Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / Department of Biology

Seizure activity is the primary symptom in a common but very serious neurological disorder known as epilepsy. Brain glycogen is utilized for neuronal function, prompting us to investigate the role of brain glycogen during seizure activity in mouse models. Seizures were induced with Pentylenetetrazole (PTZ) in both wild-type mice and mice lacking brain glycogen (MGSKO/GSL30 mice). A time course of brain glycogen utilization after onset of seizure activity revealed a reduction of brain glycogen in wild-type mice. The glycogen synthase activity ratio increased after onset of seizure activity, while the glycogen phosphorylase activity ratio remained constant. Brain and blood glucose levels increased after seizure onset in wild-type mice. Despite lacking brain glycogen, MGSKO/GSL30 mice exhibited acute seizure activity. No differences were observed in seizure intensity, onset time, and duration between genotypes. These findings suggest that brain glycogen is important, but not required for PTZ-induced acute seizure activity in mice. / Access to thesis permanently restricted to Ball State community only / Department of Biology

Le cerveau humain est un organe très métaboliquement actif. Cet énorme besoin énergétique l’expose à un risque accru de détérioration causée par un dérèglement de ce métabolisme. Dans la phase précoce de la maladie d’Alzheimer, un hypométabolisme cérébral du glucose est observé. Cette carence énergétique serait à l’origine des détériorations observée lors du développement de cette maladie. Le cerveau a accès à une autre source endogène d’énergie : les cétones. Les cétones sont particulièrement importantes pour le cerveau puisqu’il ne possède pas la capacité d’utiliser les acides gras comme source énergétique à l’instar des autres organes. Les cétones sont issues de la β-oxydation hépatique des acides gras. Ils sont produits en situation de jeûne lorsque les niveaux circulants de glucose et d’insuline sont bas. Les cétones se sont déjà montré efficaces dans le traitement de divers troubles neurologiques comme l’épilepsie. Par contre, outre les diètes cétogènes et le jeûne prolongé, il n’existe pas de traitement efficace pour maintenir une cétonémie modérée chez l’adulte. Le métabolisme énergétique cérébral en situation de cétose modérée reste encore mal compris dans cette population. Les travaux de cette thèse se sont donc concentrés à étudier la possibilité d’une combinaison d’approche nutritionnelle et pharmacologique afin de stimuler la cétogenèse chez l’adulte. Ils ont aussi exploré les changements de métabolisme cérébral chez l’adulte durant une cétose modérée. L’objectif de la première étude était d’étudier le potentiel du bezafibrate à stimuler la cétogenèse induite par une supplémentation en triglycérides de moyennes chaînes (MCT). Cette première étude a démontré que le bezafibrate avait peu d’effet sur la stimulation de la cétogenèse induite par les MCT et que le facteur limitant dans cette stimulation était donc la disponibilité des substrats et non la capacité cétogène des cellules hépatiques. L’objectif de la seconde étude était d’étudier les changements de capture des cétones et du glucose au cerveau durant un état de cétose modérée chez l’adulte. Les résultats de cette deuxième étude ont montré que la capture des cétones au cerveau est directement proportionnelle à leur concentration plasmatique. Cette étude a aussi démontré que la capture cérébrale des cétones était directement reliée à leur concentration plasmatique alors que la capture cérébrale du glucose est modulée par les besoins énergétiques du cerveau. Une stimulation cétogénique chez des personnes atteintes de déclin cognitif pourrait donc aider à rétablir la balance énergétique et ralentir l’apparition des symptômes chez ces personnes mais cet effet devra être étudié dans une étude ultérieure. / Abstract : The human brain is the most metabolically active organ of the body. This high need for energy exposes it to an increase risk in case of hypometabolism. Such a glucose hypometabolism is seen during the early stages of Alzheimer’s disease. This factor is believed to be one of the cause of the disease. Ketones are the main alternate substrate for the human brain. Ketones are particularly important since, unlike other organs, the brain can not use fatty acids as alternative fuel. Ketones are mainly produce through β-oxidation of fatty acid by the liver. This happens mainly during fasting when circulating levels of glucose and insulin are low. Studies have shown that ketones can have a therapeutic effect in a variety of neurological diseases, mainly epilepsy and Alzheimer’s disease. Nevertheless, apart from ketogenic diet and prolonged fasting, there is currently no effective ways to induce and maintain moderate ketosis in adults. Brain energy metabolism under moderate ketosis remains also misunderstood in this population. This thesis aimed look at the effect of a combination of a pharmacological treatment and a nutritional supplementation to induce moderate sustain ketosis in adults. It also studied the effect of a moderate ketosis on brain energy metabolism in adults. The aim of the first study was to study the effect of a pharmacological treatment, bezafibrate, on the potentiation of the ketogenic effect induced by a medium-chain triglycerides (MCT) supplementation. The results of this study that bezafibrate had little effect on the ketosis induced by a MCT supplementation and, therefore, that the limiting factor in human ketosis was not the liver cells capacity to produce ketones but the availability of substrates for ketogenesis. The aim of the second study was to study the impact of a nutritional moderate ketosis on brain glucose and ketone uptake. The results of this study showed a direct correlation between brain ketone uptake and plasma ketone concentrations. This study also showed that brain ketone uptake is regulated by blood ketone concentration whereas brain glucose uptake is regulated by the brain energy needs. Further studies should then look if such a moderate ketosis induced in cognitively impaired patients could re-equilibrate the energy balance in the brain and then slow the apparition of clinical symptoms in this population.

Alzheimer's disease (AD) is associated with decreased brain energy metabolism. Hypometabolism in the posterior cingulate cortex (PCC) occurs before the onset of memory deficits in subjects at genetic risk for AD who are not yet cognitively impaired. There is a specific inhibition in cytochrome oxidase (C.O.) in the PCC, an area involved in spatial navigation. Creating an animal model that exhibits the early pathophysiology of AD is important for developing and testing drugs that could reverse memory problems associated with such deficits. Methylene blue (MB) is a compound that improves C.O. activity and memory retention in rats. This dissertation had three specific aims: 1) to examine if isolated PCC hypometabolism causes spatial memory deficits in rats; 2) to find a dose of MB that improves memory without nonspecific behavioral effects; and 3) to prevent memory deficits from PCC hypometabolism with low dose MB. PCC hypometabolism was produced by focal administration of sodium azide, an inhibitor of C.O. activity. PCC hypometabolism resulted in impaired spatial memory in a hole board food-search task, increased oxidative damage, and neurotoxicity in the PCC. In addition, PCC hypometabolism resulted in reduced inter-regional correlations in brain activity. Our second set of studies examined the dose-response effects of MB. Our findings demonstrated that a low dose of MB: 1) enhanced memory in open field habituation and object recognition tasks; 2) did not affect general locomotor activity, exploration, motivation, or anxiety; and 3) increased brain oxygen consumption 24 hr after in vivo administration. Finally, our last study found that low dose MB prevented the deficits caused by PCC hypometabolism. MB did not prevent PCC inhibition or cell loss caused by sodium azide. Inter-regional correlations of brain metabolic activity suggested that rats treated with MB were using a different, but equally efficient, strategy for memory retrieval. This animal model of C.O. hypometabolism in the PCC can provide information to understand the mechanisms that regulate early pathological degeneration and reveal new therapeutic strategies aimed at reducing or preventing cognitive decline. Studies of low dose MB in humans are needed to examine its effects in AD patients.

Diss. Linköping : Univ., 2001.

No description available.

Epilepsia é uma desordem neurológica que afeta o sistema nervoso central, predispondo o paciente a crises recorrentes, as quais apresentam uma alta demanda energética cerebral, e que culminam na depleção dos níveis de glicose cerebrais conforme a crise epiléptica progride de aguda (até 5 min) à prolongada (de 5 min até algumas horas). A presente tese mapeou os diferentes modelos de crises e síndromes epilépticas com enfoque em peixe-zebra, no intuito de selecionar o melhor modelo em nosso universo experimental para investigar quais outros substratos energéticos poderiam ser utilizados pelo cérebro frente ao hipometabolismo da glicose em crises epilépticas prolongadas induzidas por pentilenotetrazol. Hipotetizou-se um ambiente produtor de peróxido de hidrogênio como agente modulatório do metabolismo energético neste tipo de crise epiléptica. Para tanto se caracterizou o protocolo de respirometria de alta resolução em dissociado cerebral de peixe-zebra adulto. Os peixes foram expostos a pentilenotetrazol por diferentes tempos. Detectou-se um desacoplamento entre o metabolismo da glicose e o consumo de O2 para produção de ATP em crises epilépticas prolongadas de 20 min. Neste momento, testou-se o impacto dos seguintes substratos energéticos sobre o consumo de O2 para produção de ATP: L-glutamato, L-glutamina, L-lactato, e β-hidroxibutirato. Também foi avaliado o sistema pró/antioxidante em amostras de cérebro de peixe-zebra adulto submetido a crises epilépticas prolongadas por 20 min (CEUA – 28043). Os resultados indicam o uso do L-glutamato e da L-glutamina como substratos energéticos para a manutenção de crises epilépticas prolongadas, e um ambiente favorável à produção de peróxido de hidrogênio, pela redução da atividade do Complexo I mitocondrial, pelo aumento da atividade das enzimas superóxido dismutase e glutationa peroxidase, e pelo aumento da oxidação de diclorofluoresceína. A literatura aponta para uma inibição da glicerol-3-fosfato-desidrogenase e piruvato-cinase, e uma ativação da glicose-6-fosfato-desidrogenase por aumento de peróxido de hidrogênio, o que culmina na diminuição da utilização da glicose como substrato energético. A completa oxidação do glutamato na presença de baixos níveis de piruvato ocorre via saída do malato da matriz mitocondrial e sua conversão a piruvato pela enzima málica. Ambas as enzimas produtoras de Fosfato de dinucleótido de nicotinamida e adenina reduzida citadas acimas apresentam atividade aumentada no modelo de convulsão abordado. Portanto, o metabolismo glutamatérgico é fundamental para a manutenção energética, e para a atividade de defesas antioxidantes em momentos de crises epilépticas prolongadas induzidas por pentilenotetrazol em peixe zebra adulto. / Epilepsy is a brain disorder, which promotes the predisposition to events of high energy expenditure known as epileptic seizure. As epileptic seizure progress form acute (until 5 min of duration) to prolonged (above 5 min of duration), lower is the concentration of glucose in the brain. This thesis mapped all models of zebrafish epileptic seizure and epileptic syndrome to choose the best model in our experimental conditions to evaluate the impact of other substrates under glucose brain hypometabolism related to prolonged epileptic seizure induced by pentylenetetrazole. It was hypothesized that an environment with high concentrations of hydrogen peroxide could be connecting with the fast metabolic modulation in this model. To do so, the highresolution respirometry protocol for zebrafish brain dissociated was characterized. Fish were exposed to pentylenetetrazole by different duration. There was a decoupling between glucose brain metabolism and O2 consumption to ATP synthesis after 20 min of exposure to pentylenetetrazole. At this moment, the impact of the following substrates were measured under O2 consume to ATP synthesis: L-glutamate, L-glutamine, L-lactate, and β-hydroxybutyrate. The redox balanced was evaluated as well (CEUA – 28043). Data indicate L-glutamate and L-glutamine as the main energy substrate to maintain prolonged epileptic seizure. There was an environment prone to hydrogen peroxide, because mitochondrial complex I activity was impered, and the enzymes superoxide dismutase and glutamine peroxidase were activity, as well as the oxidation of diclorofluoresceine was increased. Hydrogen peroxide activates glucose-6-phosphate-dehydrogenase, and inhibits glycerol-3-phosphatedehydroganase as well as piruvate kinase. Therefore the glucose metabolism would be modulated to antioxidant defense instead of glycolysis. In low pyruvate concentrations, malate from glutamate is transported to the cytosol and converted to pyruvate and Nicotinamide adenine dinucleotide phosphate. The activity of glucose-6- phosphate-dehydrogenase and citosolic malic enzyme were increased. Therefore, glutamate metabolismo is imperative to energy maintain prolonged epileptic seizure and to antioxidante defense to avoid further damage.

Epilepsia é uma desordem neurológica que afeta o sistema nervoso central, predispondo o paciente a crises recorrentes, as quais apresentam uma alta demanda energética cerebral, e que culminam na depleção dos níveis de glicose cerebrais conforme a crise epiléptica progride de aguda (até 5 min) à prolongada (de 5 min até algumas horas). A presente tese mapeou os diferentes modelos de crises e síndromes epilépticas com enfoque em peixe-zebra, no intuito de selecionar o melhor modelo em nosso universo experimental para investigar quais outros substratos energéticos poderiam ser utilizados pelo cérebro frente ao hipometabolismo da glicose em crises epilépticas prolongadas induzidas por pentilenotetrazol. Hipotetizou-se um ambiente produtor de peróxido de hidrogênio como agente modulatório do metabolismo energético neste tipo de crise epiléptica. Para tanto se caracterizou o protocolo de respirometria de alta resolução em dissociado cerebral de peixe-zebra adulto. Os peixes foram expostos a pentilenotetrazol por diferentes tempos. Detectou-se um desacoplamento entre o metabolismo da glicose e o consumo de O2 para produção de ATP em crises epilépticas prolongadas de 20 min. Neste momento, testou-se o impacto dos seguintes substratos energéticos sobre o consumo de O2 para produção de ATP: L-glutamato, L-glutamina, L-lactato, e β-hidroxibutirato. Também foi avaliado o sistema pró/antioxidante em amostras de cérebro de peixe-zebra adulto submetido a crises epilépticas prolongadas por 20 min (CEUA – 28043). Os resultados indicam o uso do L-glutamato e da L-glutamina como substratos energéticos para a manutenção de crises epilépticas prolongadas, e um ambiente favorável à produção de peróxido de hidrogênio, pela redução da atividade do Complexo I mitocondrial, pelo aumento da atividade das enzimas superóxido dismutase e glutationa peroxidase, e pelo aumento da oxidação de diclorofluoresceína. A literatura aponta para uma inibição da glicerol-3-fosfato-desidrogenase e piruvato-cinase, e uma ativação da glicose-6-fosfato-desidrogenase por aumento de peróxido de hidrogênio, o que culmina na diminuição da utilização da glicose como substrato energético. A completa oxidação do glutamato na presença de baixos níveis de piruvato ocorre via saída do malato da matriz mitocondrial e sua conversão a piruvato pela enzima málica. Ambas as enzimas produtoras de Fosfato de dinucleótido de nicotinamida e adenina reduzida citadas acimas apresentam atividade aumentada no modelo de convulsão abordado. Portanto, o metabolismo glutamatérgico é fundamental para a manutenção energética, e para a atividade de defesas antioxidantes em momentos de crises epilépticas prolongadas induzidas por pentilenotetrazol em peixe zebra adulto. / Epilepsy is a brain disorder, which promotes the predisposition to events of high energy expenditure known as epileptic seizure. As epileptic seizure progress form acute (until 5 min of duration) to prolonged (above 5 min of duration), lower is the concentration of glucose in the brain. This thesis mapped all models of zebrafish epileptic seizure and epileptic syndrome to choose the best model in our experimental conditions to evaluate the impact of other substrates under glucose brain hypometabolism related to prolonged epileptic seizure induced by pentylenetetrazole. It was hypothesized that an environment with high concentrations of hydrogen peroxide could be connecting with the fast metabolic modulation in this model. To do so, the highresolution respirometry protocol for zebrafish brain dissociated was characterized. Fish were exposed to pentylenetetrazole by different duration. There was a decoupling between glucose brain metabolism and O2 consumption to ATP synthesis after 20 min of exposure to pentylenetetrazole. At this moment, the impact of the following substrates were measured under O2 consume to ATP synthesis: L-glutamate, L-glutamine, L-lactate, and β-hydroxybutyrate. The redox balanced was evaluated as well (CEUA – 28043). Data indicate L-glutamate and L-glutamine as the main energy substrate to maintain prolonged epileptic seizure. There was an environment prone to hydrogen peroxide, because mitochondrial complex I activity was impered, and the enzymes superoxide dismutase and glutamine peroxidase were activity, as well as the oxidation of diclorofluoresceine was increased. Hydrogen peroxide activates glucose-6-phosphate-dehydrogenase, and inhibits glycerol-3-phosphatedehydroganase as well as piruvate kinase. Therefore the glucose metabolism would be modulated to antioxidant defense instead of glycolysis. In low pyruvate concentrations, malate from glutamate is transported to the cytosol and converted to pyruvate and Nicotinamide adenine dinucleotide phosphate. The activity of glucose-6- phosphate-dehydrogenase and citosolic malic enzyme were increased. Therefore, glutamate metabolismo is imperative to energy maintain prolonged epileptic seizure and to antioxidante defense to avoid further damage.

Epilepsia é uma desordem neurológica que afeta o sistema nervoso central, predispondo o paciente a crises recorrentes, as quais apresentam uma alta demanda energética cerebral, e que culminam na depleção dos níveis de glicose cerebrais conforme a crise epiléptica progride de aguda (até 5 min) à prolongada (de 5 min até algumas horas). A presente tese mapeou os diferentes modelos de crises e síndromes epilépticas com enfoque em peixe-zebra, no intuito de selecionar o melhor modelo em nosso universo experimental para investigar quais outros substratos energéticos poderiam ser utilizados pelo cérebro frente ao hipometabolismo da glicose em crises epilépticas prolongadas induzidas por pentilenotetrazol. Hipotetizou-se um ambiente produtor de peróxido de hidrogênio como agente modulatório do metabolismo energético neste tipo de crise epiléptica. Para tanto se caracterizou o protocolo de respirometria de alta resolução em dissociado cerebral de peixe-zebra adulto. Os peixes foram expostos a pentilenotetrazol por diferentes tempos. Detectou-se um desacoplamento entre o metabolismo da glicose e o consumo de O2 para produção de ATP em crises epilépticas prolongadas de 20 min. Neste momento, testou-se o impacto dos seguintes substratos energéticos sobre o consumo de O2 para produção de ATP: L-glutamato, L-glutamina, L-lactato, e β-hidroxibutirato. Também foi avaliado o sistema pró/antioxidante em amostras de cérebro de peixe-zebra adulto submetido a crises epilépticas prolongadas por 20 min (CEUA – 28043). Os resultados indicam o uso do L-glutamato e da L-glutamina como substratos energéticos para a manutenção de crises epilépticas prolongadas, e um ambiente favorável à produção de peróxido de hidrogênio, pela redução da atividade do Complexo I mitocondrial, pelo aumento da atividade das enzimas superóxido dismutase e glutationa peroxidase, e pelo aumento da oxidação de diclorofluoresceína. A literatura aponta para uma inibição da glicerol-3-fosfato-desidrogenase e piruvato-cinase, e uma ativação da glicose-6-fosfato-desidrogenase por aumento de peróxido de hidrogênio, o que culmina na diminuição da utilização da glicose como substrato energético. A completa oxidação do glutamato na presença de baixos níveis de piruvato ocorre via saída do malato da matriz mitocondrial e sua conversão a piruvato pela enzima málica. Ambas as enzimas produtoras de Fosfato de dinucleótido de nicotinamida e adenina reduzida citadas acimas apresentam atividade aumentada no modelo de convulsão abordado. Portanto, o metabolismo glutamatérgico é fundamental para a manutenção energética, e para a atividade de defesas antioxidantes em momentos de crises epilépticas prolongadas induzidas por pentilenotetrazol em peixe zebra adulto. / Epilepsy is a brain disorder, which promotes the predisposition to events of high energy expenditure known as epileptic seizure. As epileptic seizure progress form acute (until 5 min of duration) to prolonged (above 5 min of duration), lower is the concentration of glucose in the brain. This thesis mapped all models of zebrafish epileptic seizure and epileptic syndrome to choose the best model in our experimental conditions to evaluate the impact of other substrates under glucose brain hypometabolism related to prolonged epileptic seizure induced by pentylenetetrazole. It was hypothesized that an environment with high concentrations of hydrogen peroxide could be connecting with the fast metabolic modulation in this model. To do so, the highresolution respirometry protocol for zebrafish brain dissociated was characterized. Fish were exposed to pentylenetetrazole by different duration. There was a decoupling between glucose brain metabolism and O2 consumption to ATP synthesis after 20 min of exposure to pentylenetetrazole. At this moment, the impact of the following substrates were measured under O2 consume to ATP synthesis: L-glutamate, L-glutamine, L-lactate, and β-hydroxybutyrate. The redox balanced was evaluated as well (CEUA – 28043). Data indicate L-glutamate and L-glutamine as the main energy substrate to maintain prolonged epileptic seizure. There was an environment prone to hydrogen peroxide, because mitochondrial complex I activity was impered, and the enzymes superoxide dismutase and glutamine peroxidase were activity, as well as the oxidation of diclorofluoresceine was increased. Hydrogen peroxide activates glucose-6-phosphate-dehydrogenase, and inhibits glycerol-3-phosphatedehydroganase as well as piruvate kinase. Therefore the glucose metabolism would be modulated to antioxidant defense instead of glycolysis. In low pyruvate concentrations, malate from glutamate is transported to the cytosol and converted to pyruvate and Nicotinamide adenine dinucleotide phosphate. The activity of glucose-6- phosphate-dehydrogenase and citosolic malic enzyme were increased. Therefore, glutamate metabolismo is imperative to energy maintain prolonged epileptic seizure and to antioxidante defense to avoid further damage.

Les traumatismes crâniens (TC) représentent la première cause de décès ou de handicap avant l'âge de 45 ans, avec une incidence en Europe de 235/100 000 habitants. Chez les patients survivant à un TC, les séquelles sont fréquentes allant de l'état végétatif chronique au syndrome post-concussionnel compliquant principalement la réinsertion socio professionnelle et familiale des victimes. Cependant la nature des lésions cérébrales provoquées par un TC est encore mal connue et les thérapies susceptibles d'empêcher la progression des lésions neurologiques sont très limitées. Un TC provoque d'abord des lésions directement dues à l'impact (lésions primaires). D'autres mécanismes secondaires vont avoir lieu dès les premières minutes suivant le TC et peuvent évoluer sur plusieurs jours. Elles sont susceptibles d'être atténuées par une thérapeutique appropriée et sont donc l'objet de la plupart des efforts de recherche actuels. Néanmoins, notre connaissance de ces phénomènes d'agression primaires et secondaires, est incomplète et ne permet pas d'expliquer correctement l'évolution des TC. Les dépolarisations corticales envahissantes (DCE) ou cortical spreading depolarizations””sont un des évènements délétères contribuant aux lésions secondaires consécutives au TC. Les DCE sont des vagues de dépolarisation massive associées à un mauvais pronostic. Elles sont caractérisées par une dépression de l'activité electrocorticographique et une dépolarisation des neurones corticaux et des astrocytes qui se propagent sur le cortex. Les DCE s'accompagnent d'une augmentation des besoins métaboliques visant à restituer au tissu son état d'homéostasie neurochimique et de polarisation cellulaire. Les conséquences des DCE sur le métabolisme cérébral sont encore mal connues aussi bien sur un tissu sain qu'après agression cérébrale. Il existe des arguments pour penser que l'incidence, le nombre et la durée des DCE sont associés à un moins bon pronostic chez l'homme après agression cérébrale. Cependant, les mécanismes par lesquels ces DCE auraient une toxicité directe reposent encore sur des arguments le plus souvent indirects et sont mal compris. L'objectif principal de ce travail de thèse a été de caractériser les conséquences neurochimiques et micro-vasculaires des DCE afin de mieux comprendre leur physiopathologie dans un cortex sain ou agressé par un TC sévère / “Traumatic brain injury” (TBI) encompasses a heterogeneous group of physio-pathological phenomenon. Prognosis, clinical course evaluation and treatment of brain trauma remain challenging. Brain damage results from both the initial physical insult (primary injury), and also continues to occur in the ensuing hours to days because of secondary brain aggressions. Among secondary injuries following TBI, Cortical Spreading Depolarizations (CSD) have emerged since the mid-90s. CSD are waves of depolarization propagating along the cortex at a speed of 1-5 mm/min that induced a massive energetic demand to repolarize the cells. CSD are participating to prognosis because their occurrence and duration are related to outcome in different acute brain injuries (TBI, sub-arachnoid hemorrhage and ischemic stroke). During my thesis, our main goal was to determine whether the CSD reinforced neuronal death following brain trauma that can explain the poor prognosis. In a first study we delineated brain regions where neuronal death occurs following lateral fluid percussion injury (LFPI) in order to record CSDs in this area. Then, as we wanted to assess the energetic balance of this tissue during CSD using biosensors, we had primarily to check for the biosensor reliability to oxygen (O2) and temperature (To). As oxygen and temperature were different from bench (in vitro) to bedside (in vivo) monitoring, we developed algorithms to compute offline the in vivo values obtained for glucose, lactate or glutamate brain concentrations respecting the local O2 concentrations and To measured in the cortex. Finally, using the biosensors, we described the dynamic real time metabolic changes occurring after CSDs in 3 conditions: A healthy cortex, an injured cortex after LFPI, and when CSD occurred in cluster after LFPI. Although the normal brain displayed a hyper-glycolytic state following CSD (transient low glucose concentrations + prolonged elevated lactate concentrations), TBI tissue exhibited a different pattern that could be metabolic crisis (very low glucose concentrations + normal to low lactateconcentrations)