Cerebral Glucose Use Research Articles

Clustering of Hypoglycemia Events in Patients With Hyperinsulinism: Extension of the Digital Phenotype Through Retrospective Data Analysis.

BackgroundHyperinsulinism (HI) due to excess and dysregulated insulin secretion is the most common cause of severe and recurrent hypoglycemia in childhood. High cerebral glucose use in the early hours results in a high risk of hypoglycemia in people with diabetes and carries a significant risk of brain injury. Prevention of hypoglycemia is the cornerstone of the management of HI, but the risk of hypoglycemia at night or the timing of hypoglycemia in children with HI has not been studied; thus, the digital phenotype remains incomplete and management suboptimal.ObjectiveThis study aims to quantify the timing of hypoglycemia in patients with HI to describe glycemic variability and to extend the digital phenotype. This will facilitate future work using computational modeling to enable behavior change and reduce exposure of patients with HI to injurious hypoglycemic events.MethodsPatients underwent continuous glucose monitoring (CGM) with a Dexcom G4 or G6 CGM device as part of their clinical assessment for either HI (N=23) or idiopathic ketotic hypoglycemia (IKH; N=24). The CGM data were analyzed for temporal trends. Hypoglycemia was defined as glucose levels <3.5 mmol/L.ResultsA total of 449 hypoglycemic events totaling 15,610 minutes were captured over 237 days from 47 patients (29 males; mean age 70 months, SD 53). The mean length of hypoglycemic events was 35 minutes. There was a clear tendency for hypoglycemia in the early hours (3-7 AM), particularly for patients with HI older than 10 months who experienced hypoglycemia 7.6% (1480/19,370 minutes) of time in this period compared with 2.6% (2405/92,840 minutes) of time outside this period (P<.001). This tendency was less pronounced in patients with HI who were younger than 10 months, patients with a negative genetic test result, and patients with IKH. Despite real-time CGM, there were 42 hypoglycemic events from 13 separate patients with HI lasting >30 minutes.ConclusionsThis is the first study to have taken the first step in extending the digital phenotype of HI by describing the glycemic trends and identifying the timing of hypoglycemia measured by CGM. We have identified the early hours as a time of high hypoglycemia risk for patients with HI and demonstrated that simple provision of CGM data to patients is not sufficient to eliminate hypoglycemia. Future work in HI should concentrate on the early hours as a period of high risk for hypoglycemia and must target personalized hypoglycemia predictions. Focus must move to the human-computer interaction as an aspect of the digital phenotype that is susceptible to change rather than simple mathematical modeling to produce small improvements in hypoglycemia prediction accuracy.

Carotid foramen size in the human skull tracks developmental changes in cerebral blood flow and brain metabolism.

In humans, neuronal processes related to brain development elevate the metabolic rate of brain tissue relative to the body during early childhood. This phenomenon has been hypothesized to contribute to slow somatic growth in preadolescent Homo sapiens. The uncoupling of the brain's metabolic rate from brain size during development complicates the study of the evolutionary emergence of these traits in the fossil record. Here, we extend a method previously developed to predict interspecific differences in cerebral blood flow (a correlate of cerebral glucose use) to predict ontogenetic changes in human brain metabolism. Radii of the carotid foramen from an ontogenetic series of modern human crania were used to predict blood flow rates through the internal carotid arteries (ICA), which were compared to empirically measured ICA flow and brain metabolism values. Predictions of both absolute ICA blood flow rates and perfusion (ICA blood flow rates relative to brain size) generally match measured values in infancy and childhood. Maximum predicted ICA blood flow rates and perfusion were found to occur between ages 5 and 8, which roughly correspond to the age of maximum measured ICA blood flow rate and absolute and brain mass-specific rate of whole brain glucose uptake. These findings suggest that, during human growth and development, the size of the carotid foramen corresponds well to blood flow requirements through the ICA, and the method tested here may provide new opportunities for studying developmental changes in brain metabolism using osteological samples, including fossil hominins.

Intranasal Insulin to Treat and Protect Against Posttraumatic Stress Disorder

Lessons learned from research on the treatment of Alzheimer’s disease (AD) suggest a new strategy for treating posttraumatic stress disorder (PTSD). The NIH recently selected intranasal insulin as a promising treatment for AD and committed 7.9 million in funding to further test it nationally (Health and Human Services Press Office for Secretary Kathleen Sebelius, 2012). The noninvasive intranasal method for bypassing the blood-brain barrier to target therapeutics (including insulin) to the brain to treat neurodegenerative disorders such as AD and stroke was first discovered in 1989 (Frey, 1991) and was later described specifically for the use of intranasal insulin to target the brain to treat AD and certain other CNS disorders (Frey, 2001). Intranasal therapeutics bypass the blood-brain barrier and rapidly reach the brain by traveling extracellularly along the olfactory and trigeminal neural pathways (Lochhead and Thorne, 2012). This increases efficacy while reducing systemic exposure and unwanted side effects. Intranasal insulin treatment improves memory in healthy adults, with no change in the blood levels of insulin or glucose (Benedict et al., 2004). Researchers in Germany conducted several additional human clinical trials showing that intranasal insulin improves memory in healthy adults (Benedict et al., 2011). In 2006, Dr Suzanne Craft, at the University of Washington and the Veterans Affairs Puget Sound Health Care System, and colleagues (of whom I was one) reported that intranasal insulin improved memory in only 20 minutes after a single intranasal insulin treatment in patients with AD (Reger et al., 2006). Intranasal insulin (twice a day) also improved memory, attention, and functioning in patients with AD during a 21-day period (Reger et al., 2008) and improved memory and general cognition and reduced loss of brain fludeoxyglucose uptake in patients with AD or amnestic mild cognitive impairment treated with intranasal insulin in a 4-month clinical trial, with no change in the blood levels of insulin or glucose (Craft, 2012). It is not surprising that intranasal insulin is an effective treatment of AD because glucose uptake and use are significantly decreased in patients with AD (de Leon et al., 1997). Glucose is the only source of energy used by brain cells under normal conditions, and the brain cells of patients with AD are starved for energy. AD has been reported to involve a deficiency of insulin and insulin signaling in the brain (Steen et al., 2005.) Type 2 diabetes is a major risk factor for developing AD. Intranasal insulin is far more than simply a treatment of AD symptoms. When intranasal insulin reaches the brain, it stimulates the formation of insulin-degrading enzyme, which is capable of degrading beta amyloid, one of the principal abnormal proteins known to accumulate in the brains of patients with AD. Further, the activity of glycogen-synthase kinase-3-beta, the enzyme that phosphorylates tau to create AD neurofibrillary tangles, has been reported to be downregulated in response to insulin. Finally, insulin receptor signaling increases synaptic density, and loss of synapses is key to the neuropathology of AD (Benedict et al., 2011). Stress has also been found to reduce the uptake and use of glucose by brain cells. In 1986, Sapolsky reported that glucocorticoids released in response to stress could damage neurons in the hippocampus. Multiple mechanisms are likely involved in this action, one of which is the inhibition of glucose use in the hippocampus by glucocorticoids. Cortisol has been reported to reduce hippocampal glucose use in healthy elderly adults on the basis of examination of the brain glucose use (cerebral metabolic rate of glucose consumption) response to hydrocortisone (cortisol; de Leon et al., 1997). It is likely that glucocorticoids also reduce the capacity of the hippocampus to survive neurological insults because glucocorticoids inhibit glucose transport 15% to 30% in both primary and secondary hippocampal astrocytic cultures, and this could impair the ability of astrocytes to aid neurons by removing damaging glutamate from the synapse during times of neurological crisis (Virgin et al., 1991). Glucocorticoids released in response to major stress inhibit local cerebral glucose use throughout the brain and inhibit glucose transport in neurons; glia; and, possibly, endothelial cells in vitro (Sapolsky et al., 2000). Baker et al. (2005) have reported that mean CSF cortisol concentrations are significantly higher in combat veterans with PTSD than in healthy comparison subjects. Concentrations of CSF COMMENTARY

ASENAPINE IN SCHIZOPHRENIA: AN OVERVIEW OF CLINICAL TRIALS IN THE OLYMPIA PROGRAM

AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.

Brain metabolic markers reflect susceptibility status in cytokine gene knockout mice with murine cerebral malaria

Treatment of cerebral malaria, a complication of the world’s most significant parasitic disease, remains problematic due to lack of understanding of its pathogenesis. Metabolic changes, along with cytokine expression alterations and blood cell sequestration in the brain, have previously been reported during severe disease in human infection and mouse models leading to the “cytopathic hypoxia” and “sequestration” theories of pathogenesis. Here, to determine the robustness of the metabolic changes and their relationship to disease development, we investigated changes in cerebral metabolic markers in a mouse model of cerebral malaria (CM) in wildtype (C57BL/6) and cytokine knockout (TNF −/−, IFNγ −/− and LTα −/−) mice using multinuclear magnetic resonance spectroscopy. Mice susceptible to CM (wildtype, TNF −/−) showed decreased cerebral glucose use, decreased Krebs cycle metabolism and decreased high-energy phosphates. Conversely, mice resistant to CM (IFNγ −/−, LTα −/−) showed little sign of these effects, despite identical levels of parasitemia. Previously reported changes in lactate were shown to be strain dependent. Elevated glutamine and decreased phosphorylation potential emerged as robust metabolic markers of susceptibility, further implicating the trytophan/NAD + pathway in disease development. Thus these metabolic changes are firmly linked both to the immune system response to malaria and to the occurrence of pathogenic changes in experimental CM.

Partial lesion of the serotonergic system by a single dose of MDMA results in behavioural disinhibition and enhances acute MDMA-induced social behaviour on the social interaction test

The acute effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) on anxiety-related behaviours were studied using indices of social interaction in Dark Agouti (DA) both drug naive rats and those pretreated with MDMA (15 mg/kg i.p.) 3 weeks earlier. The functional neuroanatomy of these MDMA effects was visualised using 2-deoxyglucose imaging of local cerebral glucose use (LCMRglu), whilst MDMA-induced serotonergic neurotoxicity was measured by radioligand binding with [ 3H]paroxetine. Acute MDMA alone markedly decreased most typical elements of social interaction but increased adjacent lying, a behaviour that also contains social elements. In animals pre-exposed to MDMA, decreased [ 3H]paroxetine binding indicated serotonergic terminal depletion, and in these animals significant increases in locomotor activity, exploratory behaviour and aggressive behaviour were found. Both behavioural effects and also the metabolic activation induced by acute MDMA were potentiated in rats previously exposed to the drug. In conclusion, a single dose of MDMA caused marked changes in social behaviour acutely that might be interpreted either as a decrease or increase in anxiety. Three weeks after MDMA a behavioural disinhibition similar to psychomotor agitation, a symptom connected to depression or mania, and a sensitization to the acute effects of MDMA are apparent in both the behavioural and brain metabolic effects of the drug.

Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography

AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.

Ictogenesis

Ictogenesis

Degeneration of the Basalocortical Pathway from the Cortex Induces a Functional Increase in Galaninergic Markers in the Nucleus Basalis Magnocellularis of the Rat

The present work aimed 1) to evaluate whether an increase in galanin or galanin receptors could be induced in the nucleus basalis magnocellularis (nbm) by degeneration of the basalocortical neurons from the cortex and 2) to analyze the consequences of such an increase on cortical activity. First, a mild ischemic insult to the frontoparietal cortex was performed to induce the degeneration of the basalocortical system; galanin immunoreactivity, galanin binding sites, and cholinergic muscarinic receptors were quantified through immunocytochemistry and autoradiography. Second, galanin infusions in the nbm were undertaken to mimic a local increase of the galaninergic innervation; cortical acetylcholine release, cerebral glucose use, and cerebral blood flow were then measured as indices of cortical activity. As a result of the cortical ischemic lesion, the postsynaptic M1 and presynaptic M2 muscarinic receptors were found to be reduced in the altered cortex. In contrast, galaninergic binding capacity and fiber density were found to be increased in the ipsilateral nbm in parallel with a local decrease in the cholinergic markers such as the muscarinic M1 receptor density. Galanin infusion into the nbm inhibited the cortical acetylcholine release and cerebral blood flow increases elicited by the activation of the cholinergic basalocortical system but failed to affect acetylcholine release, cerebral blood flow, and cerebral glucose use when injected alone in the nbm. These results demonstrate that degeneration of the basalocortical system from the cortex induces an increase in galaninergic markers in the nbm, a result that might suggest that the galaninergic overexpression described in the basal forebrain of patients with Alzheimer's disease can result from a degeneration of the cholinergic basalocortical system from the cortex. Because galanin was found to reduce the activity of the basalocortical cholinergic system only when this one is activated, galanin might exert its role rather during activation deficits than under resting conditions such as the resting cortical hypometabolism, which is characteristic of Alzheimer's disease.

Spatially dissociated flow-metabolism coupling in brain activation

The relationships among cerebral blood flow (CBF), oxygen consumption (CMRO 2) and glucose use (CMR glc) constitute the basis of functional brain-imaging. Here we report spatially dissociated changes of CMRO 2 and CBF during motor activity that lead us to propose a revision of conventional CBF-CMRO 2 coupling models. In the left primary and supplementary motor cortices, CBF and CMRO 2 rose significantly during finger-thumb tapping. However, in the right putamen CBF did not rise, despite a significant increase in CMRO 2. We explain these observations by invoking a central command mechanism that regulates CBF in the putamen in anticipation of movement. By this mechanism, CBF rose in the putamen before the measurements of CBF and CMRO 2 while CMRO 2 rose when actual motion commenced.

Delta 9-tetrahydrocannabinol-induced alterations in limbic system glucose use in the rat.

The effects of Delta9-tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [14C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly increased it at 1 mg/kg. Significant reductions were seen at the higher dose in regions of the hippocampus and limbic system, and in structures associated with sensory and sensorimotor process ing, consistent with the effects of THC on memory, sensory perception and motor control. Glucose use was increased in the shell of the nucleus accumbens at 1 mg/kg but not reduced at 5 mg/kg. This may reflect increases in activity in mesolimbic reward pathways which at the higher dose are mitigated by reduced glutamatergic outflow from the hippocampus.

Local Coupling of Cerebral Blood Flow to Cerebral Glucose Metabolism during Inhalational Anesthesia in Rats

It is not known whether the effects of desflurane on local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) are different from those of other volatile anesthetics. Using the autoradiographic iodoantipyrine and deoxyglucose methods, LCGU, LCBF, and their overall means were measured in 60 Sprague-Dawley rats (10 groups, n = 6 each) during desflurane and isoflurane anesthesia and in conscious controls. During anesthesia, mean cerebral glucose utilization was decreased compared with conscious controls: 1 minimum alveolar concentration (MAC) desflurane: -52%; 1 MAC isoflurane: -44%; 2 MAC desflurane: -62%; and 2 MAC isoflurane: -60%. Local analysis showed a reduction of LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased: 1 MAC desflurane: +40%; 1 MAC isoflurane: +43%; 2 MAC desflurane and 2 MAC isoflurane: +70%. LCBF was increased in all brain structures investigated except in the auditory cortex. No significant differences (P < 0.05) could be observed between both anesthetics for mean values of cerebral glucose use and blood flow. Correlation coefficients obtained for the relation between LCGU and LCBF were as follows: controls: 0.95; 1 MAC desflurane: 0.89; 2 MAC desflurane: 0.60; 1 MAC isoflurane: 0.87; and 2 MAC isoflurane: 0.68. Differences in the physicochemical properties of desflurane compared with isoflurane are not associated with major differences in the effects of both volatile anesthetics on cerebral glucose utilization, blood flow, and the coupling between LCBF and LCGU.

Neurochemical stimulation of the rat substantia innominata increases cerebral blood flow (but not glucose use) through the parallel activation of cholinergic and non-cholinergic pathways

Neurochemical activation of the substantia innominata (SI) in the rat, through the direct injection of the cholinergic agonist carbachol, has been reported to induce large increases in cerebral blood flow (CBF) throughout cortical and subcortical projection regions. The present study aimed to determine whether the vasomotor responses to cholinergic stimulation of the SI were, or were not, the consequence of an increase in metabolic activity. To this end, coupled measurements of CBF and cerebral glucose use (CGU) were undertaken during carbachol-elicited stimulation of the SI. Infusion of carbachol into the basal forebrain induced significant CBF increases in several ipsilateral cortical and subcortical areas including the amygdala. In contrast, CGU increased only in the ipsilateral amygdala and SI. Thus, we tested the hypothesis of a direct neurogenic, rather than metabolic, contribution of the basalocortical system. In this respect, carbachol-elicited stimulation resulted in significant increases in extracellular acetylcholine concentrations in the ipsilateral parietal cortex; systemic pretreatment with the muscarinic receptor antagonist scopolamine completely abolished the increase in cortical CBF elicited by cholinergic stimulation of the SI in the ipsilateral frontoparietal motor cortex while it failed to affect the increase observed in the ipsilateral temporal cortex. Several conclusions can be drawn from the present study. The stimulation of the SI by carbachol induces an increase in CBF that can be dissociated from changes in underlying glucose metabolism. Secondly, these induced changes in cortical CBF are paralleled by an increase in acetylcholine release. Lastly, the failure of scopolamine to block the flow response in all cortical regions would suggest that SI stimulation will evoke the release of vasodilatatory neurotransmitter(s) as well as acetylcholine itself.

Regional cerebral blood flow during rewarming of cardiopulmonary bypass correlates with posthypothermic regional glucose use

Background and objectives: Although global measurements of cerebral blood flow and metabolism during and after profoundly hypothermic cardiopulmonary bypass have been performed both in experimental animals and in human beings, little is known about their regional changes. The purpose of this study was to investigate the changes in regional cerebral blood flow during profoundly hypothermic cardiopulmonary bypass and regional cerebral glucose use after cardiopulmonary bypass. Methods: We measured regional cerebral blood flow with positron emission tomography during both the cooling ( n = 5) and rewarming ( n = 5) of hypothermic cardiopulmonary bypass in anesthetized dogs by continuously infusing 15O-labeled water. We altered the core temperature between 20° and 37° C. To assess the integrity of brain metabolism, we measured the regional cerebral glucose use by bolus injections of 18F-labeled 2-fluoro-2-deoxy- d-glucose. Results: Regional cerebral blood flow decreased homogeneously during cooling. The regional cerebral blood flow at 20° C was about one fourth of that at 37° C. In contrast, at 24°, 28°, and 32° C during rewarming, there were significant interregional differences in the regional cerebral blood flow for given temperatures ( p = 0.0075, 0.034, and 0.048, respectively). These interregional differences disappeared after rewarming. Although the regional cerebral blood flow significantly correlated with the regional cerebral glucose use in the control condition at 37° C without cardiopulmonary bypass ( r = 0.75; p = 0.00012), this correlation disappeared after profoundly hypothermic cardiopulmonary bypass ( r = 0.204; p = 0.388). Regional cerebral blood flow at 32° C during rewarming positively correlated with the regional cerebral glucose use after cardiopulmonary bypass ( r = 0.655; p = 0.0017). Conclusion: The altered regional cerebral blood flow during rewarming of profoundly hypothermic cardiopulmonary bypass might affect regional brain metabolism. (J Thorac Cardiovasc Surg 1998;116:503-10)

Differential diagnosis of parkinsonism with [18F]fluorodeoxyglucose and PET.

The clinical differentiation between typical idiopathic Parkinson's disease (IPD) and atypical parkinsonian disorders (APD) is complicated by the presence of signs and symptoms common to both forms of parkinsonism. Metabolic brain imaging with [18F]fluorodeoxyglucose (FDG) and positron emission tomography (PET) may be a useful adjunct in differentiating APD from IPD. To explore this possibility, we studied 48 parkinsonian patients suspected as having possible APD because of a deteriorating response to dopaminergic treatment, the development of autonomic dysfunction, or both. A group of 56 patients with likely IPD served as control subjects. We used quantitative FDG/PET to measure regional rates of cerebral glucose use in IPD and APD patients. We used discriminant analysis to categorize IPD and APD patients based on their regional metabolic data. We found that a linear combination of caudate, lentiform, and thalamic values accurately discriminated APD from IPD patients (p < 0.0001). Significant metabolic abnormalities were present in the striatum and the thalamus of 36 of 48 (75%) APD patients. Our findings show that measurements of regional glucose metabolism can be used to discriminate patients with suspected APD from their counterparts with classic IPD. FDG/PET may be a useful adjunct to the clinical examination in the differential diagnosis of parkinsonism.

Local uncoupling of the cerebrovascular and metabolic responses to somatosensory stimulation after neuronal nitric oxide synthase inhibition.

It has recently been shown, using either genetically engineered mutant mice (nitric oxide synthase [NOS] knockout) or specific pharmacological tools, that type I NOS (neuronal isoform of NOS, [nNOS]) participates in coupling cerebral blood flow to functional activation. However, it has not been clearly established whether the associated metabolic response was preserved under nNOS inhibition and whether this action was exerted homogeneously within the brain. To address these issues, we analyzed the combined circulatory and metabolic consequences of inhibiting the nNOS both at rest and during functional activation in the rat anesthetized with alpha-chloralose. Cerebral blood flow and cerebral glucose use (CGU) were measured autoradiographically using [14C]iodoantipyrine and [14C]2-deoxyglucose during trigeminal activation induced by unilateral whiskers stimulation in vehicle- and 7-nitroindazole-treated rats. Our data show that inhibition of nNOS globally decreased CBF without altering CGU, indicating that NO-releasing neurons play a significant role in maintaining a resting cerebrovascular tone in the whole brain. During whisker stimulation, nNOS inhibition totally abolished the cerebrovascular response only in the second order relay stations (thalamus and somatosensory cortex) of the trigeminal relay without altering the metabolic response. These findings provide evidence that the involvement of neurally-derived NO in coupling flow to somatosensory activation is region-dependent, and that under nNOS inhibition, CBF and CGU may vary independently during neuronal activation.

Loss and Subsequent Recovery of Local Cerebral Glucose Use in Visual Targets after Controlled Optic Nerve Crush in Adult Rats

A mild crush of the adult rat optic nerve serves as a model to study the restoration of function after traumatic brain injury. It causes a progressive degeneration of retinal ganglion cells, but visually guided behavior is partially restored within 2–3 weeks. The purpose of this study was to determine to what extent local cerebral glucose use (LCGU) decreases and if it recovers in retinofugal targets following unilateral optic nerve crush. At intervals of 2, 9, and 22 days after crush, LCGU was monitored in rats in which the visual system was stimulated by a strobe-light and pattern. In the ipsilateral retinofugal targets there was only a minimal loss of LCGU use, but in the contralateral retinofugal targets, LCGU was reduced at Postlesion Day 2: to 50% in the superior colliculus (SC), to 60% in the lateral geniculate nucleus of the thalamus (LGN), and to 87% in the visual cortex. On Postoperative Days 9 and 22 we observed a partial restoration of LCGU in the contralateral SC and LGN to 68 and 79%, respectively. As recovery of visual performance is known to follow a similar time course, we conclude that restoration of metabolic activity in target structures may contribute to the restoration of vision after optic nerve crush.

Evaluation of a “mental effort” hypothesis for correlations between cortical metabolism and intelligence

Previous research indicates that low scores on the Raven's Advanced Progressive Matrices (RAPM) test are associated with increased cortical glucose utilization during problem solving. We hypothesized that previous results may reflect the neurophysiological consequences of patterns of effort requirements; that is, high-effort expenditure from lower aptitude participants (for whom the problems are hard) and low-effort expenditure from higher aptitude participants (for whom the problems are easy). In this experiment, positron emission tomography (PET) data were gathered on participants ( N = 28) who solved easy and hard problems that were tailored to the participants' own ability levels, thereby eliminating aptitude group differences in effort requirements. Contrary to previous results, high aptitude was associated with high cortical glucose use. Average aptitude participants showed diminished glucose use in the hard condition. A significant Group X Condition X Hemisphere Effect was also noted, with greater right hemisphere activation in the hard condition for the high-aptitude group. These results demonstrate that the relation of cerebral glucose use and cognitive ability is sensitive to participant and task selection.

Inhibition of Neuronal Nitric Oxide Synthase by 7-Nitroindazole: Effects upon Local Cerebral Blood Flow and Glucose Use in the Rat

The novel nitric oxide synthase inhibitor 7-nitroindazole (7-NI) is relatively specific for the neuronal isoform of the enzyme and in this study we have used this compound to investigate the physiological role of perivascular nitric oxide-containing nerves in the cerebrovascular bed. Following injection of 7-NI (25 or 50 mg/kg, i.p.), cerebral blood flow and glucose utilization were measured in the conscious rat using the fully quantitative [14C]iodoantipyrine and 2-[14C]deoxyglucose techniques, respectively. Neither dose of the drug produced any change in arterial blood pressure, confirming a lack of effect upon the endothelial isoform of the enzyme, although there was a pronounced decrease in heart rate (-28% by 10 min postinjection). Throughout the brain 25 mg/kg 7-NI i.p. resulted in decreases in blood flow of between -20% in the hippocampus and -58% in the substantia nigra. Increasing the dose to 50 mg/kg resulted in a further generalized decrease, to almost -60% in parts of the thalamus and hippocampus, but in every animal this higher dose of 7-NI also produced randomly distributed areas of relative hyperaemia, which were most commonly found in those areas where the most intense hypoperfusion was otherwise in evidence. Despite these changes in blood flow, in all but a very few areas of the brain no significant decrease in glucose use was measured at either of the two doses of 7-NI. Thus despite the greater specificity of 7-NI for neuronal nitric oxide synthase, the cerebrovascular effects of the drug in vivo are very similar to that reported for the arginine analogues. However, these data do suggest that nitric oxide-releasing neurones in the brain may have an important role to play in the regulation of cerebral blood flow.

Idazoxan-induced reductions in cortical glucose use are accompanied by an increase in noradrenaline release: Complementary [ 14C]2-deoxyglucose and microdialysis studies

The autoradiographic [ 14C]2-deoxyglucose procedure was used to map function-related alterations in local cerebral glucose use following acute administration of the α 2-adrenoceptor antagonist, idazoxan (0.3–3 mg kg −1 s.c.). The most prominent feature of the results obtained was the significant reduction in glucose use in certain locus coeruleus projection areas. Thus, in various cortical, hippocampal and thalamic regions, as well as structures involved in auditory and visual function, idazoxan administration was associated with a 13–20% decrease in glucose use. In a complementary microdialysis study, the effect of idazoxan on extracellular noradrenaline levels in the frontal cortex of rats, manipulated in the same fashion as during the [ 14C]2-deoxyglucose procedure (i.e. following the application of surgery and partial restraint), was examined. Both surgery and restraint were associated with a modest but significant increase in basal noradrenaline release ( + 31% and + 26%, respectively). Subsequent administration of idazoxan (3 mg kg −1 s.c.) evoked a further increase in noradrenaline release, the magnitude of which was the same as that observed following its administration to freely-moving rats (+ 113%). These combined data suggest that idazoxan-induced reductions in cerebral glucose use, at least in the frontal cortex, may occur as a consequence of the increase in noradrenaline release. In addition, it appears that surgery and partial restraint do not alter α 2-adrenoceptor tone in the frontal cortex.