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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 15O-water (0–10 min) and 18F-FDDNP (0–6 min) for measuring cerebral blood flow in patients with TBI.

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.

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.

Drug and alcohol use are common in neurotrauma patients. Despite growing methamphetamine use there are few studies of the impact of methamphetamine use on outcome after traumatic brain injury (TBI).

Optic nerve crush injury leads to death of retinal ganglion cells (RGCs), both as a direct result of the primary injury and via secondary degeneration induced by neurotoxins secreted by dying RGCs. Studies have shown that, if optic nerve crush is preceded by an unrelated injury to another part of the central nervous system, for example, the spinal cord, the ensuing T cell–mediated protective autoimmunity results in a significant increase in RGC survival. In this study, we used the controlled cortical impact paradigm to induce unilateral traumatic brain injury (TBI) in rats at different times before they were contralaterally subjected to a mild optic nerve crush. Survival of RGCs, assessed 2 weeks after crush injury, was significantly increased when the crush was inflicted 11 days after TBI, but not when the two injuries were concomitant. The beneficial effect was unaffected by injection of low-dose methylprednisolone MP (1 mg/kg), but was inhibited after a high-dose injection (30 mg/kg). Brain-derived neurotrophic factor (BDNF) mRNA, assayed at intervals after TBI, was increased in the retina ipsilateral to TBI but decreased in the contralateral retina. BDNF peaked 1 day after TBI, decreased on day 11, and rose again on day 21. It thus seems that brain injury sustained a certain time before optic nerve injury has a protective effect on RGC survival. This neuroprotective effect, which appears unrelated to retinal BDNF, is inhibited by high-dose MP, commonly used clinically to treat traumatic optic neuropathy.

Traumatic brain injury (TBI) is a major cause of disability in the pediatric population and can result in abnormal development. Experimental studies conducted in animals have revealed impaired plasticity following developmental TBI, even in the absence of significant anatomical damage. The N-methyl-D-aspartate receptor (NMDAR) is clearly involved in both normal development and in the pathophysiology of TBI. Following lateral fluid percussion injury in postnatal day (PND) 19 rats, we tested the hypothesis that TBI sustained at an early age would result in impaired NMDAR expression. Using immunoblotting and reverse transcriptase–polymerase chain reaction (RT-PCR), protein and RNA levels of NMDAR subunits were measured in the cerebral cortex and hippocampus on post-injury days (PID) 1, 2, 4, and 7 (though the PID7 analysis was only for protein) and compared with age-matched shams. Significant effects of hemisphere (analysis of variance [ANOVA], p < 0.01), and interactions between hemisphere and injury (ANOVA, p < 0.05) and hemisphere and PID (ANOVA, p < 0.05) were found for synaptic protein levels of the NR2A subunit in hippocampus. Specifically, within the ipsilateral hippocampus, NR2A was reduced by 9.9%, 47.9%, 40.8%, and 6.3% on PID1, PID2, PID4, and PID7, respectively. Within the cortex, there was a significant effect of injury (ANOVA, p < 0.05) without any hemispheric differences. These bilateral cortical reductions measured 30.5%, 3.2%, 5.7%, and 13.4% at the same timepoints after injury. Injury had no significant main effect on NR1 or NR2B protein levels. RT-PCR analysis showed no significant changes in NR1, NR2A, or NR2B gene expression; however, as a positive control, hsp70 was induced more than twofold in ipsilateral cortex and hippocampus on PID1. It is known that NR2A expression levels increase during normal development, and in response to environmental stimuli. Our data suggest that injury-induced reduction in the expression of NR2A is one likely mechanism for the impaired experience-dependent neuroplasticity seen following traumatic injury to the immature brain.

The metabolic fate of [1,2 13C]–labeled glucose was determined in male control and unilateral controlled cortical impact (CCI) injured rats at 3.5 and 24 h after surgery. The concentration of 13C-labeled glucose, lactate, glutamate and glutamine were measured in the injured and contralateral cortex. CCI animals showed a 145% increase in 13C lactate in the injured cortex at 3.5 h, but not at 24 h after injury, indicating increased glycolysis in neurons and/or astrocytes ipsilateral to CCI. Total levels of 13C glutamate in cortical tissue extracts did not differ between groups. However, 13C glutamine increased by 40% in the left and 98% in the right cortex at 3.5 h after injury, most likely resulting from an increase in astrocytic metabolism of glutamate. Levels of 13C incorporation into the glutamine isotopomers had returned to control levels by 24 h after CCI. The singlet to doublet ratio of the lactate C3 resonances was calculated to estimate the flux of glucose through the pentose phosphate pathway (PPP). CCI resulted in bilateral increases (9–12%) in the oxidation of glucose via the PPP, with the largest increase occurring at 24 h. Since an increase in PPP activity is associated with NADPH generation, the data suggest that there was an increasing need for reducing equivalents after CCI. Furthermore, 13C was incorporated into glutamate and glutamine isotopomers associated with multiple turns of the tricarboxylic acid (TCA) cycle, indicating that oxidative phosphorylation of glucose was maintained in the injured cortex at 3.5 and 24 h after a moderate to severe CCI injury.

Traumatic brain injury (TBI) results in significant acute reductions in regional cerebral blood flow (rCBF). However, the mechanisms by which TBI impairs CBF and cerebral vascular reactivity have remained elusive. In the present study, the effect of verapamil, an L-type calcium (Ca2+) channel blocker, on post-traumatic vascular reactivity was evaluated following a lateral fluid percussion injury (FPI) in rats. rCBF was measured by [14C]-iodoantipyrine autoradiography 1 h after FPI. Following FPI, significant rCBF reductions were documented in all examined cortical areas. These reductions were the most prominent (72.0%) at the primary injury site. Intravenous infusion of verapamil (VE; 200 µg/kg/min), and norepinephrine (NE; 20 µg/mL/min) to maintain normal blood pressure, increased rCBF by 141.5% at the primary injury site when compared to untreated, FPinjured animals. Under stimulated conditions, both the ipsilateral and contralateral hemispheres failed to show any increases in rCBF at 1 h following FPI. In direct contrast, following VE+NE treatment all cortical areas measured showed near normal vascular reactivity to direct cortical stimulation (normal reactivity = 45% increase in rCBF vs. 47% increase in FPI+VE+NE cases). These findings suggest that the majority of post-traumatic hemodynamic depressions are closely related to mechanisms involving vasoconstriction. Furthermore, Ca2+ may play a causative role in this vasoconstriction and the loss of vasoreactivity.

This article comprehensively reviews the lateral fluid percussion (LFP) model of traumatic brain injury (TBI) in small animal species with particular emphasis on its validity, clinical relevance and reliability. The LFP model, initially described in 1989, has become the most extensively utilized animal model of TBI (to date, 232 PubMed citations), producing both focal and diffuse (mixed) brain injury. Despite subtle variations in injury parameters between laboratories, universal findings are evident across studies, including histological, physiological, metabolic, and behavioral changes that serve to increase the reliability of the model. Moreover, demonstrable histological damage and severity-dependent behavioral deficits, which partially recover over time, validate LFP as a clinically-relevant model of human TBI. The LFP model, also has been used extensively to evaluate potential therapeutic interventions, including resuscitation, pharmacologic therapies, transplantation, and other neuroprotective and neuroregenerative strategies. Although a number of positive studies have identified promising therapies for moderate TBI, the predictive validity of the model may be compromised when findings are translated to severely injured patients. Recently, the clinical relevance of LFP has been enhanced by combining the injury with secondary insults, as well as broadening studies to incorporate issues of gender and age to better approximate the range of human TBI within study design. We conclude that the LFP brain injury model is an appropriate tool to study the cellular and mechanistic aspects of human TBI that cannot be addressed in the clinical setting, as well as for the development and characterization of novel therapeutic interventions. Continued translation of pre-clinical findings to human TBI will enhance the predictive validity of the LFP model, and allow novel neuroprotective and neuroregenerative treatment strategies developed in the laboratory to reach the appropriate TBI patients.

Microdialysis (MD) was introduced as an intracerebral sampling method for clinical neurosurgery by Hillered et al. and Meyerson et al. in 1990. Since then MD has been embraced as a research tool to measure the neurochemistry of acute human brain injury and epilepsy. In general investigators have focused their attention to relative chemical changes during neurointensive care, operative procedures, and epileptic seizure activity. This initial excitement surrounding this technology has subsided over the years due to concerns about the amount of tissue sampled and the complicated issues related to quantification. The interpretation of mild to moderate MD fluctuations in general remains an issue relating to dynamic changes of the architecture and size of the interstitial space, blood–brain barrier (BBB) function, and analytical imprecision, calling for additional validation studies and new methods to control for in vivo recovery variations. Consequently, the use of this methodology to influence clinical decisions regarding the care of patients has been restricted to a few institutions. Clinical studies have provided ample evidence that intracerebral MD monitoring is useful for the detection of overt adverse neurochemical conditions involving hypoxia/ischemia and seizure activity in subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), thromboembolic stroke, and epilepsy. There is some data strongly suggesting that MD changes precede the onset of secondary neurological deterioration following SAH, hemispheric stroke, and surges of increased ICP in fulminant hepatic failure. These promising investigations have relied on MD-markers for disturbed glucose metabolism (glucose, lactate, and pyruvate) and amino acids. Others have focused on trying to capture other important neurochemical events, such as excitotoxicity, cell membrane degradation, reactive oxygen species (ROS) and nitric oxide (NO) formation, cellular edema, and BBB dysfunction. However, these other applications need additional validation. Although these cerebral events and their corresponding changes in neurochemistry are important, other promising MD applications, as yet less explored, comprise local neurochemical provocations, drug penetration to the human brain, MD as a tool in clinical drug trials, and for studying the proteomics of acute human brain injury. Nevertheless, MD has provided new important insights into the neurochemistry of acute human brain injury. It remains one of very few methods for neurochemical measurements in the interstitial compartment of the human brain and will continue to be a valuable translational research tool for the future. Therefore, this technology has the potential of becoming an established part of multimodality neuro-ICU monitoring, contributing unique information about the acute brain injury process. However, in order to reach this stage, several issues related to quantification and bedside presentation of MD data, implantation strategies, and quality assurance need to be resolved. The future success of MD as a diagnostic tool in clinical neurosurgery depends heavily on the choice of biomarkers, their sensitivity, specificity, and predictive value for secondary neurochemical events, and the availability of practical bedside methods for chemical analysis of the individual markers. The purpose of this review was to summarize the results of clinical studies using cerebral MD in neurosurgical patients and to discuss the current status of MD as a potential method for use in clinical decision-making. The approach was to focus on adverse neurochemical conditions in the injured human brain and the MD biomarkers used to study those events. Methodological issues that appeared critical for the future success of MD as a routine intracerebral sampling method were addressed.

Microarray technology was employed to determine the differential pattern of gene expression within the hippocampus as a result of traumatic brain injury (TBI). The validity of the microarray data was confirmed using real-time RT-PCR. Following either moderate or severe lateral fluid percussion injury, rats were studied 0.5, 4, and 24 h after injury. In general, animals exhibited mRNA up or down regulation of approximately 10% of the genes studied. However, it was clear that the pattern of gene expression was influenced by both the severity of injury and the time after injury at which animals were studied. For example, genes encoding molecules for cellular signaling, synaptic plasticity, metabolism, ion channels and transporters were up regulated following severe injury, but down regulated following moderate injury. Furthermore, moderate injury was associated with an increasing number of responsive genes as a function of time post-injury. However, animals sustaining a severe level of injury exhibited decreasing number of responsive genes during the same post-injury period. The different patterns of gene expression between injury severity and across time after the insult suggests that the pathophysiological cascade induced by TBI is accompanied by a molecular response which, like the other aspects of the cellular response for survival, may indicate a “molecular window” that may offer an opportunity for therapeutic interventions involving gene therapy. Our results also suggest that fundamentally different pathophysiological processes or cascades may be induced by different severities of injury.

Animals housed in an enriched environment develop thicker cortices, with increased numbers of dendrites, synapses, blood vessels, and glial cells. This study examines the responses of adult rats, developmentally reared in an enriched environment, to traumatic brain injury. Rats were placed in an enriched environment for 15 days, starting on postnatal day 21. Following enrichment, they were placed in standard vivarium conditions until adulthood. At 3 months of age, enriched and age-matched control rats received a mild unilateral controlled cortical impact and were allowed to recover for 41 days. During this time, they were examined for motor coordination deficits and for preferences in forelimb use. Results demonstrate that enriched animals had a larger contusion cavity and a greater initial deficit in forelimb use. However, this deficit quickly diminished in comparison to that seen in non-enriched injured rats. The deficit in motor coordination recovered more quickly in enriched rats, 1 week sooner than in controls. These data suggest that the response of enriched animals to brain injury results in more marked neurodegeneration and acute behavioral dysfunction, with a higher capacity for compensation and recovery.

The aim of this study was to determine whether the apparent loss of overall gray-white matter contrast (GM/WM) seen on FDG-PET imaging reflects the differential changes of glucose metabolic rate (CMRglc) in cortical gray mater (GM) and subcortical white mater (WM) following TBI. The clinical significance of the CMRglc GM-to-WM ratio was also evaluated. Nineteen normal volunteers and 14 TBI patients were studied. Each subject had a quantitative FDG-PET, a quantitative H215O-PET and a MR scan acutely following TBI. Stabilities of the global and regional FDG lumped constants (LC) were studied. Parametric images (pixel unit: mg/min/100g) of FDG uptake rate (CURFDG) and CMRglc were generated. The changes of CMRglc in whole brain, GM and WM were studied separately by using a MRI-segmentation-based technique. The GM-to-WM ratios of both CURFDG and CMRglc images were significantly (p < 0.001) decreased (>31%) in TBI patients. The global LC value reduced significantly (p < 0.01) in TBI patients. The CMRglc decreased significantly (p < 0.001) in GM but not in WM (p > 0.1). Kinetic analysis revealed significant (p < 0.001) decrease of GM hexokinase activity in TBI patients. The GM-to-WM ratios of CMRglc correlated (r = 0.64) with the initial Glasgow Coma Score (GCS) of TBI patients. The patients with higher CMRglc GM-to-WM ratios (>1.54) showed good recovery 12 months after TBI. There was a selective CMRglc reduction in cortical GM following TBI. The pathophysiological basis for the reduction in GM-to-WM CMRglc ratio seen on FDG-PET imaging following TBI remains to be determined.

This study was designed to determine whether a secondary increase in neuronal activity induced by a low dose of kainic acid (KA), a glutamate analogue, exacerbates the anatomical damage in hippocampal regions following a mild lateral fluid percussion (LFP) brain injury. KA (9 mg/kg) was injected intraperitoneally in LFP-injured rats (n = 16) 1 h post-trauma. The neuronal loss in the CA3, CA4, and hilar regions at 7 days was quantified by two-dimensional cell counts. Hippocampal activation 15 min following KA injection was assessed by measuring local glucose metabolic rates (lCMRglc). Following LFP + KA, the ipsilateral side exhibited a 62.7%, 75.7%, and 52.1% decrease in the number of CA3, CA4 and hilar neurons, respectively, compared to naive rats (n = 3). These CA3 and CA4 neuronal counts were also significantly decreased compared to LFP + saline (n = 5) and sham + KA (n = 9) groups. The median Racine Score, used to rate the severity of behavioral seizures, was 4 in LFP + KA and 2 in sham + KA groups (p < 0.015), suggesting a reduction in seizure threshold following injury. lCMRglc in CA3 following LFP + KA was 121.8 ± 2.0 (mean ± SE) ipsilaterally and 71.5 ± 5.4 contralaterally (p < 0.0012). No changes were found in the BBB permeability as measured by [14C]aminoisobutyric acid in CA3, CA4, and hilar regions. We conclude that the presence of low-level KA 1 h after LFP dramatically increases the extent of hippocampal activation and induces a striking loss of ipsilateral CA3 and CA4 pyramidal neurons. Neuronal excitation during a time of cellular vulnerability may trigger or amplify the cycle of secondary damage in functionally impaired, but potentially viable, tissue.

Traumatic brain injury (TBI) is the leading cause of injury-related death and disability among children under the age of 15 years in the United States. Epidemiological studies have revealed that even within the pediatric population there are differences in incidence, gender differences, causes, types of injuries sustained, and mortality within age subdivisions. This heterogeneity must be taken into account when developing appropriate models to address TBI in children. This review explores the current developmental TBI models, including fluid percussion, weight drop, and controlled cortical impact. It also addresses unique considerations to modeling pediatric brain injury that require special attention when modeling and designing studies: age appropriateness, injury severity, evaluation of recovery, plasticity, and anesthesia.

Clinical and animal studies indicate that hyperthermia during or after traumatic brain injury (TBI) is associated with poor outcome. Alcohol intoxication, a complicating risk factor in many cases of head injury, has been found to both worsen or attenuate posttraumatic neural damage and outcome. The purpose of the present study was to determine whether chronic ethanol consumption would affect TBI-induced hyperthermia and deficits in spatial learning. TBI was produced by cortical contusion injury in adult male rats. We first characterized the TBI-induced febrile response using probes implanted intraperitoneally (ip) or intracerebroventricularly for continuous biotelemetric recording of core body and brain temperatures and locomotor activity. In another experiment, rats, implanted with ip probes, were fed a liquid diet containing ethanol (5% w/v, 35% ethanol-derived calories); control rats were pair-fed the isocaloric liquid diet (P-P). At 14 days after commencement of diet feeding, TBI or sham surgery was performed, and the ethanol-fed rats were divided into two groups: half were transferred to the isocaloric diet (E-P) and the other half remained on the ethanol-containing diet (E-E). TBI produced a significant febrile response in all rats, that persisted for at least 6 days in the E-P and P-P groups but lasted for only 2 days in the E-E group. When tested at 3–4 weeks after TBI, E-E rats required significantly fewer trials than E-P rats to reach criterion in the Morris water maze. In sum, continuous consumption of ethanol before and after TBI attenuated TBI-induced hyperthermia and deficits in spatial learning. Whereas the results suggest that this ethanol regimen may be neuroprotective, a causal relationship between the two outcomes remains to be determined.

Brain-derived neurotrophic factor (BDNF), its signal transduction receptor trkB, and its downstream effector, synapsin I, were measured in the hippocampus and occipital cortex of young animals after fluid-percussion brain injury (FPI). Isofluorane anaesthetized postnatal day 19 rats were subjected to a mild lateral FPI or sham injury. Rats were sacrificed at 24 h, 7 days, or 14 days after injury in order to determine mRNA expression. Additional animals were sacrificed at 7 and 14 days after injury for protein analysis. Only FPI animals exhibited hemispheric differences in BDNF levels. These animals exhibited a contralateral increase, ranging from 40% to 75%, in BDNF mRNA within both the hippocampus and occipital cortex at 24 h and 7 days after injury. The increase in message within the occipital cortex was accompanied by an increase in BDNF protein at 7 and 14 days after injury. However, hippocampal BDNF protein increased in both hemispheres at postinjury day 7 and was restricted to the ipsilateral hippocampus at postinjury day 14. At postinjury day 7, both trkB and synapsin I mRNA expression increased ipsilaterally and decreased contralaterally in the occipital cortex. In addition, synapsin I phosphorylation was increased by 20% in the ipsilateral cortex and by 30% in the hippocampus on this day. These results indicate that the developing brain responds to a mild injury by modifying factors related to synaptic plasticity and suggest that regions remote from the site of injury express neurotrophic signals potentially needed for compensatory responses.

We have recently demonstrated that fluid percussion injury (FPI) sustained early in life prevents the neural plasticity response associated with rearing in an enriched environment (EE). In order to determine if this reduction in plasticity capacity is reflected in alterations in dendritic arborization, the present study examined dendritic changes in response to EE, FPI, and FPI followed by EE. Twenty postnatal day 19–20 rat pups were subjected to FPI or sham injury and were subsequently housed in EE (17 days) or standard conditions. Brains were processed according to the Golgi-Cox method and were analyzed using dendritic density (Sholl) and dendritic branching analyses in frontal, parietal, and occipital cortices. Rearing in EE induced an increase in dendritic density, primarily within the occipital cortex. FPI induced an increase in dendritic density, primarily in regions remote from the injury site, namely contralateral parietal cortex and ipsilateral and contralateral occipital cortex. In injured animals subsequently housed in EE, FPI appeared to inhibit the experience-dependent dendritic density effects of EE. However, an unexpected enhancement of dendritic density was seen in the ipsilateral occipital cortex, indicating a unique response of this region based on its distance-specific sensitivity to injury-induced plasticity and its region-specific sensitivity to experience-dependent plasticity. These results suggest that dendritic changes mediate the anatomical and behavioral changes characteristic of impaired developmental plasticity following FPI, and that these changes are dependent on location within the cerebral cortex.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Following a subarachnoid hemorrhage (SAH), adult rats exhibit dynamic regional changes in cerebral glucose metabolism characterized by an increase in metabolic rates and a subsequent upregulation of cytochrome oxidase (CO). We evaluated both local cerebral metabolic rates for glucose (lCMRglc: (mol/100 g/min) and CO in 23 brain regions of interest (ROI). Sham animals underwent anesthesia and superficial surgery; saline-controls received an injection of 0.9% saline into the cisterna magna; and SAH rats received an injection of autologous blood into the cisterna magna. This blood, measured by albumin labeled with radioactive carbon 14, distributed throughout the brain but predominated ventrally. After experimental animals were sacrificed at day 0 (3 h), 1, 3, and 7 days postinjection, ROI were analyzed using [14C]2-deoxy-D-glucose autoradiography and CO histochemistry. lCMRglc in SAH rats increased in many regions (ranging from 0.7% to 32.2% above sham levels). Cytochrome oxidase also increased from 1% to 9% above sham levels, peaking on day 3. Conversely, saline-controls exhibited prolonged depression of lCMRglc (ranging from 11% to 35% below sham levels) and CO (ranging from 4% to 11% below sham levels) from day 0 through day 7. All saline-control ROI for all time points showed this metabolic depression, and between 91% and 95% of saline-control ROI presented lower CO levels as compared to sham. Overall, lCMRglc and CO levels were greater in SAH than in saline-control ROI. However, when considering the influence of subarachnoid blood on metabolic changes in SAH animals, both CO and 2DG levels did not correlate well with the amount of 14C-albumin binding. While previous studies have measured both metabolic rates of glucose and CO soon after SAH, this is the first to simultaneously conduct these measurements in the same SAH rat model.

Fluid percussion (FP) brain injury leads to immediate indiscriminate depolarization and massive potassium efflux from neurons. Using Northern blotting, we examined the post-FP expression of primary response/immediate early genes previously described as induced by depolarization in brain. RNA from ipsilateral and contralateral hippocampus was harvested from immature and adult rats 1 h following mild, moderate, or severe lateral fluid percussion injury and compared against age-matched sham animals. C-fos gene expression was used as a positive control and showed marked induction in both pups (6-25-fold with increasing severity) and adults (9.7-17.1-fold). Kinase-induced-by-depolarization-1 (KID-1) and salt-inducible kinase (SIK) gene expression was increased in adult (KID-1 1.5-1.6-fold; SIK 1.3-3.9-fold) but not developing rats. NGFI-b RNA was elevated after injury in both ages (pups 1.8-6.1-fold; adults 3.5-5-fold), in a pattern similar to that seen for c-fos. Secretogranin I (sec I) demonstrated no significant changes. Synaptotagmin IV (syt IV) was induced only following severe injury in the immature rats (1.4-fold). Our results reveal specific severity- and age-dependent patterns of hippocampal immediate early gene expression for these depolarization-induced genes following traumatic brain injury. Differential expression of these genes may be an important determinant of the distinct molecular responses of the brain to varying severities of trauma experienced at different ages.

This study was designed to determine the regional and temporal profile of 45calcium (45Ca2+) accumulation following mild lateral fluid percussion (LFP) injury and how this profile differs when traumatic brain injury occurs early in life. Thirty-six postnatal day (P) 17, thirty-four P28, and 17 adult rats were subjected to a mild (~2.75 atm) LFP or sham injury and processed for 45Ca2+ autoradiography immediately, 6 h, and 1, 2, 4, 7, and 14 days after injury. Optical densities were measured bilaterally within 16 regions of interest. 45Ca2+ accumulation was evident diffusely within the ipsilateral cerebral cortex immediately after injury (18-64% increase) in all ages, returning to sham levels by 2-4 days in P17s, 1 day in P28s, and 4 days in adults. While P17s showed no further 45Ca2+ accumulation, P28 and adult rats showed an additional delayed, focal accumulation in the ipsilateral thalamus beginning 2-4 days postinjury (12-49% increase) and progressing out to 14 days (26-64% increase). Histological analysis of cresyl violet-stained, fresh frozen tissue indicated little evidence of neuronal loss acutely (in all ages), but considerable delayed cell death in the ipsilateral thalamus of the P28 and adult animals. These data suggest that two temporal patterns of 45Ca2+ accumulation exist following LFP: acute, diffuse calcium flux associated with the injury-induced ionic cascade and blood brain barrier breakdown and delayed, focal calcium accumulation associated with secondary cell death. The age-dependency of posttraumatic 45Ca2+ accumulation may be attributed to differential biomechanical consequences of the LFP injury and/or the presence or lack of secondary cell death.

Previous studies have demonstrated that, compared to adults, postnatal day 17 (P17) and P28 rats show remarkable cognitive recovery in the Morris water maze (MWM) following fluid percussion injury (FPI). This observed age-at-trauma effect could result from either younger animals solving the MWM task using noninjured neural circuitry or an inability of adult and P28 brains to activate appropriate neural networks due to trauma-induced neurological dysfunction. To address these possibilities, we compared "activated" brain regions during normal MWM acquisition and following FP injury. To generate "activated" images of the brain while animals were performing the MWM task, qualitative [14C]2-deoxy-D-glucose was conducted on days 2, 5, and 14 during training in sham and injured adult, P28, and P17 rats. When maturational changes in cerebral glucose metabolism are taken into account, the results suggests similar activity changes in the cerebral cortex and lacunosum moleculare of CA1 during acquisition in all age groups, suggesting that the developmental rates of MWM learning do not correspond to different patterns of activated cerebral metabolism. Injured P17s, showing no latency deficits, revealed activated cerebral metabolic patterns similar to noninjured P17 animals. In P28 and adult cases, animals exhibited cognitive deficits and their metabolic studies indicated that the cortical-hippocampal pattern of activation was disrupted by marked injury-induced metabolic depression, which primarily affected the ipsilateral hemisphere and lasted for as long as 14 days in adult animals.

With the advent and emerging importance of neurobiology and its relation to behavior, scientists desire the capability to apply noninvasive, quantitative imaging of neuronal activity to small rodents. To this end, the authors' laboratory has developed microPET, a high-resolution positron emission tomography (PET) scanner that is capable of performing in vivomolecular imaging at a resolution sufficient to resolve major structures in the rat brain. The authors report in this article that, in conjunction with 2-[18F]fluoro-2-deoxyglucose (FDG), microPET provides accurate rates of cerebral glucose metabolism (59.7 to 108.5 μmol/100 g·min) in conscious adult rats as validated by within-subject autoradiographic measurements (59.5 to 136.2 μmol/100 g·min;r= 0.88; F[1,46]= 168.0;P< 0.001). By conducting repeated quantitative scanning, the authors demonstrate the sensitivity and accuracy of FDG-microPET to detect within-subject metabolic changes induced by traumatic brain injury. In addition, the authors report that longitudinal recovery from traumatic brain injury-induced metabolic depression, as measured by quantitative FDG-microPET, is significantly correlated (r= 0.65;P< 0.05) to recovery of behavioral dysfunction, as assessed by the Morris Water Maze performance of the same rats, after injury. This is the first study to demonstrate that FDG-microPET is quantitative, reproducible, and sensitive to metabolic changes, introducing a new approach to the longitudinal study of small animal models in neuroscience research.

Following fluid percussion (FP) traumatic brain injury (TBI), adult rats exhibit dynamic regional changes in cerebral glucose metabolism characterized by an acute (hours) increase and subsequent chronic (weeks) decrease in metabolic rates. The injury-induced hyperglycolysis is the result of ionic fluxes across cell membranes and the degree and extent of metabolic depression is predictive of neurobehavioral deficits. Given that younger animals appear to exhibit similar physiological responses to injury yet show an improved rate of recovery compared to adults, we wanted to determine if this injury-induced dynamic metabolic response to TBI is different if the injury is sustained early in life. Local cerebral metabolic rates for glucose (ICMRglc: μmol/100 g/min) using [14C]2-deoxy-D-glucose were measured immediately, 30 min, 1 day, and 3 days following a mild to moderate level of lateral FP injury in postnatal day 17 (P17) rats. Even though gross morphological damage was not evident, injured pups exhibited ipsilateral hyperglycolysis immediately after injury, predominantly in cortical regions (ranging from 59.2% to 116.5% above controls). This hyperglycolytic state subsided within 30 min, and by 1 day all cerebral structures, except the ipsilateral cerebellar cortex, showed lower rates of glucose metabolism (ranging from 5.7% to 63.0% below controls). This period of posttraumatic metabolic depression resolved within 3 days for all structures measured. Compared to previous adult studies these results suggest that the young rat pup, although exhibiting acute hyperglycolysis, is not subjected to a prolonged period of metabolic depression, which supports the findings that at this level of injury severity, these young animals show remarkable neurological sparing following TBI.

To test the hypothesis that brain injury impairs control of vascular tone during compensation from hemorrhagic shock, Sprague-Dawley rats underwent fluid-percussion brain injury (or sham injury control) followed by a stepwise hemorrhage period to 1/2 baseline mean arterial pressure (1/2 MAP), a shock period holding at 1/2 MAP for 30 min, and a resuscitation period. Aortic blood flow (ABF) was measured and vascular conductance (ABF/MAP) was calculated. No differences occurred between groups during the stepwise hemorrhage period. During the 30 min shock period, controls decreased conductance from .2 ± .07 to .16 ± .04 and required repeated additional hemorrhage (3.4 ± 1.3 cc) to maintain 1/2 MAP. In contrast, brain-injured animals increased conductance from .21 ± .07 to .24 ± .06 (p < .05) during the shock period and required repeated fluid replacements (3.0 ± 1.3 cc lactated Ringer's (LR), p < .05) to maintain 1/2 MAP. Following resuscitation, conductance appropriately increased to .31 ± .05 in controls but did not change (.25 ± .04, p < .05) in brain-injured animals. We conclude that brain injury adversely affects control of vascular tone during shock and resuscitation in this model.

Previously, using positron emission tomography (PET), we showed that local cerebral metabolic rates for glucose (lCMRglc) in children undergo dynamic maturational trends before reaching adult values. In order to develop an animal model that can be used to explore the biological significance of the different segments of the lCMRglcmaturational curve, we measured lCMRglcin kittens at various stages of postnatal development and in adult cats using quantitative [14C]2-deoxyglucose autoradiography. In the kitten, very low lCMRglclevels (0.14 to 0.53 μmol min−1g−1) were seen during the first 15 days of life, with phylogenetically older brain regions being generally more metabolically mature than newer structures. After 15 days of age, many brain regions (particularly telencephalic structures) underwent sharp increases of lCMRglcto reach, or exceed, adult rates by 60 days. This developmental period (15 to 60 days) corresponds to the time of rapid synaptic proliferation known to occur in the cat. At 90 and 120 days, a slight decline in lCMRglcwas observed, but this was followed by a second, larger peak occurring at about 180 days, when sexual maturation occurs in the cat. Only after 180 days did lCMRglcdecrease to reach final adult values (0.21 to 2.04 μmol min−1g−1). In general, there was good correlation between the metabolic maturation of various neuroanatomical regions and the emergence of behaviors mediated by the specific region. At least in the kitten visual cortex, which has been extensively studied with respect to developmental plasticity, the “critical period” corresponded to that portion of the lCMRglcmaturational curve surrounding the 60-day metabolic peak. These normal maturational lCMRglcdata will serve as baseline values with which to compare anatomical and metabolic plasticity changes induced by age-related lesions in the cat.

Immediately following concussive brain injury, cells exhibit an increase of energy demand represented by the activation of glucose utilization. We have proposed that this trauma-induced hypermetabolism reflects the effort of cells to restore normal ionic balance disrupted by massive ionic fluxes through transmitter-gated ion channels. In the present study, changes in local CMRglcfollowing fluid-percussion concussive injury were determined using [14C]2-deoxy-d-glucose autoradiography, and the effects of in situ administration (via microdialysis) of excitatory amino acid (EAA) antagonists [kynurenic acid (KYN), 2-amino-5-phosphonovaleric acid (APV; 100 μM, 1 mM, and 10 mM), and 6-cyano-7-nitroquinoxaline-2,3-dine (CNQX; 300 μM, 1 mM, and 10 mM] on glucose utilization were investigated. Animals that did not receive dialysis showed a remarkable increase (up to 181% of normal control) in cortical glucose utilization following injury. In contrast, this high demand for glucose was reduced in areas infiltrated with KYN, APV, and CNQX. These results indicate that EAA-activated ion channels are involved in the posttraumatic increase in glucose utilization, reflecting the energy demand of cells required to drive pumping mechanisms against an ionic perturbation seen immediately following the concussive injury. The effects of KYN, APV, and CNQX suggest that although all subtypes of the glutamate receptor appear to be involved in this phenomenon, N-methyl-d-aspartate-activated channels may play a major role.

Unilateral motor cortex injury in the cat results in a prolonged loss of tactile placing in the forelimb contralateral to the injury. Amphetamine (5 mg/kg) temporarily reverses this tactile placing deficit as early as 4 days following the injury. Racemic amphetamine was found to produce a significantly more prolonged restoration of placing than the d isomer, which was significantly more effective than the l isomer. Haloperidol (0.4 mg/kg) blocked the amphetamineinduced recovery of placing responses and also blocked placing in nondrugged cats showing partial spontaneous recovery. This dosage of haloperidol had no effect on tactile placing in normal cats. Apomorphine at moderate dosages (0.25 and 0.5 mg/kg) produced a weak restoration of tactile placing in motor cortex-injured animals. These pharmacological data suggest that the loss of tactile placing after motor cortex injury is due to a depression of catecholaminergic function, which is temporarily reversible by catecholaminergic stimulation.

The effect of seizures on recovery of motor function was studied in rats following unilateral contusion of the sensorimotor cotex. Animals receiving two electroconvulsive seizures (ECSs) within the first 24 hours postcontusion showed accelerated recovery of beam-walking ability, reduced volume of necrosis and less spontaneous activity compared to animals receiving only contusions. Animals receiving seven ECSs after contusion had an even smaller volume of necrosis and also reduced spontaneous activity compared to the two ECS group and to controls receiving contusions alone. However, for recovery of beam-walking ability, the seven ECS group did not differ from control rats receiving only contusions. The results are discussed in terms of the effects of seizures on catcholamines, gamma-amino butyric acid, cerebral blood flow and possible effects on remote functional depression after brain injury.

In the cat, cerebral hemispherectomy sustained neonatally results in a remarkable degree of recovery and/or sparing of function as compared with the effects of a similar lesion but sustained in adulthood. We have proposed that this effect is due to a combination of reduced neuronal loss within partially denervated structures and a lesion-induced reorganization of corticofugal projections arising from the remaining intact hemisphere in the neonatally lesioned animal. The current study was designed to assess the physiological consequences of these anatomical changes utilizing [14C]2-deoxy-D-glucose autoradiography. A total of 17 adult cats were studied. Seven animals served as intact controls, five received a left cerebral hemineodecortication as neonates (NH; mean age 11.4 days), and five sustained the same lesion in adulthood (AH). Histological analysis indicated that the lesion was very similar between the two age groups and essentially represented a unilateral hemineodecortication. Local CMRglc(LCMRglc; μmol 100 g-1min-1) values were calculated for 50 structures bilaterally and indicated that in the remaining intact contralateral (right) cerebral cortex (including all areas measured), AH cats exhibited a significantly (p < 0.05) lower level of LCMRglc(ranging from 20 to 72 μmol 100 g-1min-1) than NH (ranging from 49 to 81 μmol 100g-1min-1). In comparison, the rates of NH cats within the cerebral cortex were very similar to those seen in intact animals (ranging from 48 to 119 μmol 100 g-1min-1). Ipsilateral to the lesion in AH cats, the structures spared by the resection, including the basal ganglia and thalamus, exhibited LCMRglcrates of between 23 and 69 μmol 100 g-1min-1, which were significantly lower (p < 0.05) than in NH cats (range 47–72 μmol 100 g-1min-1). Considering all structures, both age-at-lesion groups exhibited a lower level of metabolism compared with similar measurements for intact control animals (LCMRglcrange 45–75 μmol 100 g-1min-1). However, this depression of glucose metabolism was more pronounced in the AH cats (p < 0.05). These results indicate that following neonatal hemineodecortication, LCMRglcis maintained at a higher level in many regions of the brain than in animals that sustain the same resection in adulthood. This higher level of glucose metabolism in NH animals suggests that the lesion-induced anatomical reorganization of structures not directly injured by the lesion plays a functional role that is probably responsible for the greater degree of recovery and/or sparing of function in these early lesioned cats.

Immediately following fluid-percussion (F-P) brain injury, the hippocampus exhibits a marked increase in its local CMRglc(LCMRglc; μmol/100 g/min) as determined using [14C]2-deoxy-d-glucose autoradiography. This injury-induced increase in metabolism is followed in 6 h by a subsequent decrease in LCMRglc. These two postinjury metabolic states may be the result of ionic disruptions following trauma via stimulation of glutamategated ion channels. To determine if endogenous glutamate innervation to the CA1region of the hippocampus can provide an anatomical basis for this proposed mechanism, it was removed by kainic-acid–induced destruction of CA3, and the effect on CA1metabolism following concussive injury was studied. Five days before a lateral F-P injury (3.5–4.5 atm), kainic acid (0.5 μg) or vehicle was stereotaxically injected into the left ventricle of 65 rats. Histological inspection indicated that kainic acid produced severe cell loss primarily in the CA3region of the hippocampus ipsilateral to the injection. The metabolic results indicated that immediately following injury, animals with an intact hippocampus exhibited an increase in LCMRglcto 84.6 ± 5 within the CA1region, representing a 81.5% increase over controls. However, in the CA3-lesioned animals, CA1showed no evidence of an injury-induced hypermetabolism, with LCMRglcremaining at control levels (51.4 ± 3.9). At 6 h postinjury, the intact hippocampus exhibited a reduction of LCMRglcto rates of 40.7 ± 4.7 within the CA1region, representing a 17.9% reduction compared with controls. In contrast, CA3-lesioned animals exhibited less of an injury-induced decrease in LCMRglcwithin the CA1region, exhibiting a mean rate of 43.4 ± 4.5, representing only a 12.5% reduction compared with controls. These results indicate that the removal of the CA3projection to CA1protects the CA1cells from the metabolic dysfunction typically seen following injury. This supports our previous work indicating the important role glutamate plays in the ionic flux and subsequent metabolic changes that follow traumatic brain injury.

The maturation of brain oxidative capacity was studied in kittens, using cytochrome oxidase histochemistry, at different ages throughout development. Optical densitometry values of reacted tissue were obtained for 50 different structures of the brain. In general, most structures reached adult levels of oxidative capacity by 30 days of age with some motor areas (e.g., cerebellum, red nucleus) exhibiting adult values as early as 7 days of age. Thereafter, some structures (e.g., basal ganglia, thalamus) exhibited levels of cytochrome oxidase activity that exceeded adult values for varying periods of time. These findings indicate regional heterogeneity in the maturation of cerebral oxidative capacity. Furthermore, these maturational patterns appear to correlate well with previous observations from anatomical, physiological and neuro-behavioral studies.

During the first few minutes following traumatic brain injury, cells are exposed to an indiscriminate release of glutamate from nerve terminals resulting in a massive ionic flux (e.g., K+ efflux) via stimulation of excitatory amino acid (EAA)-coupled ion channels. The present study was undertaken to elucidate the causal relationship between these ionic shifts and lactate accumulation in the injured brain, by examining the effects of ouabain (an inhibitor of Na+/K+-ATPase), Ba2+ (an inhibitor of non-energy-dependent glial K+ uptake) and kynurenic acid (KYN; a broad-spectrum EAA antagonist) on lactate accumulation. Two microdialysis probes were placed bilaterally in the rat parietal cortex. One was perfused with a test drug (1.0 mM ouabain, 2.0 mM Ba2+ or 10 mM KYN) and the other with Ringer's solution (control) for 30 min prior to injury. Following a 2.2–2.7 atm fluid-percussion injury, lactate levels in the dialysate increased (up to 116.6% above baseline) for the first 16 min and returned to baseline levels within 20 min after injury. This lactate accumulation was attenuated by preinjury administration of ouabain and KYN and was prolonged by Ba2+ administration. These findings indicate that lactate accumulation following concussive brain injury is a result of increased glycolysis which supports ion-pumping mechanisms, thereby, restoring the ionic balance which was disrupted by stimulation of EAA-coupled ion channels.

To test the hypothesis that brain injury impairs control of vascular tone during compensation from hemorrhagic shock, Sprague-Dawley rats underwent fluid-percussion brain injury (or sham injury control) followed by a stepwise hemorrhage period to 1/2 baseline mean arterial pressure (1/2 MAP), a shock period holding at 1/2 MAP for 30 min, and a resuscitation period. Aortic blood flow (ABF) was measured and vascular conductance (ABF/MAP) was calculated. No differences occurred between groups during the stepwise hemorrhage period. During the 30 min shock period, controls decreased conductance from .2 ± .07 to .16 ± .04 and required repeated additional hemorrhage (3.4 ± 1.3 cc) to maintain 1/2 MAP. In contrast, brain-injured animals increased conductance from .21 ± .07 to .24 ± .06 (p< .05) during the shock period and required repeated fluid replacements (3.0 ± 1.3 cc lactated Ringer's (LR), p< .05) to maintain 1/2 MAP. Following resuscitation, cnductance appropriately increased to .31 ± .05 in controls but did not change (.25 ± .04, p< .05) in brain-injured animals. We conclude that brain injury adversely affects control of vascular tone during shock and resuscitation in this model.

Developments in emergency medical services and intensive management of patients with head injury have resulted in improved outcome. The initial insult leaves the brain metabolically deranged and susceptible to secondary injuries. Further advances in the treatment of head injuries focus on manipulating the cellular and extracellular milieu, which renders neurons dysfunctional but still salvageable. The role of lactate, excitatory amino acids, and oxygen-free radicals in head injury metabolism and related therapies under development are reviewed.

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 notwith 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.

Measurements of oxidative metabolic capacity following the ablation of rat sensorimotor cortex and ,he administration of amphetamine were examined to determine their effects on the metabolic dysfunction that follows brain injury. Twenty-four hours after surgery, rats sustaining either sham operations or unilateral cortical ablation were administered a single injection of D-amphetamine (2 mg/kg; i.p.) or saline and then sacrificed 24 h later. Brain tissue was processed for cytochrome oxidase histochemistry, and 12 bilateral cerebral areas were measured, using optical density as an index of the relative amounts of the enzyme. Compared with that of the control groups, cytochrome oxidase in the injured animals was significantly reduced throughout the cerebral cortex and in 5 of II subcortical structures. This injury-induced depression of oxidative capacity was most pronounced in regions of the hemisphere ipsilateral to the ablation. Animals given D-amphetamine had less depression of oxidative capacity, which was most pronounced bilaterally in the cerebral cortex, red nucleus, and superior colliculus; and in the nucleus accumbens, caudateputamen, and globus pallidus ipsilaterai to the ablation. The ability of D-amphetamine to alleviate depressed cerebral oxidative metabolism following cortical injury may be one mechanism by which drugs increasing noradrenaline release accelerate functional recovery in both animals and humans.