Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1-13 C]pyruvate.

PURPOSE: Pyruvate, produced from either glucose, glycogen, or lactate, is the dominant precursor of cerebral oxidative metabolism. Pyruvate dehydrogenase (PDH) flux is a direct measure of cerebral mitochondrial function and metabolism. Detection of [13 C]bicarbonate in the brain from hyperpolarized [1-13 C]pyruvate using carbon-13 (13 C) MRI provides a unique opportunity for assessing PDH flux in vivo. This study is to assess changes in cerebral PDH flux in response to visual stimuli using in vivo 13 C MRS with hyperpolarized [1-13 C]pyruvate. METHODS: From seven sedentary adults in good general health, time-resolved [13 C]bicarbonate production was measured in the brain using 90° flip angles with minimal perturbation of its precursors, [1-13 C]pyruvate and [1-13 C]lactate, to test the hypothesis that the appearance of [13 C]bicarbonate signals in the brain reflects the metabolic changes associated with neuronal activation. With a separate group of healthy participants (n = 3), the likelihood of the bolus-injected [1-13 C]pyruvate being converted to [1-13 C]lactate prior to decarboxylation was investigated by measuring [13 C]bicarbonate production with and without [1-13 C]lactate saturation. RESULTS: In the course of visual stimulation, the measured [13 C]bicarbonate signal normalized to the total 13 C signal in the visual cortex increased by 17.1% ± 15.9% (p = 0.017), whereas no significant change was detected in [1-13 C]lactate. Proton BOLD fMRI confirmed the regional activation in the visual cortex with the stimuli. Lactate saturation decreased bicarbonate-to-pyruvate ratio by 44.4% ± 9.3% (p < 0.01). CONCLUSION: We demonstrated the utility of 13 C MRS with hyperpolarized [1-13 C]pyruvate for assessing the activation of cerebral PDH flux via the detection of [13 C]bicarbonate production.

Longitudinal assessment of mitochondrial dysfunction in acute traumatic brain injury using hyperpolarized [1-13 C]pyruvate.

PURPOSE: [13 C]Bicarbonate formation from hyperpolarized [1-13 C]pyruvate via pyruvate dehydrogenase, a key regulatory enzyme, represents the cerebral oxidation of pyruvate and the integrity of mitochondrial function. The present study is to characterize the chronology of cerebral mitochondrial metabolism during secondary injury associated with acute traumatic brain injury (TBI) by longitudinally monitoring [13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate in rodents. METHODS: Male Wistar rats were randomly assigned to undergo a controlled-cortical impact (CCI, n = 31) or sham surgery (n = 22). Seventeen of the CCI and 9 of the sham rats longitudinally underwent a 1 H/13 C-integrated MR protocol that includes a bolus injection of hyperpolarized [1-13 C]pyruvate at 0 (2 h), 1, 2, 5, and 10 days post-surgery. Separate CCI and sham rats were used for histological validation and enzyme assays. RESULTS: In addition to elevated lactate, we observed significantly reduced bicarbonate production in the injured site. Unlike the immediate appearance of hyperintensity on T2 -weighted MRI, the contrast of bicarbonate signals between the injured region and the contralateral brain peaked at 24 h post-injury, then fully recovered to the normal level at day 10. A subset of TBI rats demonstrated markedly increased bicarbonate in normal-appearing contralateral brain regions post-injury. CONCLUSION: This study demonstrates that aberrant mitochondrial metabolism occurring in acute TBI can be monitored by detecting [13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate, suggesting that [13 C]bicarbonate is a sensitive in-vivo biomarker of the secondary injury processes.

ENIGMA brain injury: Framework, challenges, and opportunities.

Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury-related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest-ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group.

Neuroimaging Correlates of Functional Outcome Following Pediatric TBI.

Neuroimaging plays an important role in assessing the consequences of TBI across the postinjury period. While identifying alterations to the brain is important, associating those changes to functional, cognitive, and behavioral outcomes is an essential step to establishing the value of advanced neuroimaging for pediatric TBI. Here we highlight research that has revealed links between advanced neuroimaging and outcome after TBI and point to opportunities where neuroimaging could expand our ability to prognosticate and potentially uncover opportunities to intervene.

The usage of a modified straight-leg raise neurodynamic test and hamstring flexibility for diagnosis of non-specific low back pain: A cross-sectional study.

OBJECTIVES: The main purpose of this research study was to compare mean modified straight-leg raise test (mSLR) and hamstring muscle length (HL) between chronic non-specific low back pain (LBP) and healthy subjects to understand the possibility of neuropathic causes in LBP population as it may impact the diagnosis and treatment of LBP. Another purpose was to compare mean mSLR between those with lumbar nerve root impingement and those without as determine by magnetic resonance imaging (MRI). METHODS: The design of the study is cross sectional and included 32 subjects with ages ranging from 18-50 years old. Clinical exam objective measures were collected such as patient questionnaires, somatosensory tests, HL range of motion, and a mSLR test, and were compared to the findings from a structural lumbar spine MRI. RESULTS: There were no significant differences in mean HL angulation and mSLR angulation between LBP and healthy subjects (p>0.05). There was no significant difference in mean HL by impingement by versus no impingement (38.3±15.6 versus 44.8±9.4, p = 0.08, Cohen's d = 0.50). On the other hand, there was a significant difference in mean mSLR angulation by impingement (57.6.3±8.7 versus 63.8±11.6, p = 0.05, Cohen's d = 0.60). CONCLUSIONS: The mSLR test was found to be associated with lumbar nerve root compression, regardless of the existence of radiating leg symptoms, and showed no association solely with the report of LBP. The findings highlight the diagnostic dilemma facing clinicians in patients with chronic nonspecific LBP with uncorrelated neuroanatomical image findings. Clinically, it may be necessary to reevaluate the common practice of exclusively using the mSLR test for patients with leg symptoms. This study may impact the way chronic LBP and neuropathic symptoms are diagnosed, potentially improving treatment methods, reducing persistent symptoms, and ultimately improving disabling effects.

White Matter Metabolite Ratios Predict Cognitive Outcome in Pediatric Traumatic Brain Injury.

The prognostic ability of global white matter and gray matter metabolite ratios following pediatric traumatic brain injury (TBI) and their relationship to 12-month neuropsychological assessments of intelligence quotient (IQ), attention, and memory is presented. Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) in pediatric subjects with complicated mild (cMild), moderate, and severe TBI was acquired acutely (6-18 days) and 12 months post-injury and compared to age-matched typically developing adolescents. A global linear regression model, co-registering MRSI metabolite maps with 3D high-resolution magnetic resonance images, was used to identify longitudinal white matter and gray matter metabolite ratio changes. Acutely, gray matter NAA/Cr, white matter NAA/Cr, and white matter NAA/Cho ratios were significantly lower in TBI groups compared to controls. Gray matter NAA/Cho was reduced only in the severe TBI group. At 12 months, all metabolite ratios normalized to control levels in each of the TBI groups. Acute gray matter and white matter NAA ratios were significantly correlated to 12-month assessments of IQ, attention, and memory. These findings suggest that whole brain gray matter and white matter metabolite ratios reflect longitudinal changes in neuronal metabolism following TBI, which can be used to predict neuropsychological outcomes in pediatric subjects.

Triangulating brain alterations in anorexia nervosa: a multimodal investigation of magnetic resonance spectroscopy, morphometry and blood-based biomarkers.

The acute state of anorexia nervosa (AN) is associated with widespread reductions in cortical gray matter (GM) thickness and white matter (WM) volume, suspected changes in myelin content and elevated levels of the neuronal damage marker neurofilament light (NF-L), but the underlying mechanisms remain largely unclear. To gain a deeper understanding of brain changes in AN, we applied a multimodal approach combining advanced neuroimaging methods with analysis of blood-derived biomarkers. In addition to standard measures of cortical GM thickness and WM volume, we analyzed tissue-specific profiles of brain metabolites using multivoxel proton magnetic resonance spectroscopy, T1 relaxation time as a proxy of myelin content leveraging advanced quantitative MRI methods and serum NF-L concentrations in a sample of 30 female, predominately adolescent patients with AN and 30 age-matched female healthy control participants. In patients with AN, we found a reduction in GM cortical thickness and GM total N-acetyl aspartate. The latter predicted higher NF-L levels, which were elevated in AN. Furthermore, GM total choline was elevated. In WM, there were no group differences in either imaging markers, choline levels or N-acetyl aspartate levels. The current study provides evidence for neuronal damage processes as well as for increased membrane lipid catabolism and turnover in GM in acute AN but no evidence for WM pathology. Our results illustrate the potential of multimodal research including tissue-specific proton magnetic resonance spectroscopy analyses to shed light on brain changes in psychiatric and neurological conditions, which may ultimately lead to better treatments.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

The effect of whole-body cooling on brain metabolism following perinatal hypoxic-ischemic injury.

INTRODUCTION: Magnetic resonance imaging (MRI) and spectroscopy (MRS) have proven valuable in evaluating neonatal hypoxic-ischemic injury (HII). RESULTS: MRI scores in the basal ganglia of HII/HT(+) neonates were significantly lower than HII/HT(-) neonates, indicating less severe injury and were associated with lower discharge encephalopathy severity scores in the HII/HT(+) group (P = 0.01). Lactate (Lac) was detected in the occipital gray matter (OGM) and thalamus (TH) of significantly more HII/HT(-) neonates (31.6 and 35.3%) as compared to the HII/HT(+) group (10.5 and 15.8%). In contrast, the -N-acetylaspartate (NAA)-based ratios in the OGM and TH did not differ between the HII groups. DISCUSSION: Our data show that the HT was associated with a decrease in the number of HII neonates with detectable cortical and subcortical Lac as well as a decrease in the number of MRI-detectable subcortical lesions. METHODS: We retrospectively compared the medical and neuroimaging data of 19 HII neonates who received 72 h of whole-body cooling (HII/HT(+)) with those of 19 noncooled HII neonates (HII/HT(-)) to determine whether hypothermia was associated with improved recovery from the injury as measured by MRI and MRS within the first 14 days of life. MRI scores and metabolite ratios of HII/HT(+) and HII/HT(-) neonates were also compared with nine healthy, nonasphyxiated "control" neonates.

Quantitative susceptibility mapping as a measure of cerebral oxygenation in neonatal piglets.

Prominence of cerebral veins using susceptibility weighted magnetic resonance imaging (SWI) has been used as a qualitative indicator of cerebral venous oxygenation (CvO2). Quantitative susceptibility mapping (QSM) adds more precision to the assessment of CvO2, but has not been applied to neonatal hypoxic ischemic injury (HII). We proposed to study QSM measures of venous susceptibility and their correlation with direct measures of brain oxygenation and cerebral blood flow (CBF) in the neonatal piglet. The association of QSM intravascular cerebral venous susceptibility, with brain tissue O2 tension, CBF, cortical tissue oxyhemoglobin saturation, and the partial pressure of oxygen in arterial blood measurement during various oxygenation states was determined by linear regression. Compared to normoxia, venous susceptibility in the straight sinus increased 56.8 ± 25.4% during hypoxia, while decreasing during hyperoxia (23.5 ± 32.9%) and hypercapnia (23.3 ± 73.1%), which was highly correlated to all other measures of oxygenation (p < 0.0001) but did not correlate to CBF (p = 0.82). These findings demonstrate a strong relationship between venous susceptibility and brain tissue O2 tension. Our results suggest that QSM-derived venous susceptibility is sensitive to cerebral oxygenation status across various oxygenation states.

Harmonization of multi-scanner in vivo magnetic resonance spectroscopy: ENIGMA consortium task group considerations.

Magnetic resonance spectroscopy is a powerful, non-invasive, quantitative imaging technique that allows for the measurement of brain metabolites that has demonstrated utility in diagnosing and characterizing a broad range of neurological diseases. Its impact, however, has been limited due to small sample sizes and methodological variability in addition to intrinsic limitations of the method itself such as its sensitivity to motion. The lack of standardization from a data acquisition and data processing perspective makes it difficult to pool multiple studies and/or conduct multisite studies that are necessary for supporting clinically relevant findings. Based on the experience of the ENIGMA MRS work group and a review of the literature, this manuscript provides an overview of the current state of MRS data harmonization. Key factors that need to be taken into consideration when conducting both retrospective and prospective studies are described. These include (1) MRS acquisition issues such as pulse sequence, RF and B0 calibrations, echo time, and SNR; (2) data processing issues such as pre-processing steps, modeling, and quantitation; and (3) biological factors such as voxel location, age, sex, and pathology. Various approaches to MRS data harmonization are then described including meta-analysis, mega-analysis, linear modeling, ComBat and artificial intelligence approaches. The goal is to provide both novice and experienced readers with the necessary knowledge for conducting MRS data harmonization studies.

Evolving White Matter Injury following Pediatric Traumatic Brain Injury.

This study is unique in that it examines the evolution of white matter injury very early and at 12 months post-injury in pediatric patients following traumatic brain injury (TBI). Diffusion tensor imaging (DTI) was acquired at two time-points: acutely at 6-17 days and 12 months following a complicated mild (cMild)/moderate (mod) or severe TBI. Regional measures of anisotropy and diffusivity were compared between TBI groups and against a group of age-matched healthy controls and used to predict performance on measures of attention, memory, and intellectual functioning at 12-months post-injury. Analysis of the acute DTI data using tract based spatial statistics revealed a small number of regional decreases in fractional anisotropy (FA) in both the cMild/mod and severe TBI groups compared with controls. These changes were observed in the occipital white matter, anterior limb of the internal capsule (ALIC)/basal ganglia, and corpus callosum. The severe TBI group showed regional differences in axial diffusivity (AD) in the brainstem and corpus callosum that were not seen in the cMild/mod TBI group. By 12-months, widespread decreases in FA and increases in apparent diffusion coefficient (ADC) and radial diffusivity (RD) were observed in both TBI groups compared with controls, with the overall number of regions with abnormal DTI metrics increasing over time. The early changes in regional DTI metrics were associated with 12-month performance IQ scores. These findings suggest that there may be regional differences in the brain's reparative processes or that mechanisms associated with the brain's plasticity to recover may also be region based.

The clinical utility of proton magnetic resonance spectroscopy in traumatic brain injury: recommendations from the ENIGMA MRS working group.

Proton (1H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo 1H magnetic resonance spectroscopy and review 1H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic 1H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of 1H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.

Challenges and opportunities for neuroimaging in young patients with traumatic brain injury: a coordinated effort towards advancing discovery from the ENIGMA pediatric moderate/severe TBI group.

Traumatic brain injury (TBI) is a major cause of death and disability in children in both developed and developing nations. Children and adolescents suffer from TBI at a higher rate than the general population, and specific developmental issues require a unique context since findings from adult research do not necessarily directly translate to children. Findings in pediatric cohorts tend to lag behind those in adult samples. This may be due, in part, both to the smaller number of investigators engaged in research with this population and may also be related to changes in safety laws and clinical practice that have altered length of hospital stays, treatment, and access to this population. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric Moderate/Severe TBI (msTBI) group aims to advance research in this area through global collaborative meta-analysis of neuroimaging data. In this paper, we discuss important challenges in pediatric TBI research and opportunities that we believe the ENIGMA Pediatric msTBI group can provide to address them. With the paucity of research studies examining neuroimaging biomarkers in pediatric patients with TBI and the challenges of recruiting large numbers of participants, collaborating to improve statistical power and to address technical challenges like lesions will significantly advance the field. We conclude with recommendations for future research in this field of study.

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes. METHODS: Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline. RESULTS: Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between d=-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027). CONCLUSIONS: WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically-meaningful patient subtypes.

Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury.

Aim: Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI. Methods: The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1ß and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing (n = 10-14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10-15 days post-injury. Results: Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1ß expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment. Conclusion: Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.

Glutamate metabolism in temporal lobe epilepsy as revealed by dynamic proton MRS following the infusion of [U13-C] glucose.

Focal metabolic dysfunction commonly observed in temporal lobe epilepsy (TLE), and is associated with the development of medical intractability and neurocognitive deficits. It has not been established if this dysfunction is due to cell loss or biochemical dysfunction in metabolic pathways. To explore this question, dynamic 1H MRS following an infusion of [U13- C] glucose was performed to measure glutamate (Glu) metabolism. Subjects (n=6) showed reduced Glu levels (p<0.01) in the ipsilateral mesial temporal lobe (MTL) compared with controls (n=4). However, the rate of 13C incorporation into Glu did not differ between those with epilepsy and controls (p=0.77). This suggests that reduced Glu concentrations in the region of the seizure focus are not due to disruptions in metabolic pathways, but may instead be due to neuronal loss or simplification.

Metabolic fate of glucose in rats with traumatic brain injury and pyruvate or glucose treatments: A NMR spectroscopy study.

Administration of sodium pyruvate (SP; 9.08 µmol/kg, i.p.), ethyl pyruvate (EP; 0.34 µmol/kg, i.p.) or glucose (GLC; 11.1 µmol/kg, i.p.) to rats after unilateral controlled cortical impact (CCI) injury has been reported to reduce neuronal loss and improve cerebral metabolism. In the present study these doses of each fuel or 8% saline (SAL; 5.47 nmoles/kg) were administered immediately and at 1, 3, 6 and 23 h post-CCI. At 24 h all CCI groups and non-treated Sham injury controls were infused with [1,2 13C] glucose for 68 min 13C nuclear magnetic resonance (NMR) spectra were obtained from cortex + hippocampus tissues from left (injured) and right (contralateral) hemispheres. All three fuels increased lactate labeling to a similar degree in the injured hemisphere. The amount of lactate labeled via the pentose phosphate and pyruvate recycling (PPP + PR) pathway increased in CCI-SAL and was not improved by SP, EP, and GLC treatments. Oxidative metabolism, as assessed by glutamate labeling, was reduced in CCI-SAL animals. The greatest improvement in oxidative metabolism was observed in animals treated with SP and fewer improvements after EP or GLC treatments. Compared to SAL, all three fuels restored glutamate and glutamine labeling via pyruvate carboxylase (PC), suggesting improved astrocyte metabolism following fuel treatment. Only SP treatments restored the amount of [4 13C] glutamate labeled by the PPP + PR pathway to sham levels. Milder injury effects in the contralateral hemisphere appear normalized by either SP or EP treatments, as increases in the total pool of 13C lactate and labeling of lactate in glycolysis, or decreases in the ratio of PC/PDH labeling of glutamine, were found only for CCI-SAL and CCI-GLC groups compared to Sham. The doses of SP, EP and GLC examined in this study all enhanced lactate labeling and restored astrocyte-specific PC activity but differentially affected neuronal metabolism after CCI injury. The restoration of astrocyte metabolism by all three fuel treatments may partially underlie their abilities to improve cerebral glucose utilization and to reduce neuronal loss following CCI injury.

Impaired neurovascular unit function contributes to persistent symptoms after concussion: a pilot study.

Research shows that approximately 14% of school age children with mild traumatic brain injury (TBI) including sports-related concussions (SRCs) remain symptomatic three months after injury. Advanced imaging studies early after injury have shown evidence of axonal damage, reduced N-acetyl aspartate (NAA) and impaired cerebral blood flow (CBF) in individuals with mild TBI. This study was undertaken to determine whether these techniques can provide valuable information in pediatric SRC patients with persistent post-concussive symptoms. Fifteen pediatric subjects ages 8 to 17 years with persistent post-concussive symptoms were evaluated using perfusion-weighted imaging (PWI), three-dimensional (3D) magnetic resonance spectroscopic imaging, and diffusion tensor imaging (DTI) three to 12 months post-SRC. Data were compared with 15 demographically similar (age, gender, and body mass index) controls. In the bilateral thalami, SRC patients showed reduced CBF (p=0.02 and p=0.02) and relative cerebral blood volume (CBV; p=0.05 and p=0.03), compared with controls. NAA/creatine (Cr) and NAA/choline (Cho) ratios were reduced in the corpus callosum (p=0.003; p=0.05) and parietal white matter (p<0.001; p=0.006) of SRC subjects, compared with controls. Significant differences in DTI metrics differentiated patients with cognitive symptoms, compared with those without cognitive symptoms and controls. Advanced imaging methods detect a spectrum of injury including impaired axonal function, neuronal metabolism and perfusion, suggesting involvement of the neurovascular unit in the presence of persistent symptoms in pediatric SRC patients.