N-3 Polyunsaturated Fatty Acids Ameliorate Neurobehavioral Outcomes Post-Mild Traumatic Brain Injury in the Fat-1 Mouse Model.

Concussions and mild traumatic brain injury (m-TBI) have been identified as a consequential public health concern because of their potential to cause considerable impairments in physical, cognitive, behavioral, and social functions. Given their prominent structural and functional roles in the brain, n-3 polyunsaturated fatty acids (PUFA) have been identified as a potentially viable prophylactic agent that may ameliorate the deleterious effects of m-TBI on brain function. The purpose of the present pilot study was to investigate the effect of n-3 PUFA on neurologic function using a weight drop injury (WDI) model. Fat-1 mice, capable of synthesizing n-3 PUFA endogenously from n-6 PUFA, and their wild-type (WT) counterparts, were subjected to a mild low-impact WDI on the closed cranium, and recovery was evaluated using the neurological severity score (NSS) to assess the motor and neurobehavioral outcomes. In comparison to the WT mice, the fat-1 mice had a significantly (p ≤ 0.05) lower NSS at all time points post-WDI, and significantly greater neurological restoration measured as the time to first movement. Overall, these findings demonstrate the protective effect of n-3 PUFA against mild brain injury.

The diffusion-tensor imaging reveals alterations in water diffusion parameters in acute pediatric concussion.

Wide-spread visualization methods which are computed tomography (CT) and magnetic resonance imaging (MRI) are not sensitive to mild traumatic brain injury (mTBI). However, mTBI may cause changes of cerebral microstructure that could be found using diffusion-tensor imaging. The aim of this study is to reveal the impact of acute mTBI (no more than 3 days after trauma) on diffusion parameters in corpus callosum, corticospinal tract, and thalamus in children (aged 14-18). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were analyzed. Significant increase in FA and decrease in ADC were observed in thalamus. The trend to an increase in FA is observed in corpus callosum.

Impaired Glutamate Receptor Function Underlies Early Activity Loss of Ipsilesional Motor Cortex after Closed-Head Mild Traumatic Brain Injury.

Although mild traumatic brain injury (mTBI) accounts for the majority of TBI patients, the effects and cellular and molecular mechanisms of mTBI on cortical neural circuits are still not well understood. Given the transient and non-specific functional deficits after mTBI, it is important to understand whether mTBI causes functional deficits of the brain and the underlying mechanism, particularly during the early stage after injury. Here, we used in vivo optogenetic motor mapping to determine longitudinal changes in cortical motor map and in vitro calcium imaging to study how changes in cortical excitability and calcium signals may contribute to the motor deficits in a closed-head mTBI model. In channelrhodopsin 2 (ChR2)-expressing transgenic mice, we recorded electromyograms (EMGs) from bicep muscles induced by scanning blue laser on the motor cortex. There were significant decreases in the size and response amplitude of motor maps of the injured cortex at 2 h post-mTBI, but an increase in motor map size of the contralateral cortex in 12 h post-mTBI, both of which recovered to baseline level in 24 h. Calcium imaging of cortical slices prepared from green fluorescent calmodulin proteins-expressing transgenic mice showed a lower amplitude, but longer duration, of calcium transients of the injured cortex in 2 h post-mTBI. Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or N-methyl-d-aspartate receptors resulted in smaller amplitude of calcium transients, suggesting impaired function of both receptor types. Imaging of calcium transients evoked by glutamate uncaging revealed reduced response amplitudes and longer duration in 2, 12, and 24 h after mTBI. Higher percentages of neurons of the injured cortex had a longer latency period after uncaging than that of the uninjured neurons. The results suggest that impaired glutamate neurotransmission contributes to functional deficits of the motor cortex in vivo, which supports enhancing glutamate neurotransmission as a potential therapeutic approach for the treatment of mTBI.

Guanosine protects against behavioural and mitochondrial bioenergetic alterations after mild traumatic brain injury.

Traumatic brain injury (TBI) constitutes a heterogeneous cerebral insult induced by traumatic biomechanical forces. Mitochondria play a critical role in brain bioenergetics, and TBI induces several consequences related with oxidative stress and excitotoxicity clearly demonstrated in different experimental model involving TBI. Mitochondrial bioenergetics alterations can present several targets for therapeutics which could help reduce secondary brain lesions such as neuropsychiatric problems, including memory loss and motor impairment. Guanosine (GUO), an endogenous neuroprotective nucleoside, affords the long-term benefits of controlling brain neurodegeneration, mainly due to its capacity to activate the antioxidant defense system and maintenance of the redox system. However, little is known about the exact protective mechanism exerted by GUO on mitochondrial bioenergetics disruption induced by TBI. Thus, the aim of this study was to investigate the effects of GUO in brain cortical and hippocampal mitochondrial bioenergetics in the mild TBI model. Additionally, we aimed to assess whether mitochondrial damage induced by TBI may be related to behavioral alterations in rats. Our findings showed that 24 h post-TBI, GUO treatment promotes an adaptive response of mitochondrial respiratory chain increasing oxygen flux which it was able to protect against the uncoupling of oxidative phosphorylation (OXPHOS) induced by TBI, restored the respiratory electron transfer system (ETS) established with an uncoupler. Guanosine treatment also increased respiratory control ratio (RCR), an indicator of the state of mitochondrial coupling, which is related to the mitochondrial functionality. In addition, mitochondrial bioenergetics failure was closely related with locomotor, exploratory and memory impairments. The present study suggests GUO treatment post mild TBI could increase GDP endogenous levels and consequently increasing ATP levels promotes an increase of RCR increasing OXPHOS and in substantial improve mitochondrial respiration in different brain regions, which, in turn, could promote an improvement in behavioral parameters associated to the mild TBI. These findings may contribute to the development of future therapies with a target on failure energetic metabolism induced by TBI.

Silymarin sex-dependently improves cognitive functions and alters TNF-α, BDNF, and glutamate in the hippocampus of mice with mild traumatic brain injury.

AIMS: Mild traumatic brain injury (mTBI) is an important risk factor for cognitive impairment. Despite intense efforts to develop efficient treatments, the current therapies are not often effective and far from satisfactory. Silymarin has been suggested as a therapeutic agent in the treatment of traumatic brain injury. This study aimed to determine whether silymarin can exert neuroprotective effects on memory impairment following mTBI in mice. MAIN METHODS: After mTBI induction, mice were treated with silymarin once daily for 20 consecutive days by oral gavage. To investigate cognitive functions, animals were subjected to Y-maze, novel-object recognition, and Morris-water maze. Levels of tumor necrosis factor (TNF)-α, glutamate, and brain derived neurotrophic factor (BDNF) were measured in the hippocampus. KEY FINDINGS: Our findings showed that mTBI resulted in a significant decline in memory in the Y-maze and Morris-water maze in both sexes, whereas only impaired cognitive function in males in the novel-object recognition. We found notable increases in TNF-α and glutamate levels in the hippocampus of both sexes, while there was only a significant decrease in hippocampal BDNF in mTBI-induced females. In addition, silymarin treatment improved cognitive impairments in mTBI-induced males but not in females. Silymarin significantly reduced TNF-α and glutamate levels, and increased BDNF levels in the hippocampus of mTBI-induced male but not in female mice. SIGNIFICANCE: This study demonstrates that silymarin treatment sex-dependently improves cognitive impairment in mTBI-induced mice, and suggests that silymarin may be a therapeutic agent for cognitive decline following mTBI in males. Further studies are needed to establish the validity of these findings in humans.

Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion.

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes and other active individuals who may sustain repetitive concussive injury during periods of exercise and exertion when core temperatures are elevated. Previous studies have emphasized the impact that increased brain temperature has on adverse neurological outcomes. A lack of diagnostic tools to assess concussive mTBI limits the ability to effectively identify the post-concussive period during which the brain is uniquely susceptible to damage upon sustaining additional injury. Studies have suggested that a temporal window of increased vulnerability that exists corresponds to a period of injury-induced depression of cerebral glucose metabolism. In the current study, we sought to evaluate the relationship between repetitive concussion, local cerebral glucose metabolism, and brain temperature using the Marmarou weight drop model to generate mTBI. Animals were injured three consecutive times over a period of 7 days while exposed to either normothermic or hyperthermic temperatures for 15 min prior to and 1 h post each injury. A 14C-2-deoxy-d-glucose (2DG) autoradiography was used to measure local cerebral metabolic rate of glucose (lCMRGlc) in 10 diverse brain regions across nine bregma levels 8 days after the initial insult. We found that repetitive mTBI significantly decreased glucose utilization bilaterally in several cortical areas, such as the cingulate, visual, motor, and retrosplenial cortices, as well as in subcortical areas, including the caudate putamen and striatum, compared to sham control animals. lCMRGlc was significant in both normothermic and hyperthermic repetitive mTBI animals relative to the sham group, but to a greater degree when exposed to hyperthermic conditions. Taken together, we report significant injury-induced glucose hypometabolism after repetitive concussion in the brain, and additionally highlight the importance of temperature management in the acute period after brain injury.

Characterizing the Link Between Glial Activation and Changed Functional Connectivity in National Football League Players Using Multimodal Neuroimaging.

OBJECTIVE: The primary objective of this preliminary study was to examine the impact of NFL play on interregional functional connectivity between two brain regions, the supramarginal gyrus (SMG) and the thalamus, identified as having higher binding of [11C]DPA-713 in NFL players. The authors' secondary objective was to examine the effect of years since play on the interregional connectivity. METHODS: Resting-state functional MRI was used to examine functional brain changes between regions with evidence of past injury in active or recently retired NFL players (defined as ≤12 years since NFL play) and distantly retired players (defined as >12 years since NFL play). Age-comparable individuals without a history of concussion or participation in collegiate or professional collision sports were included as a control group. RESULTS: Compared with healthy control subjects, NFL players showed a loss of anticorrelation between the left SMG and bilateral thalami (mean z score=-2.434, p=0.015). No difference was observed when examining right SMG connectivity. The pattern of connectivity in active and recently retired players mimicked the pattern observed in distantly retired players and older control subjects. CONCLUSIONS: Further study of the clinical significance of this altered pattern of interregional connectivity in active and recently retired NFL players is needed.

Analysis of magnetic resonance spectroscopy relative metabolite ratios in mild traumatic brain injury and normative controls.

INTRODUCTION: We evaluated magnetic resonance spectroscopy (MRS) in United States military personnel with persistent symptoms after mild traumatic brain injury (mTBI), comparing over time two groups randomized to receive hyperbaric oxygen or sham chamber sessions and a third group of normative controls. METHODS: Active-duty or veteran military personnel and normative controls underwent MRS outcome measures at baseline, 13 weeks (mTBI group only), and six months. Participants received 3.0 Tesla brain MRS for analysis of water-suppressed two-dimensional (2D) multivoxel 1H-MRS of the brain using point resolved spectroscopy (PRESS) with volume selection localized above the lateral ventricles and within the brain parenchyma, of which one voxel was chosen in each hemisphere without artifact. Script-based automatic data processing was used to assess N-acetylaspartate (NAA), creatine (Cr), and choline (Cho). Metabolite ratios for white matter were then calculated for NAA/Cr (Area), Cho/Cr (Area), and Cho/NAA (Area). These ratios were compared using standard analysis methodology. RESULTS: There were no observable differences between participants with mTBI and normative controls nor any observable changes over time in the NAA/Cr (area), Cho/Cr (area), and Cho/NAA (area) ratios. Similarly, the control and injured participants were indistinguishable. DISCUSSION: While participants with mild TBI showed no difference in MRS compared to normative controls, our results are limited by the few voxels chosen and potentially by less sensitive MRS markers.

Visualization of thalamic calcium influx with quantitative susceptibility mapping as a potential imaging biomarker for repeated mild traumatic brain injury.

A key event in the pathophysiology of traumatic brain injury (TBI) is the influx of substantial amounts of Ca2+ into neurons, particularly in the thalamus. Detection of this calcium influx in vivo would provide a window into the biochemical mechanisms of TBI with potentially significant clinical implications. In the present work, our central hypothesis was that the Ca2+ influx could be imaged in vivo with the relatively recent MRI technique of quantitative susceptibility mapping (QSM). Wistar rats were divided into five groups: naive controls, sham-operated experimental controls, single mild TBI, repeated mild TBI, and single severe TBI. We employed the lateral fluid percussion injury (FPI) model, which replicates clinical TBI without skull fracture, performed 9.4 Tesla MRI with a 3D multi-echo gradient-echo sequence at weeks 1 and 4 post-injury, computed susceptibility maps using V-SHARP and the QUASAR-HEIDI technique, and performed histology. Sham, experimental controls animals, and injured animals did not demonstrate calcifications at 1 week after the injury. At week 4, calcifications were found in the ipsilateral thalamus of 25-50% of animals after a single TBI and 83% of animals after repeated mild TBI. The location and appearance of calcifications on stained sections was consistent with the appearance on the in vivo susceptibility maps (correlation of volumes: r = 0.7). Our findings suggest that persistent calcium deposits represent a primary pathology of repeated injury and that FPI-QSM has the potential to become a sensitive tool for studying pathophysiology related to mild TBI in vivo.

Investigating the Role of the Hypothalamus in Outcomes to Repetitive Mild Traumatic Brain Injury: Neonatal Monosodium Glutamate Does Not Exacerbate Deficits.

Repetitive mild traumatic brain injury (RmTBI) is a prevalent and costly head injury particularly among adolescents. These injuries may result in long-term consequences, especially during this critical period of development. Insomnia and sleeping difficulties are frequently reported following RmTBI and greatly impair recovery. We sought to develop an animal model of exacerbated deficits following RmTBI by disrupting the hypothalamic circadian system. To accomplish this, we conducted RmTBI on adolescent rats that had received neonatal injections of monosodium glutamate (MSG), a known hypothalamic neurotoxin. We then examined behavioral, circadian, and epigenetic changes. MSG treated rats showed lower anxiety-like behaviors and displayed poor short-term working memory. We also showed changes in the morphology of the circadian clock in the suprachiasmatic nucleus (SCN) vasoactive intestinal polypeptide (VIP) immunostaining. VIP optical density in the SCN increased with MSG but decreased with RmTBI. There were changes in the expression of the clock genes and upregulation of the orexin receptors in response to RmTBI. MSG treated rats had longer telomere lengths than controls. Finally, although both MSG and RmTBI alone produced attenuated circadian amplitudes of activity and body temperature, exacerbated deficits were not identified in animals that received MSG and RmTBI. In sum, both MSG and RmTBI can alter behavior, circadian rhythm amplitude, SCN morphology, and gene expression independently, but the effects do not appear to be additive. Specific damage in the hypothalamus and SCN should be considered when patients experience sleeping problems following RmTBI, as this may improve therapeutic strategies.

Glutamate and GABA concentrations following mild traumatic brain injury: a pilot study.

Animal models of mild traumatic brain injury (mTBI) suggest that metabolic changes in the brain occur immediately after a mechanical injury to the head. Proton magnetic resonance spectroscopy (1H-MRS) can be used to determine relative concentrations of metabolites in vivo in the human brain. The purpose of this study was to determine concentrations of glutamate and GABA in the brain acutely after mTBI and throughout 2 mo of recovery. Concentrations of glutamate and GABA were obtained using 1H-MRS in nine individuals who had suffered an mTBI and nine control individuals in two brain regions of interest: the primary motor cortex (M1), and the dorsolateral prefrontal cortex (DLPFC), and at three different time points postinjury: 72 h, 2 wk, and 2 mo postinjury. There were no differences between groups in concentrations of glutamate or GABA, or the ratio of glutamate to GABA, in M1. In the DLPFC, glutamate concentration was lower in the mTBI group compared with controls at 72 h postinjury (d = 1.02), and GABA concentration was lower in the mTBI group at 72 h and 2 wk postinjury (d = 0.81 and d = 1.21, respectively). The ratio of glutamate to GABA in the DLPFC was higher in the mTBI group at 2 wk postinjury (d = 1.63). These results suggest that changes in glutamate and GABA concentrations in the brain may be region-specific and may depend on the amount of time that has elapsed postinjury. NEW & NOTEWORTHY To our knowledge, this is the first study to examine neurotransmitter concentrations in vivo at multiple time points throughout recovery from mild traumatic brain injury in humans.

Astaxanthin improves cognitive performance in mice following mild traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) produces lasting neurological deficits that plague patients and physicians. To date, there is no effective method to combat the source of this problem. Here, we utilized a mild, closed head TBI model to determine the modulatory effects of a natural dietary compound, astaxanthin (AST). AST is centrally active following oral administration and is neuroprotective in experimental brain ischemia/stroke and subarachnoid hemorrhage (SAH) models. We examined the effects of oral AST on the long-term neurological functional recovery and histological outcomes following moderate TBI in a mice model. METHODS: Male adult ICR mice were divided into 3 groups: (1) Sham+olive oil vehicle treated, (2) TBI+olive oil vehicle treated, and (3) TBI+AST. The olive oil vehicle or AST were administered via oral gavage at scheduled time points. Closed head brain injury was applied using M.A. Flierl weight-drop method. NSS, Rotarod, ORT, and Y-maze were performed to test the behavioral or neurological outcome. The brain sections from the mice were stained with H&E and cresyl-violet to test the injured lesion volume and neuronal loss. Western blot analysis was performed to investigate the mechanisms of neuronal cell survival and neurological function improvement. RESULTS: AST administration improved the sensorimotor performance on the Neurological Severity Score (NSS) and rotarod test and enhanced cognitive function recovery in the object recognition test (ORT) and Y-maze test. Moreover, AST treatment reduced the lesion size and neuronal loss in the cortex compared with the vehicle-treated TBI group. AST also restored the levels of brain-derived neurotropic factor (BDNF), growth-associated protein-43 (GAP-43), synapsin, and synaptophysin (SYP) in the cerebral cortex, which indicates the promotion of neuronal survival and plasticity. CONCLUSION: To the best of our knowledge, this is the first study to demonstrate the protective role and the underlining mechanism of AST in TBI. Based on these neuroprotective actions and considering its longstanding clinical use, AST should be considered for the clinical treatment of TBI.

Startle suppression after mild traumatic brain injury is associated with an increase in pro-inflammatory cytokines, reactive gliosis and neuronal loss in the caudal pontine reticular nucleus.

Mild traumatic brain injury (mTBI) can produce somatic symptoms such as headache, dizziness, fatigue, sleep disturbances and sensorimotor dysfunction. Sensorimotor function can be measured by tests such as the acoustic startle reflex (ASR), an evolutionarily conserved defensive response to a brief yet sharp acoustic stimulus. mTBI produces a long-lasting suppression of ASR in rodents and humans; however, the mechanism of this suppression is unknown. The present study examined whether inflammatory processes in the brainstem (particularly the caudal pontine reticular nucleus, PnC) could account for the suppression of ASR after mTBI, because the PnC is an essential nucleus of the ASR circuit. Furthermore, while inflammation after mTBI is commonly observed in brain regions proximal to the site of impact (cortex and hippocampus), the effects of mTBI in brainstem structures remains largely understudied. The present study demonstrated a suppression of ASR one day after injury and lasting at least three weeks after an mTBI, replicating previous findings. Within the PnC, transient elevations of IL-1ß and TNF-α mRNA were observed at one day after injury, while IL-1α mRNA exhibited a delayed increase at three weeks after injury. Reactive gliosis (via IBA-1-ir for microglia and GFAP-ir for astrocytes) were also observed in the PnC, at one day and seven days after injury, respectively. Finally, the number of giant neurons (the major functional cell population in the PnC) was decreased three weeks after injury. The results indicate that glial activation precedes neuronal loss in the PnC, and correlates with the behavioral suppression of the ASR. The results also raise implications for brainstem involvement in the development of post-traumatic symptoms.

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury.

The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism. Preclinical studies employing both pre- and postinjury implementation of the ketogenic diet have demonstrated improved structural and functional outcome in traumatic brain injury (TBI) models, mild TBI/concussion models, and spinal cord injury. Further clinical studies are required to determine the optimal method to induce cerebral ketone metabolism in the postinjury brain, and to validate the neuroprotective benefits of ketogenic therapy in humans.

Clinical relevance of optimizing vitamin D status in soldiers to enhance physical and cognitive performance.

Vitamin D deficiency initiates a loss of combat effectiveness by impairing physical and cognitive functioning of combat Operators. Synthesized in response to sunlight and consumed in the diet, vitamin D functions as a hormone and regulates gene expression for nearly 300 genes throughout the human body. These target genes are involved processes essential to combat operations, such as immune function, response to stress, inflammation, and regulation of calcium movement. Since widespread vitamin D deficiency is observed across the U.S. population, poor vitamin D status is expected in Servicemembers. Physical conditions linked to vitamin D deficiency include increased risk for muscle or bone injury, muscle weakness, and reduced neuromuscular function. Hormonally, vitamin D levels have been positively correlated with testosterone levels. Vitamin D deficiency is also associated with cognitive decline, depression, and may prolong recovery following mild traumatic brain injury (mTBI). Since vitamin D deficiency elevates systemic inflammation, poor vitamin D status at the time of brain injury may prolong the inflammatory response and exacerbate postconcussive symptoms. Furthermore, veterans with mTBI experience chronic endocrine dysfunction. While vitamin D status has not been assessed post-mTBI, it is plausible that vitamin D levels are altered along with testosterone and growth hormone, raising the question of whether vitamin D deficiency results from trauma-related hormonal abnormalities or whether vitamin D deficiency increases the risk for endocrine dysfunction. Through its association with testosterone production, vitamin D deficiency may increase the risk for posttraumatic stress disorder (PTSD) since testosterone levels are altered in veterans with PTSD. Therefore, vitamin D status has a significant impact on Operator health and performance. Supplementing vita-min D to deficient Operators provides a noninvasive and low-cost intervention to maintain combat force.

Multimodal assessment of primary motor cortex integrity following sport concussion in asymptomatic athletes.

OBJECTIVE: Recent studies have shown, in asymptomatic concussed athletes, metabolic disruption in the primary motor cortex (M1) and abnormal intracortical inhibition lasting for more than six months. The present study aims to assess if these neurochemical and neurophysiological alterations are persistent and linked to M1 cortical thickness. METHODS: Sixteen active football players who sustained their last concussion, on average, three years prior to testing and 14 active football players who never sustained a concussion were recruited for a single session of proton magnetic resonance spectroscopy ((1)H-MRS) and transcranial magnetic stimulation (TMS). Measures of M1 and whole brain cortical thickness were acquired, and (1)H-MRS data were acquired from left M1 using a MEGA-PRESS sequence. Cortical silent period (CSP) and long-interval intracortical inhibition (LICI) were measured with TMS applied over left M1. RESULTS: No significant group differences were observed for metabolic concentrations, TMS measures, and cortical thickness. However, whereas GABA and glutamate levels were positively correlated in control athletes, this relationship was absent in concussed athletes. CONCLUSION: These data suggest the general absence of neurophysiologic, neurometabolic and neuroanatomical disruptions in M1 three years following the last concussive event. However, correlational analyses suggest the presence of a slight metabolic imbalance between GABA and glutamate concentrations in the primary motor cortex of concussed athletes. SIGNIFICANCE: The present study highlights the importance of multimodal assesments of the impacts of sport concussions.

Postconcussion syndrome and mild head injury: the role of early diagnosis using neuropsychological tests and functional magnetic resonance/spectroscopy.

OBJECTIVE: Postconcussion syndrome (PCS) is usually underestimated in cases of mild head injury (MHI). It is one of the most common causes of physical, cognitive, and psychomotor disturbances that affect the quality of life, work, and social reintegration of individuals. Until now, we did not have evidence of structural abnormalities shown by traditional imaging methods. We describe a series of instruments that confirm PCS with satisfactory evidence. METHODS: We conducted a clinical prospective study of 19 adult patients selected from a pool of 320 adults who had MHI. The cognitive, executive, and memory functions of subjects were examined within the first 72 hours using neuropsychological tests. These results were analyzed with neurological examination and functional MR/spectroscopy. RESULTS: Neurobehavioral alterations were found in 47% of cases, with posttraumatic amnesia. Around 55% of subjects experienced physical disturbances such as headache and postural vertigo due to PCS. The spectroscopy reports revealed neurometabolite disturbances in 54% of cases, particularly N-acetylaspartate (Naa) and the Naa/lactate ratio in the frontal lobe. We observed a relationship between metabolite disturbances in spectroscopy and the digit span backward test (P = .045). CONCLUSIONS: This first diagnostic strategy supports with scientific evidence the presence of PCS in MHI. We identified physical and neuropsychological abnormalities from this group, affecting the areas of memory and learning. Evidence of neurometabolite disturbances were found specifically in the frontal lobe. It is necessary to complete comparative follow-up for an extended period of time. The neuropsychological and spectroscopy tests allow us to confirm the diagnosis of a syndrome that is usually neglected.

Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity.

Sports concussion is a major problem that affects thousands of people in North America every year. Despite negative neuroimaging findings, many athletes display neurophysiological alterations and post-concussion symptoms such as headaches and sensitivity to light and noise. It is suspected that neurometabolic changes may underlie these changes. In this study we investigated the effects of sports concussion on brain metabolism using (1)H-MR spectroscopy by comparing a group of 12 non-concussed athletes with a group of 12 concussed athletes of the same age (mean 22.5 years) and education (mean 16 years). All athletes were scanned 1-6 days post-concussion in a 3T Siemens MRI, and were administered a symptom scale to evaluate post-concussion symptomatology. Participants also completed a neuropsychological test battery to assess verbal memory, visual memory, information processing speed, and reaction time, and no group differences were detected relative to controls. Concussed athletes showed a higher number of symptoms than non-concussed athletes, and they also showed a significant decrease in glutamate in the primary motor cortex (M1), as well as significant decreases in N-acetylaspartate in the prefrontal and primary motor cortices. No changes were observed in the hippocampus. Furthermore, the metabolic changes in M1 correlated with self-reported symptom severity despite equivalent neuropsychological performance. These results confirm cortical neurometabolic changes in the acute post-concussion phase, and demonstrate for the first time a correlation between subjective self-reported symptoms and objective physical changes that may be related to increased vulnerability of the concussed brain.

Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury.

Accumulation of calcium following experimental traumatic brain injury (TBI) has been demonstrated to be a prominent pathophysiological component that can compromise mitochondrial functioning and threaten cell survival. The omega-conopeptide SNX-111, also known as Ziconotide, is a potent antagonist of the voltage-gated N-type calcium channel and has demonstrated significant neuroprotective effects against ischemia-induced neuronal injury. To determine whether this compound would be effective in reducing calcium accumulation associated with TBI, SNX-111 was administered intravenously to rats 1 hour following a moderate (2.2 to 2.75 atm) lateral fluid-percussion injury (or sham) at doses of 1 (n = 30), 3 (n = 31), or 5 (n = 30) mg/kg; another group received 0.9% saline solution (n = 35). Brains were processed for calcium 45 (45Ca) autoradiography at 6, 12, 24, 48, and 96 hours following insult. Optical density measurements of 20 cortical and subcortical regions were analyzed. Injured animals administered saline solution exhibited a significant increase in 45Ca uptake within 12 regions ipsilateral to the site of injury. The most prominent increases were evident throughout the ipsilateral cerebral cortex. SNX-111 reduced the injury-induced calcium accumulation within the ipsilateral cortex in a dose-response fashion when measured at 6, 12, and 48 hours after insult. These drug-induced reductions in calcium accumulation were as high as 75% in the ipsilateral cerebral cortex, and up to 50% in other ipsilateral regions (including thalamus and hippocampus). Consequently, the results suggest that posttraumatic blocking of the voltage-gated N-type calcium channel after injury reduces prolonged, trauma-induced calcium accumulation.