 months postinjury and pubertal onset, reproductive organ growth, erectile function and reproductive behaviors were assessed at 1 and 2 months postinjury. RTBI resulted in both acute and chronic decreases in testosterone production and delayed onset of puberty. Significant deficits were observed in reproductive organ growth, erectile function and reproductive behaviors in adult rats at both 1 and 2 months postinjury. These data suggest adolescent RTBI-induced hypopituitarism underlies abnormal behavioral changes observed during adulthood. The impact of undiagnosed hypopituitarism following RTBI in adolescence has significance not only for growth and puberty, but also for brain development and neurobehavioral function as adults., (© 2014 Wiley Periodicals, Inc.)

The brain has the capability to adapt to function when tissue is compromised. This capability of adaptation paves the road to recovery and allows for rehabilitation after a traumatic brain injury (TBI). This chapter addresses neuroplasticity within the context of TBI. Here neuroplasticity is defined as changes in neuronal structure and function, including synaptic changes as well as modifications in neural pathways. First, the influence of TBI pathology on neuroplasticity is addressed. Here, proteins that are important in neuroplasticity are introduced and a description given of how these are affected in a temporal and severity-dependent manner. Secondly, given that we are becoming increasingly aware that the brain's response to injury is highly influenced by the environmental milieu, the manner in which behavioral manipulations have an effect on TBI-associated neuroplasticity is addressed. A description is given of how specific environmental qualities may facilitate or hinder neuroplasticity. Finally, the long-term effects of neuroplasticity and the relevance it has to rehabilitation are described., (© 2015 Elsevier B.V. All rights reserved.)

Since the original descriptions of postconcussive pathophysiology, there has been a significant increase in interest and ongoing research to study the biological underpinnings of concussion. The initial ionic flux and glutamate release result in significant energy demands and a period of metabolic crisis for the injured brain. These physiological perturbations can now be linked to clinical characteristics of concussion, including migrainous symptoms, vulnerability to repeat injury, and cognitive impairment. Furthermore, advanced neuroimaging now allows a research window to monitor postconcussion pathophysiology in humans noninvasively. There is also increasing concern about the risk for chronic or even progressive neurobehavioral impairment after concussion/mild traumatic brain injury. Critical studies are underway to better link the acute pathobiology of concussion with potential mechanisms of chronic cell death, dysfunction, and neurodegeneration. This "new and improved" article summarizes in a translational fashion and updates what is known about the acute neurometabolic changes after concussive brain injury. Furthermore, new connections are proposed between this neurobiology and early clinical symptoms as well as to cellular processes that may underlie long-term impairment.

Background: Traumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms., Methods: Nineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors., Results: Early trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks., Conclusions: These results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma., (© 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.)

The acute response of the rodent subventricular zone (SVZ) to traumatic brain injury (TBI) involves a physical expansion through increased cell proliferation. However, the cellular underpinnings of these changes are not well understood. Our analyses have revealed that there are two distinct transit-amplifying cell populations that respond in opposite ways to injury. Mash1+ transit-amplifying cells are the primary SVZ cell type that is stimulated to divide following TBI. In contrast, the EGFR+ population, which has been considered to be a functionally equivalent progenitor population to Mash1+ cells in the uninjured brain, becomes significantly less proliferative after injury. Although normally quiescent GFAP+ stem cells are stimulated to divide in SVZ ablation models, we found that the GFAP+ stem cells do not divide more after TBI. We found, instead, that TBI results in increased numbers of GFAP+/EGFR+ stem cells via non-proliferative means-potentially through the dedifferentiation of progenitor cells. EGFR+ progenitors from injured brains only were competent to revert to a stem cell state following brief exposure to growth factors. Thus, our results demonstrate previously unknown changes in lineage relationships that differ from conventional models and likely reflect an adaptive response of the SVZ to maintain endogenous brain repair after TBI., (Copyright © 2014. Published by Elsevier B.V.)

We have recently shown that there is a heightened stress response after a mild traumatic brain injury (TBI) during the first 2 post-injury weeks. This corresponds to the same post-injury period when exercise does not increase brain-derived neurotrophic factor (BDNF) and autonomic dysfunction becomes evident with exercise. Here we determined stress and autonomic responses to voluntary and forced exercise at a post-injury time window when exercise has been found to elicit beneficial effects. Rats underwent a mild fluid percussion injury and were exercised at post-injury days 28-32 and 35-39. Cardiac and temperature autonomic function were evaluated. Hippocampal tissue was obtained immediately after exercise for analysis of BDNF. In contrast to the sub-acute period, corticosterone and adrenocorticotropic hormone responses to exercise were normalized in the TBI group. Irrespective of injury, forced exercise markedly stimulated the corticotrophic axis and did not increase BDNF. BDNF levels were increased with voluntary exercise in all animals. Rats exposed to forced exercise had lower activity levels during periods of non-exercise. This effect was more pronounced in the TBI rats. Cardiac and temperature autonomic responses to delayed exercise also recuperated. Rats with TBI that underwent forced exercise, however, had higher core body temperatures during experimental manipulations, thus suggesting that exposure to a potent stressor facilitates responsiveness to environmental stimulations.

The following report reviews our current understanding of the neurobiological response to concussion which is often referred to as mild traumatic brain injury. The historical accomplishments to reveal the brain's response to this injury are discussed along with the neurochemical and metabolic cascade that results in an energy crisis. The massive ionic flux induced by cerebral concussion is discussed as it pertains to primarily potassium and calcium. The ensuing metabolic demands placed on cells exposed to this ionic flux is discussed as it relates to an injury-induced diaschisis. As this cascade produces neuronal dysfunction and corresponding deficits, it also results in a state of vulnerability to secondary insults and long-term neurological problems. While experimental studies are the primary focus of this report, relevant human observations are discussed and put into context. It is now clear that cerebral concussion is not a benign event. It carries with it neuroscientific consequences that result in symptoms and an increase in risk for many other challenges to the central nervous system., (© 2014 S. Karger AG, Basel.)

Clinical studies have indicated an association between acute hyperglycemia and poor outcomes in patients with traumatic brain injury (TBI), although optimal blood glucose levels needed to maximize outcomes for these patients' remain under investigation. Previous results from experimental animal models suggest that post-TBI hyperglycemia may be harmful, neutral, or beneficial. The current studies determined the effects of single or multiple episodes of acute hyperglycemia on cerebral glucose metabolism and neuronal injury in a rodent model of unilateral controlled cortical impact (CCI) injury. In Experiment 1, a single episode of hyperglycemia (50% glucose at 2 g/kg, i.p.) initiated immediately after CCI was found to significantly attenuate a TBI-induced depression of glucose metabolism in cerebral cortex (4 of 6 regions) and subcortical regions (2 of 7) as well as to significantly reduce the number of dead/dying neurons in cortex and hippocampus at 24 h post-CCI. Experiment 2 examined effects of more prolonged and intermittent hyperglycemia induced by glucose administrations (2 g/kg, i.p.) at 0, 1, 3 and 6h post-CCI. The latter study also found significantly improved cerebral metabolism (in 3 of 6 cortical and 3 of 7 subcortical regions) and significant neuroprotection in cortex and hippocampus 1 day after CCI and glucose administration. These results indicate that acute episodes of post-TBI hyperglycemia can be beneficial and are consistent with other recent studies showing benefits of providing exogenous energy substrates during periods of increased cerebral metabolic demand., (© 2013 Elsevier B.V. All rights reserved.)

Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as 'frontal-temporal' in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis-related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.

In this study, we investigated the hypothesis that mild traumatic brain injury (mTBI) triggers a controlled gene program as an adaptive response finalized to neuroprotection, similar to that found in hibernators and in ischemic preconditioning. A stretch injury device was used to produce an equi-biaxial strain field in rat organotypic hippocampal slice cultures at a specified Lagrangian strain of 10 % and a constant strain rate of 20 s(-1). After 24 h from injury, propidium iodide staining, HPLC analysis of metabolites and microarray analysis of cDNA were performed to evaluate cell viability, cell energy state and gene expression, respectively. Compared to control cultures, 10 % stretch injured cultures showed no change in viability, but demonstrated a hypometabolic state (decreased ATP, ATP/ADP, and nicotinic coenzymes) and a peculiar pattern of gene modulation. The latter was characterized by downregulation of genes encoding for proteins of complexes I, III, and IV of the mitochondrial electron transport chain and of ATP synthase; downregulation of transcriptional and translational genes; downregulation and upregulation of genes controlling the synthesis of glutamate and GABA receptors, upregulation of calmodulin and calmodulin-binding proteins; proper modulation of genes encoding for proapoptotic and antiapoptotic proteins. These results support the hypothesis that, following mTBI, a hibernation-type response is activated in non-hibernating species. Unlike in hibernators and ischemic preconditioning, this adaptive gene programme, aimed at achieving maximal neuroprotection, is not triggered by decrease in oxygen availability. It seems rather activated to avoid increase in oxidative/nitrosative stress and apoptosis during a transient period of mitochondrial malfunctioning.

Abstract The pathophysiological changes in the pericontusional region after traumatic brain injury (TBI) have classically been considered to be ischemic. Using [F-18]fluorodeoxyglucose (FDG) and triple-oxygen PET studies, we examined the pericontusional "penumbra" to assess for increased oxygen extraction fraction (OEF), anaerobic metabolism, and tissue viability. Acute (≤4 days) CT, MRI, and PET studies were performed in eight patients with TBI who had contusions. Four regions-of-interest (ROI) containing the contusion core, pericontusional hypodense gray matter (GM), pericontusional normal-appearing GM, and remote normal-appearing GM, were defined using a semi-automatic method. The correlations of cerebral blood flow (CBF) with OEF, cerebral metabolic rate of oxygen (CMRO2), and cerebral metabolic rate of glucose (CMRglc) were examined. The oxygen-glucose ratio (OGR) in each brain region was evaluated for anaerobic metabolism. The results show that pericontusional tissue had progressively diminishing OEF, CBF, CMRO2, or CMRglc approaching the contusion core. In general, there was a preserved ratio of CBF to CMRO2 in pericontusional hypodense GM. The OGR of the pericontusional hypodense GM was low (<4.0) and was inversely correlated (r=-0.68) with time after injury. A large proportion (%area: 22-76%) of pericontusional hypodense GM tissue had CMRO2 values less than 35 μmol/100 g/min, with this percentage increased with time after injury.

We have previously reported that mild fluid percussion injury (FPI) is associated with a heightening of the hypothalamic-pituitary-adrenal axis response during the first post-injury weeks. This is the same time period when rehabilitative exercise has been strongly suggested to be ineffective. Here, we explored whether cardiac and temperature autonomic function may also be compromised during this early post-injury period. Following an FPI or sham injury, rats were exercised with forced (fRW) or voluntary (vRW) running wheels on post-injury days 0-4 and 7-11. Results indicated that overall activity levels were decreased and circadian rhythm was affected after FPI. Autonomic disruptions became evident when exercise was introduced, and these disruptions were dependent upon the characteristics of exercise. Elevations in heart rate (HR) and core body temperature (CBT) were observed as a response to vRW and fRW. FPI animals had more pronounced increases in HR as a result of vRW. Likewise, increases in HR were observed with fRW in all animals. A strong stress response has recently been associated with fRW exercise. FPI rats exposed to fRW were more responsive to experimental manipulations and had higher a CBT after the FRW session. The results suggest that subacute exercise, particularly if linked to a strong stress response, may be counterproductive. Here we show that cardiac and temperature autonomic function are compromised during the subacute period following a mild TBI.

Proton nuclear magnetic resonance (H-NMR) spectroscopic analysis of cerebral spinal fluid provides a quick, non-invasive modality for evaluating the metabolic activity of brain-injured patients. In a prospective study, we compared the CSF of 44 TBI patients and 13 non-injured control subjects. CSF was screened for ten parameters: β-glucose (Glu), lactate (Lac), propylene glycol (PG), glutamine (Gln), alanine (Ala), α-glucose (A-Glu), pyruvate (PYR), creatine (Cr), creatinine (Crt), and acetate (Ace). Using mixed effects measures, we discovered statistically significant differences between control and trauma concentrations (mM). TBI patients had significantly higher concentrations of PG, while statistical trends existed for lactate, glutamine, and creatine. TBI patients had a significantly decreased concentration of total creatinine. There were no significant differences between TBI patients and non-injured controls regarding β- or α-glucose, alanine, pyruvate or acetate. Correlational analysis between metabolites revealed that the strongest significant correlations in non-injured subjects were between β- and α-glucose (r = 0.74), creatinine and pyruvate (r = 0.74), alanine and creatine (r = 0.62), and glutamine and α-glucose (r = 0.60). For TBI patients, the strongest significant correlations were between lactate and α-glucose (r = 0.54), lactate and alanine (r = 0.53), and α-glucose and alanine (r = 0.48). The GLM and multimodel inference indicated that the combined metabolites of PG, glutamine, α-glucose, and creatinine were the strongest predictors for CMRO2, ICP, and GOSe. By analyzing the CSF of patients with TBI, our goal was to create a metabolomic fingerprint for brain injury.

Among the 3.5 million annual new head injury cases is a subpopulation of children and young adults who experience repeated traumatic brain injury (TBI). The duration of vulnerability after a single TBI remains unknown, and biomarkers have yet to be determined. Decreases in glucose metabolism (cerebral metabolic rate of glucose [CMRglc]) are consistently observed after experimental and human TBI. In the current study, it is hypothesized that the duration of vulnerability is related to the duration of decreased CMRglc and that a single mild TBI (mTBI) increases the brain's vulnerability to a second insult for a period, during which a subsequent mTBI will worsen the outcome. Postnatal day 35 rats were given sham, single mTBI, or two mTBI at 24-h or 120-h intervals. (14)C-2-deoxy-D-glucose autoradiography was conducted at 1 or 3 days post-injury to calculate CMRglc. At 24 h after a single mTBI, CMRglc is decreased by 19% in both the parietal cortex and hippocampus, but approached sham levels by 3 days post-injury. When a second mTBI is introduced during the CMRglc depression of the first injury, the consequent CMRglc is depressed (36.5%) at 24 h and remains depressed (25%) at 3 days. In contrast, when the second mTBI is introduced after the metabolic recovery of the first injury, the consequent CMRglc depression is similar to that seen with a single injury. Results suggest that the duration of metabolic depression reflects the time-course of vulnerability to second injury in the juvenile brain and could serve as a valuable biomarker in establishing window of vulnerability guidelines.

Purpose of Review: According to recent Centers for Disease Control (CDC) data, the annual incidence of traumatic brain injury (TBI) in the United States is 1.6-3.2 million, of which the majority is classified as mild. Over half of these injuries occur in the pediatric population, and can often be attributed to a sports-related mechanism. Although postconcussion symptoms are usually short-lived, more lasting deficits can occur, which can be particularly disruptive to the developing brain. Recent literature detailing the pathophysiology of mild TBI (mTBI), with attention to pediatric studies, is presented., Recent Findings: Although concussion generally does not produce any structural damage on conventional computed tomography (CT) or MRI, advanced neuroimaging modalities reveal microstructural and functional neurobiological changes. Diffuse axonal injury, metabolic impairment, alterations in neural activation and cerebral blood flow perturbations can occur and may contribute to acute symptomatology. Although these physiological changes usually recover to baseline in 7-10 days, sustaining recurrent injury before full recovery may increase the potential for persistent deficits., Summary: Understanding the pathophysiology of concussion in the pediatric population can potentially open therapeutic avenues to decrease symptom persistence and prevent further injury. Future studies in the pediatric population are necessary given the pathophysiologic differences between the developing and adult brains.

Recent contributions to the body of knowledge on traumatic brain injury (TBI) favor the view that multimodal neuroimaging using structural and functional magnetic resonance imaging (MRI and fMRI, respectively) as well as diffusion tensor imaging (DTI) has excellent potential to identify novel biomarkers and predictors of TBI outcome. This is particularly the case when such methods are appropriately combined with volumetric/morphometric analysis of brain structures and with the exploration of TBI-related changes in brain network properties at the level of the connectome. In this context, our present review summarizes recent developments on the roles of these two techniques in the search for novel structural neuroimaging biomarkers that have TBI outcome prognostication value. The themes being explored cover notable trends in this area of research, including (1) the role of advanced MRI processing methods in the analysis of structural pathology, (2) the use of brain connectomics and network analysis to identify outcome biomarkers, and (3) the application of multivariate statistics to predict outcome using neuroimaging metrics. The goal of the review is to draw the community's attention to these recent advances on TBI outcome prediction methods and to encourage the development of new methodologies whereby structural neuroimaging can be used to identify biomarkers of TBI outcome.

Objective: To determine the effects of tight glycemic control on brain metabolism after traumatic brain injury using brain positron emission tomography and microdialysis., Design: Single-center, randomized controlled within-subject crossover observational trial., Setting: Academic intensive care unit., Methods: We performed a prospective, unblinded randomized controlled within-subject crossover trial of tight (80-110 mg/dL) vs. loose (120-150 mg/dL) glycemic control in patients with severe traumatic brain injury to determine the effects of glycemic control on brain glucose metabolism, as measured by [18F] deoxy-D-glucose brain positron emission tomography. Brain microdialysis was done simultaneously., Measurements and Main Results: Thirteen severely injured traumatic brain injury patients underwent the study between 3 and 8 days (mean 4.8 days) after traumatic brain injury. In ten of these subjects, global brain and gray matter tissues demonstrated higher glucose metabolic rates while glucose was under tight control as compared with loose control (3.2 ± 0.6 vs. 2.4 + 0.4, p = .02 [whole brain] and 3.8 ± 1.4 vs. 2.9 ± 0.8, p = .05 [gray matter]). However, the responses were heterogeneous with pericontusional tissue demonstrating the least state-dependent change. Cerebral microdialysis demonstrated more frequent critical reductions in glucose (p = .02) and elevations of lactate/pyruvate ratio (p = .03) during tight glycemic control., Conclusion: Tight glycemic control results in increased global glucose uptake and an increased cerebral metabolic crisis after traumatic brain injury. The mechanisms leading to the enhancement of metabolic crisis are unclear, but delivery of more glucose through mild hyperglycemia may be necessary after traumatic brain injury.

Background: Mild traumatic brain injury (cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders, including posttraumatic stress disorder. However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether traumatic brain injury itself is a cause of augmented fear and anxiety., Methods: Rats were trained with one of five fear-conditioning procedures (n = 105) 2 days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring N-methyl-D-aspartate receptor subunits and glutamic acid decarboxylase, 67 kDa isoform protein levels in the hippocampus and basolateral amygdala complex (BLA)., Results: Injured rats exhibited an overall increase in fear conditioning, regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to overgeneralize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant upregulation of excitatory N-methyl-D-aspartate receptors in the BLA. There was a trend toward decreased γ-aminobutyric acid-related inhibition (glutamic acid decarboxylase, 67 kDa isoform) in the BLA and hippocampus., Conclusions: These results suggest that mild traumatic brain injury predisposes the brain toward heightened fear learning during stressful postinjury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the comorbidity of posttraumatic stress disorder and traumatic brain injury., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Available approaches to the investigation of traumatic brain injury (TBI) are frequently hampered, to some extent, by the unsatisfactory abilities of existing methodologies to efficiently define and represent affected structural connectivity and functional mechanisms underlying TBI-related pathology. In this paper, we describe a patient-tailored framework which allows mapping and characterization of TBI-related structural damage to the brain via multimodal neuroimaging and personalized connectomics. Specifically, we introduce a graphically driven approach for the assessment of trauma-related atrophy of white matter connections between cortical structures, with relevance to the quantification of TBI chronic case evolution. This approach allows one to inform the formulation of graphical neurophysiological and neuropsychological TBI profiles based on the particular structural deficits of the affected patient. In addition, it allows one to relate the findings supplied by our workflow to the existing body of research that focuses on the functional roles of the cortical structures being targeted. A graphical means for representing patient TBI status is relevant to the emerging field of personalized medicine and to the investigation of neural atrophy.

The pulsatility index (PI) and the intracranial -pressure (ICP) may or may not be correlated; the evidence to date differs widely. A study of multiple measures of PI and the corresponding ICP in patients with severe traumatic brain injury (TBI) showed that some of the relationships were moderately strong when calculated as conventional Pearson correlation coefficients. However, that method makes no adjustment of any kind for statistical outliers in the data. With the TBI patients demonstrating a large fraction of skewed measurements, a set of robust correlations were calculated that demonstrated that the apparent relationships between PI and ICP were entirely attributable to the statistical outliers. We conclude that the fundamental relationship of PI to ICP is weakly positive at best.

Although neuroimaging is essential for prompt and proper management of traumatic brain injury (TBI), there is a regrettable and acute lack of robust methods for the visualization and assessment of TBI pathophysiology, especially for of the purpose of improving clinical outcome metrics. Until now, the application of automatic segmentation algorithms to TBI in a clinical setting has remained an elusive goal because existing methods have, for the most part, been insufficiently robust to faithfully capture TBI-related changes in brain anatomy. This article introduces and illustrates the combined use of multimodal TBI segmentation and time point comparison using 3D Slicer, a widely-used software environment whose TBI data processing solutions are openly available. For three representative TBI cases, semi-automatic tissue classification and 3D model generation are performed to perform intra-patient time point comparison of TBI using multimodal volumetrics and clinical atrophy measures. Identification and quantitative assessment of extra- and intra-cortical bleeding, lesions, edema, and diffuse axonal injury are demonstrated. The proposed tools allow cross-correlation of multimodal metrics from structural imaging (e.g., structural volume, atrophy measurements) with clinical outcome variables and other potential factors predictive of recovery. In addition, the workflows described are suitable for TBI clinical practice and patient monitoring, particularly for assessing damage extent and for the measurement of neuroanatomical change over time. With knowledge of general location, extent, and degree of change, such metrics can be associated with clinical measures and subsequently used to suggest viable treatment options.

Previous studies have shown that the change of cerebral metabolic rate of glucose (CMRglc) in response to traumatic brain injury (TBI) is different in young (PND35) and adult rats (PND70), and that prolonged ketogenic diet treatment results in histological and behavioral neuroprotection only in younger rat brains. However, the mechanism(s) through which ketones act in the injured brain and the biochemical markers of their action remain unknown. Therefore, the current study was initiated to: 1) determine the effect of injury on the neurochemical profile in PND35 compared to PND70 rats; and 2) test the effect of early post-injury administration of ketogenic diet on brain metabolism in PND35 versus PND70 rats. The data show that alterations in energy metabolites, amino acid, and membrane metabolites were not evident in PND35 rats on standard diet until 24  h after injury, when the concentration of most metabolites was reduced from sham-injured values. In contrast, acute, but transient deficits in energy metabolism were measured at 6  h in PND70 rats, together with deficits in N-acetylaspartate that endured until 24  h. Administration of a ketogenic diet resulted in significant increases in plasma β-hydroxybutyrate (βOHB) levels. Similarly, brain βOHB levels were significantly elevated in all injured rats, but were elevated by 43% more in PND35 rats compared to PND70 rats. As a result, ATP, creatine, and phosphocreatine levels at 24  h after injury were significantly improved in the ketogenic PND35 rats, but not in the PND70 group. The improvement in energy metabolism in the PND35 brains was accompanied by the recovery of NAA and reduction of lactate levels, as well as amelioration of the deficits of other amino acids and membrane metabolites. These results indicate that the PND35 brains are more resistant to the injury, indicated by a delayed deficit in energy metabolism. Moreover, the younger brains revert to ketones metabolism more quickly than do the adult brains, resulting in better neurochemical and cerebral metabolic recovery after injury.

Prior work indicates that cerebral glycolysis is impaired following traumatic brain injury (TBI) and that pyruvate treatment acutely after TBI can improve cerebral metabolism and is neuroprotective. Since extracellular levels of glucose decrease during periods of increased cognitive demand and exogenous glucose improves cognitive performance, we hypothesized that pyruvate treatment prior to testing could ameliorate cognitive deficits in rats with TBI. Based on pre-surgical spatial alternation performance in a 4-arm plus-maze, adult male rats were randomized to receive either sham injury or unilateral (left) cortical contusion injury (CCI). On days 4, 9 and 14 after surgery animals received an intraperitoneal injection of either vehicle (Sham-Veh, n=6; CCI-Veh, n=7) or 1000 mg/kg of sodium pyruvate (CCI-SP, n=7). One hour after each injection rats were retested for spatial alternation performance. Animals in the CCI-SP group showed no significant working memory deficits in the spatial alternation task compared to Sham-Veh controls. The percent four/five alternation scores for CCI-Veh rats were significantly decreased from Sham-Veh scores on days 4 and 9 (p<0.01) and from CCI-SP scores on days 4, 9 and 14 (p<0.05). Measures of cortical contusion volume, regional cerebral metabolic rates of glucose and regional cytochrome oxidase activity at day 15 post-injury did not differ between CCI-SP and CCI-Veh groups. These results show that spatial alternation testing can reliably detect temporal deficits and recovery of working memory after TBI and that delayed pyruvate treatment can ameliorate TBI-induced cognitive impairments., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Concussion or mild traumatic brain injury (mTBI) is a condition that affects hundreds of thousands of patients worldwide. Understanding the pathophysiology of this disorder can help manage its acute and chronic repercussions. Immediately following mTBI, there are several metabolic, hemodynamic, structural, and electric changes that alter normal cerebral function. These alterations can increase the brain's vulnerability to repeat injury and long-term disability. This review evaluates current studies from the bench to the bedside of mTBI. Acute and chronic effects of concussion are measured in both animal and clinical studies. Also, the effect of repeat concussions is analyzed. Concussion-induced pathophysiology with regards to glucose metabolism changes, mitochondrial dysfunction, axonal injury, and structural damage are evaluated. Translational studies such as functional magnetic resonance imaging, magnetic resonance spectroscopy and diffusion tensor imaging prove to be effective clinical tools for both prognostic and treatment parameters. Understanding the neurobiology of concussion will lead to development and validation of physiological biomarkers of this common injury. These biomarkers (eg, laboratory tests, imaging, electrophysiology) will then allow for improved detection, better functional assessment and evidence-based return to play recommendations., (Published by Elsevier Inc.)

Despite various lines of evidence pointing to the compartmentation of metabolism within the brain, few studies have reported the effect of a traumatic brain injury (TBI) on neuronal and astrocyte compartments and/or metabolic trafficking between these cells. In this study we used ex vivo ¹³C NMR spectroscopy following an infusion of [1-¹³C] glucose and [1,2-¹³C₂] acetate to study oxidative metabolism in neurons and astrocytes of sham-operated and fluid percussion brain injured (FPI) rats at 1, 5, and 14 days post-surgery. FPI resulted in a decrease in the ¹³C glucose enrichment of glutamate in neurons in the injured hemisphere at day 1. In contrast, enrichment of glutamine in astrocytes from acetate was not significantly decreased at day 1. At day 5 the ¹³C enrichment of glutamate and glutamine from glucose in the injured hemisphere of FPI rats did not differ from sham levels, but glutamine derived from acetate metabolism in astrocytes was significantly increased. The ¹³C glucose enrichment of the C3 position of glutamate (C3) in neurons was significantly decreased ipsilateral to FPI at day 14, whereas the enrichment of glutamine in astrocytes had returned to sham levels at this time point. These findings indicate that the oxidative metabolism of glucose is reduced to a greater extent in neurons compared to astrocytes following a FPI. The increased utilization of acetate to synthesize glutamine, and the acetate enrichment of glutamate via the glutamate-glutamine cycle, suggests an integral protective role for astrocytes in maintaining metabolic function following TBI-induced impairments in glucose metabolism.

Traumatic brain injury (TBI) results in enduring functional deficits. Strategies aimed at promoting plasticity within the injured brain may aid in enhancing functional outcome. We have previously shown that spontaneous pericontusional axon sprouting occurs within 7-14 days after controlled cortical impact injury in the adult rat, but ultimately fails due to an increasingly growth-inhibitory environment. We therefore sought to determine whether acute infusion of chondroitinase ABC into the site of the cortical contusion, to further reduce pericontusional growth-inhibitory chondroitin sulfate proteoglycans (CSPGs), would enhance and prolong the sprouting response. We also wanted to determine if chondroitinase-enhanced sprouting would ameliorate the behavioral deficits in forelimb function that occur in this model. Acute chondroitinase infusion decreased intact CSPGs and significantly increased pericontusional cortical grey and white matter growth-associated protein 43 (GAP43)-positive axon sprouting at 7 days post-injury. A return of intact CSPGs at later time points likely contributed to the absence of persistently increased levels of axon sprouting by 14-21 days post-injury. There was no overall benefit on forelimb function during the time of maximal sprouting or at any subsequent times in three of four behavioral outcome measures. However, there was a chondroitinase-induced improvement in recovery from unskilled limb use deficits on the staircase forelimb reaching test toward sham-injured values at 28 days, which was not achieved by the vehicle-treated rats, indicating that there is some minor functional benefit of the increased sprouting induced by chondroitinase treatment. The current results, together with data from spinal cord injury models after chondroitinase intervention, suggest that a combinatorial approach with the addition of neurotrophins and rehabilitation would result in more robust axon sprouting and consequently improve behavioral outcome.

Chronic brain atrophy after traumatic brain injury (TBI) is a well-known phenomenon, the causes of which are unknown. Early nonischemic reduction in oxidative metabolism is regionally associated with chronic brain atrophy after TBI. A total of 32 patients with moderate-to-severe TBI prospectively underwent positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) within the first week and at 6 months after injury. Regional lobar assessments comprised oxidative metabolism and glucose metabolism. Acute MRI showed a preponderance of hemorrhagic lesions with few irreversible ischemic lesions. Global and regional chronic brain atrophy occurred in all patients by 6 months, with the temporal and frontal lobes exhibiting the most atrophy compared with the occipital lobe. Global and regional reduction in cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose were observed. The extent of metabolic dysfunction was correlated with the total hemorrhage burden on initial MRI (r=0.62, P=0.01). The extent of regional brain atrophy correlated best with CMRO(2) and CBF. Lobar values of OEF were not in the ischemic range and did not correlate with chronic brain atrophy. Chronic brain atrophy is regionally specific and associated with regional reductions in oxidative brain metabolism in the absence of irreversible ischemia.

We previously reported that pericontusional extracellular chondroitin sulfate proteoglycans (CSPGs) are profoundly reduced for 3 weeks after experimental traumatic brain injury, indicating a potential growth-permissive window for plasticity. Here, we investigate the extracellular environment of sprouting neurons after controlled cortical impact injury in adult rats to determine the spatial and temporal arrangement of inhibitory and growth-promoting molecules in relation to growth-associated protein 43-positive (GAP43+) neurons. Spontaneous cortical sprouting was maximal in pericontused regions at 7 and 14 days after injury but absent by 28 days. Perineuronal nets containing CSPGs were reduced at 7 days after injury in the pericontused region (p < 0.05), which was commensurate with a reduction in extracellular CSPGs. Sprouting was restricted to the perineuronal nets and CSPG-deficient regions at 7 days, indicating that the pericontused region is temporarily and spatially permissive to new growth. At this time point,GAP43+ neurons were associated with brain regions containing cells positive for polysialic acid neural cell adhesion molecule but not with fibronectin-positive cells. Brain-derived neurotrophic factor was reduced in the immediate pericontused region at 7 days. Along with prior Western blot evidence, these data suggest that a lowered intrinsic growth stimulus, together with a later return of growth-inhibitory CSPGs, may contribute to the ultimate disappearance of sprouting neurons after traumatic brain injury.

Traumatic brain injury (TBI), one of the most frequent causes of neurologic and neurobehavioral morbidity in the pediatric population, can result in lifelong challenges not only for patients, but also for their families. Survivors of a brain injury experienced during childhood - when the brain is undergoing a period of rapid development - frequently experience unique challenges as the consequences of their injuries are overlaid on normal developmental changes. Experimental studies have significantly advanced our understanding of the mechanisms and underlying molecular underpinnings of the injury response and recovery process following a TBI in the developing brain. In this paper, normal and TBI-related alterations in growth, development and metabolism are comprehensively reviewed in the postweanling/juvenile age range in the rat (postnatal days 21-60). As part of this review, TBI-related changes in gene expression are presented, with a focus on the injury-induced alterations related to cerebral growth and metabolism, and discussed in the context of existing literature related to physiological and behavioral responses to experimental TBI. Increasing evidence from the existing literature and from our own gene microarray data indicates that molecular responses related to growth, development and metabolism may play a particularly important role in the injury response and the recovery trajectory following developmental TBI. While gene expression analysis shows many of these changes occur at the level of transcription, a comprehensive review of other studies suggests that the control of metabolic substrates may preferentially be regulated through changes in transporters and enzymatic activity. The interrelation between cellular metabolism and activity-dependent neuroplasticity shows great promise as an area for future study for an optimal translation of experimental data to clinical TBI, with the ultimate goal of guiding therapeutic interventions., (Copyright © 2010 S. Karger AG, Basel.)

Detection of novelty is an essential component of recognition memory, which develops throughout cerebral maturation. To better understand the developmental aspects of this memory system, the novel object recognition task (NOR) was used with the immature rat and ontogenically profiled. It was hypothesized that object recognition would vary across development and be inferior to adult performance. The NOR design was made age-appropriate by downsizing the testing objects and arena. Weanling (P20-23), juvenile (P29-40), and adult (P50+) rats were tested after 0.25, 1, 24, and 48 hr delays. Weanlings exhibited novel object recognition at 0.25 and 1 hr, while older animals showed a preference for the novel object out to 24 hr. These findings are consistent with previous research performed in humans and monkeys, as well as to studies using the NOR after medial temporal lobe damage in adult rats.

Following experimental and clinical traumatic brain injury (TBI), the local cerebral metabolic rate of glucose (lCMR(Glc)) is commonly estimated using the 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) method. The adequate estimation of lCMR(Glc) using FDG requires a correction factor, the lumped constant (LC), to convert FDG net uptake into lCMR(Glc). The LC, and thus lCMR(Glc) calculations, require a steady-state that may be disrupted following TBI. In the present report, we hypothesized that [1-(14)C]glucose uptake would accurately reflect glucose dynamics early post-injury, and was compared to the regional uptake of FDG in 44 rats subjected to moderate (2.4-2.6 atm) lateral fluid percussion brain injury (FPI) or sham injury. Cortical energy state and adenylate (ATP, ADP, and AMP) levels were also measured. Early (7-42 min) after FPI, FDG uptake was increased in the ipsilateral cortex and hippocampus (p < 0.05). In contrast, no change in [1-(14)C]glucose uptake (7 and 17 min post-injury) or cortical adenylate content (42 min post-injury) was observed. At 12 h following FPI, the ipsilateral FDG and [1-(14)C]glucose uptake were decreased in the cortex and hippocampus, and the ipsilateral cortical ATP concentration was decreased in comparison to sham-injured controls (p < 0.05). Under the present experimental conditions, the rate of cerebral uptake of FDG and of [1-(14)C]glucose differed, and indicated that following TBI, regional changes in the LC may occur in the immediate, but not in the late, post-injury phase. These results should be considered when interpreting results obtained using FDG for the estimation of lCMR(Glc) early following experimental TBI.