Global and regional brain metabolic scaling and its functional consequences

Background: Information processing in the brain requires large amounts of metabolic energy, the spatial distribution of which is highly heterogeneous reflecting complex activity patterns in the mammalian brain. Results: Here, it is found based on empirical data that, despite this heterogeneity, the volume-specific cerebral glucose metabolic rate of many different brain structures scales with brain volume with almost the same exponent around -0.15. The exception is white matter, the metabolism of which seems to scale with a standard specific exponent -1/4. The scaling exponents for the total oxygen and glucose consumptions in the brain in relation to its volume are identical and equal to $0.86\pm 0.03$, which is significantly larger than the exponents 3/4 and 2/3 suggested for whole body basal metabolism on body mass. Conclusions: These findings show explicitly that in mammals (i) volume-specific scaling exponents of the cerebral energy expenditure in different brain parts are approximately constant (except brain stem structures), and (ii) the total cerebral metabolic exponent against brain volume is greater than the much-cited Kleiber's 3/4 exponent. The neurophysiological factors that might account for the regional uniformity of the exponents and for the excessive scaling of the total brain metabolism are discussed, along with the relationship between brain metabolic scaling and computation.Comment: Brain metabolism scales with its mass well above 3/4 exponen

Magnetic resonance spectroscopy in migraine: what have we learned so far?

Objective: To summarize and evaluate proton (H-1) and phosphorus (P-31) magnetic resonance spectroscopy (MRS) findings in migraine. Methods: A thorough review of H-1 and/or P-31-MRS studies in any form of migraine published up to September 2011. Results: Some findings were consistent in all studies, such as a lack of ictal/interictal brain pH change and a disturbed energy metabolism, the latter of which is reflected in a drop in phosphocreatine content, both in the resting brain and in muscle following exercise. In a recent interictal study ATP was found to be significantly decreased in the occipital lobe of migraine with aura patients, reinforcing the concept of a mitochondrial component to the migraine threshold, at least in a subgroup of patients. In several studies a correlation between the extent of the energy disturbance and the clinical phenotype severity was apparent. Less consistent but still congruent with a disturbed energy metabolism is an observed lactate increase in the occipital cortex of several migraine subtypes (MwA, migraine with prolonged aura). No increases in brain glutamate levels were found. Conclusion: The combined abnormalities found in MRS studies imply a mitochondrial component in migraine neurobiology. This could be due to a primary mitochondrial dysfunction or be secondary to, for example, alterations in brain excitability. The extent of variation in the data can be attributed to both the variable clinical inclusion criteria used and the variation in applied methodology. Therefore it is necessary to continue to optimize MRS methodology to gain further insights, especially concerning lactate and glutamate

Brain glycogen—new perspectives on its metabolic function and regulation at the subcellular level

Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia. In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies—it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms underlying glycogen metabolism. Based on (1) the compartmentation of the interconnected second messenger pathways controlling glycogen metabolism (calcium and cAMP), (2) alterations in the subcellular location of glycogen-associated enzymes and proteins induced by the metabolic status and (3) a sequential component in the intermolecular mechanisms of glycogen metabolism, we suggest that glycogen metabolism in astrocytes is compartmentalized at the subcellular level. As a consequence, the meaning and importance of conventional terms used to describe glycogen metabolism (e.g., turnover) is challenged. Overall, this review represents an overview of contemporary knowledge about brain glycogen and its metabolism and function. However, it also has a sharp focus on what we do not know, which is perhaps even more important for the future quest of uncovering the roles of glycogen in brain physiology and pathology

Energy metabolisme and brain damage:Investigations by positron emission tomography (PET); the role of ketone bodies in cerebral protection

In a general sense this thesis comprises three subjects: a) the changes in energy metabolism of the brain during cerebral pathology, b) the effect of alterations in energy metabolism on the extent of brain damage, and c) measures to prevent or limit brain damage. In this context the formation of brain damage and possible restorative processes are studied in two models of cerebral pathology: a) a (modified) Levine model of hypoxic and ischemic brain damage in rats, and b) the freezing lesion in cats; the latter is a model of disruption of the blood-brain barrier (BBB) and formation of vasogenic brain edema. Furthermore, some methods to protect the brain against (hypoxic-ischemic) brain damage are evaluated. ... Zie: Summar

Human neuromaturation, juvenile extreme energy liability, and adult cognition/cooperation

Human childhood and adolescence is the period in which adult cognitive competences (including those that create the unique cooperativeness of humans) are acquired. It is also a period when neural development puts a juvenile’s survival at risk due to the high vulnerability of their brain to energy shortage. The brain of a 4 year-old human uses ≈50% of its total energy expenditure (TEE) (cf. adult ≈12%). This brain expensiveness is due to (1) the brain making up ≈6% of a 4 year-old body compared to 2% in an adult, and (2) increased energy metabolism that is ≈100% greater in the gray matter of a child than in an adult (a result of the extra costs of synaptic neuromaturation). The high absolute number of neurons in the human brain requires as part of learning a prolonged neurodevelopment. This refines inter- and intraarea neural networks so they become structured with economical “small world” connectivity attributes (such as hub organization and high cross-brain differentiation/integration). Once acquired, this connectivity enables highly complex adult cognitive capacities. Humans evolved as hunter-gatherers. Contemporary hunter-gatherers (and it is also likely Middle Paleolithic ones) pool high energy foods in an egalitarian manner that reliably supported mothers and juveniles with high energy intake. This type of sharing unique to humans protects against energy shortage happening to the immature brain. This cooperation that protects neuromaturation arises from adults having the capacity to communicate and evaluate social reputation, cognitive skills that exist as a result of extended neuromaturation. Human biology is therefore characterized by a presently overlooked bioenergetic-cognition loop (called here the “HEBE ring”) by which extended neuromaturation creates the cooperative abilities in adults that support juveniles through the potentially vulnerable period of the neurodevelopment needed to become such adults

Cerebral Energy Metabolism: Measuring and Understanding Its Rate

The study of brain energy metabolism has taken second place to that of muscle ever since the dawn of this field of research. Consequently, each new discovery made using muscle tissue that advanced our understanding of the biochemistry of energy metabolic processes was attempted to be duplicated in brain tissue. It was only when the brain\u27s high energy needs were recognized that researchers realized its vulnerability to any mishap in its energy supplies and that this vulnerability may play a role in various brain disorders. Understanding of the mechanisms by which the brain deals with energy shortage is of utmost importance in shedding light on the fundamentals of brain disorders and their potential treatment. To achieve such understanding, accurate measurement of brain energy metabolic rates is necessary. This chapter summarizes the history of the current knowledge of the biochemical processes responsible for the production of adenosine triphosphate (ATP) in the brain. It briefly reviews the various techniques used to measure cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRglucose), and elaborates on the potential of measuring the cerebral metabolic rate of lactate (CMRlactate) to improve our understanding of brain energy metabolism

Sleep deprivation and brain energy metabolism : in vivo studies in rats and humans

Sleep deprivation leads to increased subsequent sleep length and depth and to deficits in cognitive performance in humans. In animals extreme sleep deprivation is eventually fatal. The cellular and molecular mechanisms causing the symptoms of sleep deprivation are unclear. This thesis was inspired by the hypothesis that during wakefulness brain energy stores would be depleted, and they would be replenished during sleep. The aim of this thesis was to elucidate the energy metabolic processes taking place in the brain during sleep deprivation. Endogenous brain energy metabolite levels were assessed in vivo in rats and in humans in four separate studies (Studies I-IV). In the first part (Study I) the effects of local energy depletion on brain energy metabolism and sleep were studied in rats with the use of in vivo microdialysis combined with high performance liquid chromatography. Energy depletion induced by 2,4-dinitrophenol infusion into the basal forebrain was comparable to the effects of sleep deprivation: both increased extracellular concentrations of adenosine, lactate, and pyruvate, and elevated subsequent sleep. This result supports the hypothesis of a connection between brain energy metabolism and sleep. The second part involved healthy human subjects (Studies II-IV). Study II aimed to assess the feasibility of applying proton magnetic resonance spectroscopy (1H MRS) to study brain lactate levels during cognitive stimulation. Cognitive stimulation induced an increase in lactate levels in the left inferior frontal gyrus, showing that metabolic imaging of neuronal activity related to cognition is possible with 1H MRS. Study III examined the effects of sleep deprivation and aging on the brain lactate response to cognitive stimulation. No physiologic, cognitive stimulation-induced lactate response appeared in the sleep-deprived and in the aging subjects, which can be interpreted as a sign of malfunctioning of brain energy metabolism. This malfunctioning may contribute to the functional impairment of the frontal cortex both during aging and sleep deprivation. Finally (Study IV), 1H MRS major metabolite levels in the occipital cortex were assessed during sleep deprivation and during photic stimulation. N-acetyl-aspartate (NAA/H2O) decreased during sleep deprivation, supporting the hypothesis of sleep deprivation-induced disturbance in brain energy metabolism. Choline containing compounds (Cho/H2O) decreased during sleep deprivation and recovered to alert levels during photic stimulation, pointing towards changes in membrane metabolism, and giving support to earlier observations of altered brain response to stimulation during sleep deprivation. Based on these findings, it can be concluded that sleep deprivation alters brain energy metabolism. However, the effects of sleep deprivation on brain energy metabolism may vary from one brain area to another. Although an effect of sleep deprivation might not in all cases be detectable in the non-stimulated baseline state, a challenge imposed by cognitive or photic stimulation can reveal significant changes. It can be hypothesized that brain energy metabolism during sleep deprivation is more vulnerable than in the alert state. Changes in brain energy metabolism may participate in the homeostatic regulation of sleep and contribute to the deficits in cognitive performance during sleep deprivation.Valvotus lisää korvausunen määrää ja johtaa ihmisillä kognitiivisen suorituskyvyn heikkenemiseen. Eläimillä on havaittu äärimmilleen pitkitetyn valvotuksen johtavan lopulta kuolemaan. Unen puutteen aiheuttamien oireiden taustalla olevat solu- ja molekyylitason mekanismit tunnetaan puutteellisesti. Väitöskirja Sleep deprivation and brain energy metabolism in vivo studies in rats and humans on saanut innoituksensa hypoteesista, jonka mukaan aivojen energiavarastot ehtyisivät valveen ja palautuisivat ennalleen unen aikana. Työssä tutkittiin aivojen energia-aineenvaihdunnan muutoksia valvotuksen aikana rotilla ja ihmisillä. Ensimmäisessä osatyössä tutkittiin aivojen paikallisen energiavajeen vaikutuksia rottien uneen ja aivojen energia-aineenvaihduntaan. Kokeellinen energiavaje etuaivojen pohjaosissa oli verrattavissa unen puutteen vaikutuksiin: molemmat aiheuttivat energia-aineenvaihduntatuotteiden (adenosiinin, laktaatin ja pyruvaatin) solunulkoisten pitoisuuksien kasvua sekä korvausunen lisääntymistä. Muissa osatöissä tutkittiin ihmisiä. Toisessa osatyössä todettiin protonispektroskopialla (1H MRS) kognitiivisen tehtävän suorittamisen nostavan terveiden aivojen laktaattipitoisuutta paikallisesti vasemmassa otsalohkossa (ns. laktaattivaste). Kolmannessa osatyössä todettiin, että tämä laktaattivaste ei tule esiin ikääntyvillä eikä valvotetuilla koehenkilöillä. Voidaan tulkita, että laktaattivasteen puuttuminen johtuu normaalin energia-aineenvaihdunnan häiriintymisestä. Pitkittyneen valveen sekä ikääntymisen aikana havaitut otsalohkon toiminnan häiriöt saattavat osin selittyä tämän havainnon pohjalta. Viimeisessä osatyössä todettiin näköaivokuoren N-asetyyliaspartaattipitoisuuden laskevan unen puutteen aikana, mikä tukee hypoteesia unen puutteen aikaisesta aivojen energia-aineenvaihdunnan häiriöstä. Myös koliiniyhdisteiden määrä näköaivokuorella laski unen puutteen aikana mutta palautui lähtötasolle näköärsytyksen myötä. Jälkimmäinen havainto viittaa solukalvojen aineenvaihdunnan muutoksiin unen puutteen aikana ja tukee aiempia havaintoja aivojen ärsytysvasteen muuttumisesta valvotetuilla koehenkilöillä. Yhteenvetona väitöskirjatyön tulosten perusteella voidaan päätellä, että valvominen muuttaa aivojen energia-aineenvaihduntaa. Unen puutteen vaikutus aivojen energia-aineenvaihduntaan voi kuitenkin vaihdella eri aivoalueiden välillä. Vaikka muutos ei aina tulekaan ilmi lepotilassa, se voi ilmetä kognitiivisen tehtävän suorittamisen tai näköärsytyksen aikana. Voidaan olettaa, että aivojen energia-aineenvaihdunta on unen puutteen aikana haavoittuvaisempi kuin virkeänä. Aivojen energia-aineenvaihdunnan muutokset saattavat osallistua unen säätelyyn sekä vaikuttaa kognitiivisen suorituskyvyn heikkenemiseen unen puutteen aikana

Technical and Comparative Aspects of Brain Glycogen Metabolism.

It has been known for over 50 years that brain has significant glycogen stores, but the physiological function of this energy reserve remains uncertain. This uncertainty stems in part from several technical challenges inherent in the study of brain glycogen metabolism, and may also stem from some conceptual limitations. Factors presenting technical challenges include low glycogen content in brain, non-homogenous labeling of glycogen by radiotracers, rapid glycogenolysis during postmortem tissue handling, and effects of the stress response on brain glycogen turnover. Here, we briefly review aspects of glycogen structure and metabolism that bear on these technical challenges, and discuss ways these can be overcome. We also highlight physiological aspects of glycogen metabolism that limit the conditions under which glycogen metabolism can be useful or advantageous over glucose metabolism. Comparisons with glycogen metabolism in skeletal muscle provide an additional perspective on potential functions of glycogen in brain

Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity

Mild hypothermia in the prevention of brain edema in acute liver failure: mechanisms and clinical prospects

Mild hypothermia (32 degrees C-35 degrees C) reduces intracranial pressure in patients with acute liver failure and may offer an effective adjunct therapy in the management of these patients. Studies in experimental animals suggest that this beneficial effect of hypothermia is the result of a decrease in blood-brain ammonia transfer resulting in improvement in brain energy metabolism and normalization of glutamatergic synaptic regulation. Improvement in brain energy metabolism by hypothermia may result from a reduction in ammonia-induced decrease of brain glucose (pyruvate) oxidation. Restoration of normal glutamatergic synaptic regulation by hypothermia may be the consequence of the removal of ammonia-induced decreases in expression of astrocytic glutamate transporters resulting in normal glutamate neurotransmitter inactivation in brain. Randomized controlled clinical trials of hypothermia are required to further evaluate its clinical impact