Cerebral Energy Utilization Research Articles

Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury

Repeated head injuries are a major public health concern both for athletes, and members of the police and armed forces. There is ample experimental and clinical evidence that there is a period of enhanced vulnerability to subsequent injury following head trauma. Injuries that occur close together in time produce greater cognitive, histological, and behavioral impairments than do injuries separated by a longer period. Traumatic brain injuries alter cerebral glucose metabolism and the resolution of altered glucose metabolism may signal the end of the period of greater vulnerability. Here, we injured mice either once or twice separated by three or 20days. Repeated injuries that were separated by three days were associated with greater axonal degeneration, enhanced inflammatory responses, and poorer performance in a spatial learning and memory task. A single injury induced a transient but marked increase in local cerebral glucose utilization in the injured hippocampus and sensorimotor cortex, whereas a second injury, three days after the first, failed to induce an increase in glucose utilization at the same time point. In contrast, when the second injury occurred substantially later (20days after the first injury), an increase in glucose utilization occurred that paralleled the increase observed following a single injury. The increased glucose utilization observed after a single injury appears to be an adaptive component of recovery, while mice with 2 injuries separated by three days were not able to mount this response, thus this second injury may have produced a significant energetic crisis such that energetic demands outstripped the ability of the damaged cells to utilize energy. These data strongly reinforce the idea that too rapid return to activity after a traumatic brain injury can induce permanent damage and disability, and that monitoring cerebral energy utilization may be a tool to determine when it is safe to return to the activity that caused the initial injury.

Oxidative Neuroenergetics in Event-Related Paradigms

Energetic basis of neural activity provides a solid foundation for noninvasive neuroimaging with calibrated functional magnetic resonance imaging (fMRI). Calculating dynamic changes in cerebral oxidative energy utilization (CMR(O(2))) is limited by uncertainties about whether or not the conventional blood oxygenation level-dependent (BOLD) model can be applied transiently using multimodal measurements of blood flow (CBF) and volume (CBV) that affect the BOLD signal. A prerequisite for dynamic calibrated fMRI is testing the linearity of multimodal signals within a temporal regimen, as assessed by signal strength (i.e., both intensity and width). If each hyperemic component (BOLD, CBV, CBF) is demonstrated to be linear with neural activity under various experimental conditions, then the respective transfer functions generated by deconvolution with neural activity should be time invariant and thus could potentially be used for calculating CMR(O(2)) transients. Hyperemic components were investigated at 11.7 T in alpha-chloralose-anesthetized rats and combined with electrophysiological recordings of local field potential (LFP) and multiunit activity (MUA) from the cortex during forepaw stimulation, in which stimulus number and frequency were varied. Although relationships between neural activity and stimulus features ranged from linear to nonlinear, associations between hyperemic components and neural activity were linear. Specific to each hyperemic component, a universal transfer function (with LFP or MUA) yielded predictions in agreement with experimental measurements. The results identified a component of the BOLD signal that can be attributed to significant changes in CMR(O(2)), even for temporal events separated by <200 ms.

Cerebral glucose metabolism in adults with early treated classic phenylketonuria

Classic phenylketonuria (PKU) is characterized by severe mental retardation in untreated individuals and mild neurocognitive abnormalities in some early treated adults. The exact biochemical mechanisms underlying this neurotoxicity remain undetermined. Several theories implicate abnormal cerebral energy utilization and alterations in biochemical pathways that involve glucose metabolism. This pilot study was undertaken to investigate whether 18F-deoxyglucose positron emission tomography (PET) is an effective tool to study cerebral glucose metabolism in early treated PKU. After PET coregistration with SPGR MRI, relative glucose metabolic rates (rGMR) at the center of standard atlas positions was determined. Repeated measures MANOVA was used to assess regional metabolic differences, which were then correlated with age-specific and day-of-scan plasma phenylalanine and age. Patients with PKU in comparison to controls had decreased rGMR in cortical regions including the prefrontal, somatosensory, and visual cortices, and increased activity in subcortical regions including the striatum and limbic system. Day-of-scan phenylalanine correlated with abnormal activity in subcortical structures, and older age was associated with decreased activity in the prefrontal and visual cortices. The clinical significance of these abnormalities of glucose metabolism in specific areas of the brain remains unknown.

Relationship between brain electrical activity and cortical perfusion in normal subjects

Cerebral glucose uptake and perfusion are accepted as tightly coupled measures of energy utilization in both normal and diseased brain. The coupling of brain electrical activity to perfusion has been demonstrated, however, only in the presence of chronic brain disease. Very few studies have examined the relationship between cerebral electrical activity and energy utilization in normal brain tissue. To clarify this relationship, we performed 33 H 2 15O-positron emission tomography (PET) scans in six normal subjects both at rest and during a simple motor task, and acquired surface-recorded quantitative electroencephalogram (QEEG) data simultaneously with isotope injection. We examined the associations between cerebral perfusion directly underlying each recording electrode and three QEEG measures (absolute power, relative power, and cordance). All EEG measures had moderately strong coupling with perfusion at most frequency bands, although the directions of the associations differed from those previously reported in subjects with stroke or dementia. Of the three QEEG measures examined, cordance had the strongest relationship with perfusion (multiple R 2=0.58). Cordance and PET were equally effective in detecting lateralized activation associated with the motor task, while EEG power did not detect this activation. Electrodes in the concordant state had a significantly higher mean perfusion than those in the discordant state. These results indicate that normal brain electrical activity has a moderately strong association with cerebral perfusion. Cordance may be the most useful QEEG measure for monitoring cerebral perfusion in subjects without chronic brain disease.

Neurophysiologic predictors of treatment response to fluoxetine in major depression

Treatment with antidepressants is marked by heterogeneity of response; predicting individual response to any given agent remains problematic. Neuroimaging studies suggest that response is accompanied by physiologic changes in cerebral energy utilization, but have not provided useful markers at pretreatment baseline. Using quantitative EEG (QEEG) techniques, we investigated pretreatment neurophysiologic features to identify responders and non-responders to fluoxetine. In a double-masked study, 24 adult subjects with current major depression of the unipolar type were studied over 8 weeks while receiving fluoxetine (20 mg QD) or placebo. Neurophysiology was assessed with QEEG cordance, a measure reflecting cerebral energy utilization. Response was determined with rating scales and clinical interview. Subjects were divided into discordant and concordant groups based upon the number of electrodes exhibiting discordance. The concordant group had a more robust response than the discordant group, judged by lower final Hamilton Depression (HAM-D) mean score (8.0±7.5 vs. 19.6±4.7, P=0.01) and final Beck Depression Inventory (BDI) mean score (14.0±9.4 vs. 27.8±3.7, P=0.015), and by faster reduction in symptoms (HAM-D: 14.0±5.0 vs. 23.8±4.1, P=0.004 at 1 week). Groups did not differ on pretreatment clinical or historical features. Response to placebo was not predicted by this physiologic measure. We conclude that cordance distinguishes depressed adults who will respond to treatment with fluoxetine from those who will not. This measure detects a propensity to respond to fluoxetine and may indicate a more general responsiveness to antidepressants.

Altered cerebral energy utilization in late life depression

Background: Global and regional changes in cerebral energy utilization are reported to characterize late life depression. Methods: Twenty seven subjects with late life depression (9 prior to starting medication, 18 after starting) and 27 matched controls were evaluated with cordance, a quantitative EEG measure that reflects cerebral energy utilization. Results: Global and focal (anterior and centrotemporal) differences were present in theta-band cordance between unmedicated depressed and control subjects. Depressed subjects receiving treatment had cordance patterns similar to controls. Conclusions: The presence of both diffuse and focal disturbances in energy utilization prior to initiating treatment indicates that cordance detects altered cerebral physiology in depressed patients, and that this measure may also be sensitive to treatment interventions.

Effect of hypoxia on glucose-modulated cerebral lactic acidosis, agonal glycolytic rates, and energy utilization.

Newborn and 1-mo-old swine were exposed to identical durations (18 min) and degrees of hypoxia (O2 content = 4 mL/dL), to examine the effects of hypoxia on cerebral energy metabolism and intracellular pH (pHi) in vivo, using 31P and 1H nuclear magnetic resonance spectroscopy. Hypoxia produced the same extent of reductions in phosphocreatine (PCr) (63 +/- 28% and 65 +/- 10%, newborns and 1-mo-olds, respectively) and pHi (6.93 +/- 0.06 and 6.89 +/- 0.06, respectively) for either age group. The magnitude of changes in PCr, lactate, and pHi was larger for subgroups of data collected when cardiovascular instability was present, suggesting that hypotension and possibly reduced cerebral perfusion contributed to cerebral energy failure and lactic-acidosis for either age group. There were no correlations between the blood plasma glucose concentration at 18 min of hypoxia and the extent of change in PCr, lactate, or pHi for either age group. During a subsequent period of complete ischemia induced via cardiac arrest after 20 min hypoxia, the decline in PCr and nucleoside triphosphate (NTP), and increase in lactate followed similar rates compared with previously studied age-matched animals that were normoxic before ischemia. The rate constants for the change in PCr, NTP, and lactate followed similar rates compared with previously studied age-matched animals that were normoxic before ischemia. The rate constants for the change in PCr, NTP, and lactate during ischemia showed no correlation with the blood plasma glucose concentration measured immediately before cardiac arrest. These results suggest that cerebral glycolytic rates and energy utilization during ischemia are unaffected by a preceding interval of hypoxia and that hyperglycemia does not delay cerebral energy failure during hypoxia or combined hypoxic-ischemia.

Cerebral Glucose and Energy Utilization during the Evolution of Hypoxic—Ischemic Brain Damage in the Immature Rat

The cerebral metabolic rate for glucose (CMRg1) and cerebral energy utilization (CEU) were assessed in immature rats during recovery from cerebral hypoxia-ischemia. CMRg1 was determined using a modification of the Sokoloff technique with 2-deoxy-[14C]glucose (2-DG) as the radioactive tracer. CEU was determined using the Lowry decapitation technique. Seven-day postnatal rats underwent unilateral common carotid artery ligation, followed 4 h thereafter by exposure to 8% oxygen at 37 degrees C for 3 h. At 1, 4, or 24 h of recovery, the rat pups underwent those procedures necessary for the measurement of either CMRg1 or CEU. At 1 h of recovery, the CMRg1 of the cerebral hemisphere ipsilateral to the carotid artery occlusion was 97% of the control rate (8.7 mumol 100 g-1 min-1) but was only 48% of the control in the contralateral hemisphere. At 4 h of recovery, the CMRg1 was increased 49% above baseline in the ipsilateral hemisphere, decreasing thereafter to 84% of the control at 24 h. The CMRg1 of the contralateral hemisphere normalized by 4 h of recovery. An inverse correlation between endogenous concentrations of ATP or phosphocreatine and CMRg1 in the ipsilateral hemisphere was apparent at 4 h of recovery. CEU in the ipsilateral cerebral hemisphere was 64 and 46% of the control (3.47 mmol approximately P/kg/min) at 1 and 24 h, respectively (p < 0.05) and 77% of the control at 4 h of recovery. CEU in the contralateral hemisphere was unchanged from the control at all measured intervals. Correlation of the alterations in CMRg1 with those in CEU at the same intervals indicated that substrate supply exceeds energy utilization during early recovery from hypoxia-ischemia. The discrepancy combined with a persistent disruption of the cerebral energy state implies the existence of an uncoupling of mitochondrial oxidative phosphorylation as one mechanism for the occurrence of perinatal hypoxic-ischemic brain damage.

Energy reserves and utilization rates in developing brain measured in vivo by 31P and 1H nuclear magnetic resonance spectroscopy.

Age-related changes in cerebral energy utilization were examined in swine, a species whose maximal rate of development is known to occur in the perinatal period. Interleaved in vivo 31P and 1H nuclear magnetic resonance spectroscopy was used to measure the rates of change in cerebral concentrations of phosphocreatine (PCr), nucleoside triphosphates, and lactate following complete ischemia, induced via cardiac arrest, in a total of 19 newborn, 10-day-old, and 1-month-old piglets. Preischemic concentrations of these three metabolites plus glucose and glycogen were determined in a separate experiment on 12 piglets whose brains were funnel-frozen in situ. The rate constants for the PCr and ATP decline and lactate increase were determined by nonlinear regression fits to the experimental data, assuming first-order kinetics. The rate constants and preischemic metabolite concentrations were used to calculate the initial flux of high-energy phosphate equivalents (approximately P), which was used as an estimate of cerebral energy utilization at the point when ischemia was initiated. Cerebral energy utilization equaled 6.5 +/- 1.9, 9.5 +/- 3.2, and 15.1 +/- 3.2 mumol approximately P/g/min in newborn, 10-day-old, and 1-month-old piglets, respectively. Within each age group the energy utilization rate was not altered by hyperglycemia-induced increases in cerebral energy reserves, but during hypoglycemia cerebral energy utilization rates decrease. The slope of approximately P versus time decreased with the duration of ischemia, indicating that cerebral energy utilization rates decrease after the first few minutes of ischemia. Newborn piglets had higher cerebral energy utilization rates compared with literature values for newborn rats and mice. This is consistent with the concept that newborns from a species with a perinatal stage of maximal growth and development will have higher cerebral energy demands compared with newborns from a species such as rodents, whose maximal growth occurs postnatally. However, this conclusion remains tentative because literature cerebral utilization rates estimated from the initial slope of approximately P-versus-time plots tend to underestimate the true rate, since the assumption of continued linearity may not be valid for the interval chosen.

Ontogeny of cerebral oxidative metabolism in the chick embryo.

The low cerebral energy requirements of most mammals at birth reflect an immaturity of the central nervous system, and it has been suggested that energy demands in fetuses are even less well developed than in newborns. Furthermore, fetal cerebral energy requirements are presumed to be met predominantly or exclusively by anaerobic glycolysis. To clarify these issues, we investigated cerebral oxidative metabolism in 9-, 14-, 16-, and 19-day-old chick embryos and in newly hatched peeps. Animals were decapitated and quick-frozen in liquid Freon 0--5 min post-mortem. Forebrain extracts were prepared and assayed for ATP, phosphocreatine, glucose, and lactate. Alterations in these metabolites post-decapitation were used to calculate cerebral metabolic rates (delta similar to P) and rates of maximal anaerobic glycolysis (delta lactate). Rates of lactate accumulation during cerebral ischemia increased progressively from embryonic day 9 through hatching. Cerebral metabolic rates were not different in 9-, 14-, and 15-day-old embryos, but increased steadily thereafter. The extent to which total cerebral energy utilization could be derived from anaerobic glycolysis (delta lactate/delta similar to P) increased from a low at day 9 (0.29) to a maximum at day 16 (0.78). The data suggest that, despite the low cerebral metabolic activity of the chick embryo, at no time during development is anaerobic glycolysis capable of entirely supporting the energy needs of the developing brain.

Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats.

The cerebral metabolic responses to perinatal hypoglycemia and anoxia were studied in newborn rats given regular insulin (30 units per kilogram of body weight). Animals were observed for up to 2 hours with no apparent ill effects in spite of blood glucose concentrations of 0.75 mmol per liter. When exposed to 100% nitrogen at 37 degrees C, hypoglycemic animals survived only one-tenth as long as littermate controls with normal blood glucose levels (4.7 mmol/L). Pretreatment of hypoglycemic rats with glucose (10 mmol/kg) 10 and 30 minutes prior to nitrogen exposure nearly completely reversed the anoxic vulnerability. Hypoglycemia led to progressive reductions in cerebral glycogen and glucose; however, only glucose reverted to normal levels 20 minutes after systemic glucose administration. The glycolytic intermediates glucose 6-phosphate and lactate were also lower during hypoglycemia. Brain glucose levels below 0.1 mmol per kilogram were associated with a disrupted cerebral energy state, reflected by declines in phosphocreatine (33%) and adenosine triphosphate (ATP) (10%). Cerebral energy utilization (metabolic rate) was minimally reduced (-7.2%) by hypoglycemia and returned to the control value (2.36 mmol approximately P/kg/min) with glucose treatment. The cerebral energy reserves ATP, adenosine diphosphate, and phosphocreatine declined more rapidly and to a lower level in hypoglycemic rats subjected to 2 1/2 minutes of anoxia than in normoglycemic animals rendered similarly hypoxic. The findings suggest that decreased anoxic resistance of hypoglycemic newborn rats is not primarily a function of reduced brain glycogen or altered cerebral metabolic rate. The presence of endogenous cerebral glucose stores combined with continued circulating glucose (cerebrovascular perfusion) appear to be critical factors for maintaining perinatal hypoxic survival.

Postischemic cerebral blood flow and oxygen utilization rate in rats anesthetized with nitrous oxide or phenobarbital.

The present experiments were undertaken to measure postischemic regional cerebral blood flow (rCBF) and oxygen utilization rate (CMRo2) in rats anesthetized with either 70% N2O or phenobarbital (150 mg x kg-1). In previous studies we have found that extensive restitution of cerbral energy metabolites occurs after 30 min of complete cerebral ischemia irrespective of the type of anesthesia used. Following 30 min of pronounced, incomplete ischemia, however, a comparable restitution of cerebral energy state was obtained in deeply anesthetized (phenobarbital 150 mg x kg-1) but not in superfically anesthetized (70% N2O) rats. The objectives of the present investigation were (1) to study whether postischemic cerebral blood flow was higher in barbiturate-anesthetized animals during the initial recirculation period, and (2) to investigate if the protective effects of phenobarbital previously observed could be attributed to a decrease in CMRo2. In both groups of animals a considerable variability in postischemic rCBF was observed between different animals. However, no signs of gross inhomogeneity in blood flow were found and no consistent differences in flow values between the two groups of animals were observed. Since the measured postischemic CMRo2 were identical in both groups of animals and since cerebral venous oxygen contents were above normal the results leave little support to the assumption that, in the present model of transient, incomplete cerebral ischemia, failure of recovery of cerebral metabolism (N2O group) is primarily due to impaired recirculation, nor do they indicate that the protective effects of barbiturates is due to their ability to reduce rate of cerebral energy utilization.

Pathologic physiology of cerebral dysfunction

Clinically, disorders of the central nervous system are expressed as dysfunction and are ordinarily classified as “organic” or “functional” syndromes. The former may be due to interference with the supply of carbohydrate or oxygen to the brain, to abnormalities of cerebral enzyme activity, or to disordered energy utilization or mediation of interneuronal impulses. Such disturbances, which are associated with or consist of anatomical, biochemical or physiological abnormalities, have not been demonstrated in the case of the “functional” disorders. Nevertheless, the nature of the “functional” syndromes suggests impaired integration of neuronal activity, which may be related to abnormal neurohumoral intersynaptic transmission. The subject of chemical mediators in the central nervous system has only recently been studied intensively and is as yet but incompletely understood. It is probable, although by no means conclusively established, that most of the currently available neuropharmacologic agents—ataractics, “psychic energizers” and psychotomimetics—act upon or substitute for the neurohumoral mediators and thereby alter cerebral energy utilization. It is this latter factor which in the final analysis may be responsible for the outward manifestations of central nervous system activity, whether normal or organically or “functionally” abnormal. Hence, it should not be surprising that the etiology of disturbances in cerebral energy utilization may be difficult or impossible to identify as “organic” or “functional” on the basis of symptomatology alone. Indeed, it is the consensus that even normal mental activity is closely associated with an organic substrate; it seems an entirely reasonable corollary that the “functional” cerebral disorders are probably related to an organic, at least physiological disturbance, however obscure.