Alterations in Cerebral Oxygen Metabolism after Traumatic Brain Injury in Children

Ragan, Dustin K.; McKinstry, Robert C.; Benzinger, Tammie L.S.; Leonard, Jeffrey R.; Pineda, José

doi:10.1038/jcbfm.2012.130

Cited by 29 publications

(17 citation statements)

References 61 publications

(80 reference statements)

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“…This physiologic mechanism linking increased blood flow to neurometabolic demand is known as neurovascular coupling, and is well preserved in normal physiology. However, neurovascular coupling becomes disrupted in many common pathologies including hypertension, ischemic stroke [7], traumatic brain injury [8], obstructive sleep apnea [9] and Alzheimer’s disease [10]. The cerebrovascular dysregulation in many of these disorders is believed to be mediated by the deleterious action of reactive oxygen species on cerebral blood vessels [11].…”

Section: Brain Oxygen Metabolismmentioning

confidence: 99%

Time-Resolved MRI Oximetry for Quantifying CMRO2 and Vascular Reactivity

Wehrli¹,

Rodgers²,

Jain³

et al. 2014

Academic Radiology

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This brief review of magnetic resonance susceptometry summarizes the methods conceived in the authors' laboratory during the past several years. It is shown how venous oxygen saturation is quantified in large draining veins by field mapping and how this information, in concert with simultaneous measurement of cerebral blood flow, yields CMRO 2 , the brain's rate of oxygen consumption. The accuracy of this model-based approach in which the blood vessel is approximated as a long, straight cylinder, for which an analytical solution for the induced field exists, is discussed. It is shown that the approach is remarkably robust, allowing for time-resolved quantification of whole-brain metabolism at rest and in response to stimuli, thereby providing detailed information on cerebral physiology in health and disease not previously amenable by noninvasive methods. Brain Oxygen MetabolismThe human brain accounts for only 2% of the body's weight but 20% of the body's total energy requirement (see, for example, [1]). This enormous energy demand, necessary to maintain the default mode of brain activity, is incompletely understood. Oxygen consumption, typically quantified as the cerebral metabolic rate of oxygen (CMRO 2 ), has been measured in various ways, most typically by positron emission tomography (PET), which yielded values on the order of 130 μmol/min/100g [2] in the resting awake state. Even during light sleep CMRO 2 is only insignificantly lower [3], and only in deep sleep [4], and more so during anesthesia [5], is energy demand substantially lower. Further, incremental CMRO 2 increases in response to mental tasks have been found to be minor relative to the brain's baseline demand. The brain's default-mode energy demand is satisfied by oxidation of glucose to water and carbon dioxide. The resulting free energy generates ATP, the body's universal currency of energy. In contrast, incremental demand during task activation is supplied via the glycolytic pathway of glucose oxidation.The ratio of the oxygen consumed over the oxygen supplied by blood flow (oxygen extraction fraction, OEF) has been found to be largely independent of the region of the brain in which it is measured [2]. Even though oxygen consumption of gray matter is four to five times greater than that of white matter, the greater oxygen demand is offset by a commensurate increase in the rate of delivery in the form of cerebral blood flow. Once OEF

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Section: Brain Oxygen Metabolismmentioning

confidence: 99%

Time-Resolved MRI Oximetry for Quantifying CMRO2 and Vascular Reactivity

Wehrli¹,

Rodgers²,

Jain³

et al. 2014

Academic Radiology

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“…Axonal shear stretch leads to the opening of voltage-gated calcium channels that, ultimately, precipitates mitochondrial dysfunction, bioenergetic failure, and the release of secondary messengers that end in apoptosis and death (Balan et al, 2013; Glenn et al, 2003; Lifshitz et al, 2003; Marcoux et al, 2008; Ragan et al, 2013; Xu et al, 2010). Thus, mitochondria play a central role in cerebral metabolism and regulation of oxidative stress, excitotoxicity, and apoptosis in acute brain injury; however, the mechanistic response and time course following diffuse TBI, especially in the immature brain at differing developmental stages, has limit investigation (Balan et al, 2013; Gilmer et al, 2010; Lifshitz et al, 2004; Robertson et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

et al. 2016

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Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. The response of mitochondria in the pediatric brain to injury has limited investigation, despite evidence that developing brain’s response differs from the adult, especially in diffuse non-impact TBI. We perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 4O) respiration was increased in both hippocampal and cortical tissue, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24 hours. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. In addition, mitochondrial respiration 24 hours after diffuse TBI that varies by location within the brain. Finally, we conclude that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain.

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“…TBI precipitates a complex, secondary pathophysiological process which can result in a cascade of deleterious side effects often far from the site of the initial injury, and which places tissue that survives the initial insult at risk for functional failure, neurodegeneration, apoptosis, and death (Hattori et al, 2003; Marcoux et al, 2008b; Ragan et al, 2013; Xu et al, 2010). A growing body of literature suggests that a main component of this secondary injury cascade is altered mitochondrial bioenergetics and cerebral metabolic crisis (Gilmer et al, 2009; Robertson et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria play a pivotal role in cerebral metabolism and regulation of oxidative stress, excitotoxicity, and apoptosis (Balan et al, 2013; Gilmer et al, 2009; Lifshitz et al, 2003; Robertson, 2004). Cerebral metabolic crisis displays regional heterogeneity, varies temporally post-injury and with gradation of injury severity, and is often sustained for a prolonged period of time (Lifshitz et al, 2003; Marcoux et al, 2008b; Ragan et al, 2013; Robertson et al, 2006, 2009; Saito et al, 2005). Unfortunately, despite evidence that such processes may vary significantly with maturation, response to cerebral metabolic and mitochondrial alterations following TBI in the immature brain is not well defined (Kilbaugh et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

Kilbaugh

Karlsson

Byro

et al. 2015

Experimental Neurology

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Traumatic brain injury (TBI) is one of the leading causes of death in children worldwide. Emerging evidence suggests that alterations in mitochondrial function are critical components of secondary injury cascade initiated by TBI that propogates neurodegeneration and limits neuroregeneration. Unfortunately, there is very little known about the cerebral mitochondrial bioenergetic response from the immature brain triggered by traumatic biomechanical forces. Therefore, the objective of this study was to perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a high-fidelity large animal model of focal controlled cortical impact injury (CCI) 24 h post-injury. This novel approach is directed at analyzing dysfunction in electron transport, ADP phosphorylation and leak respiration to provide insight into potential mechanisms and possible interventions for mitochondrial dysfunction in the immature brain in focal TBI by delineating targets within the electron transport system (ETS). Development and application of these methodologies have several advantages, and adds to the interpretation of previously reported techniques, by having the added benefit that any toxins or neurometabolites present in the ex-vivo samples are not removed during the mitochondrial is olation process, and simulates the in situ tricarboxylic acid (TCA) cycle by maximizing key substrates for convergent flow of electrons through both complexes I and II. To investigate alterations in mitochondrial function after CCI, ipsilateral tissue near the focal impact site and tissue from the corresponding contralateral side were examined. Respiration per mg of tissue was also related to citrate synthase activity (CS) and calculated flux control ratios (FCR), as an attempt to control for variability in mitochondrial content. Our biochemical analysis of complex interdependent pathways of electron flow through the electron transport system, by most measures, reveals a bilateral decrease in complex I-driven respiration and an increase in complex II-driven respiration 24 h after focal TBI. These alterations in convergent electron flow though both complex I and II-driven respiration resulted in significantly lower maximal coupled and uncoupled respiration in the ipsilateral tissue compared to the contralateral side, for all measures. Surprisingly, increases in complex II and complex IV activities were most pronounced in the contralateral side of the brain from the focal injury, and where oxidative phosphorylation was increased significantly compared to sham values. We conclude that 24 h after focal TBI in the immature brain, there are significant alterations in cerebral mitochondrial bioenergetics, with pronounced increases in complex II and complex IV respiration in the contralateral hemisphere. These alterations in mitochondrial bioenergetics present multiple targets for therapeutic intervention to limit secondary brain injury and support recovery.

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Alterations in Cerebral Oxygen Metabolism after Traumatic Brain Injury in Children

Cited by 29 publications

References 61 publications

Time-Resolved MRI Oximetry for Quantifying CMRO2 and Vascular Reactivity

Time-Resolved MRI Oximetry for Quantifying CMRO2 and Vascular Reactivity

Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

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