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Functional brain imaging during anesthesia in humans: effects of halothane on global and regional cerebral glucose metabolism.

BACKGROUND: Propofol and isoflurane anesthesia were studied previously with functional brain imaging in humans to begin identifying key brain areas involved with mediating anesthetic-induced unconsciousness. The authors describe an additional positron emission tomography study of halothane's in vivo cerebral metabolic effects. METHODS: Five male volunteers each underwent two positron emission tomography scans. One scan assessed awake-baseline metabolism, and the other scan assessed metabolism during halothane anesthesia titrated to the point of unresponsiveness (mean +/- SD, expired = 0.7+/-0.2%). Scans were obtained using a GE2048 scanner and the F-18 fluorodeoxyglucose technique. Regions of interest were analyzed for changes in both absolute and relative glucose metabolism. In addition, relative changes in metabolism were evaluated using statistical parametric mapping. RESULTS: Awake whole-brain metabolism averaged 6.3+/-1.2 mg x 100 g(-1) x min(-1) (mean +/- SD). Halothane reduced metabolism 40+/-9% to 3.7+/-0.6 mg x 100 g(-1) x min(-1) (P< or =0.005). Regional metabolism did not increase in any brain areas for any volunteer. The statistical parametric mapping analysis revealed significantly less relative metabolism in the basal forebrain, thalamus, limbic system, cerebellum, and occiput during halothane anesthesia. CONCLUSIONS: Halothane caused a global whole-brain metabolic reduction with significant shifts in regional metabolism. Comparisons with previous studies reveal similar absolute and relative metabolic effects for halothane and isoflurane. Propofol, however, was associated with larger absolute metabolic reductions, suppression of relative cortical metabolism more than either inhalational agent, and significantly less suppression of relative basal ganglia and midbrain metabolism.

Anesthesia, General↗

Molecular diversity of glutamate receptors and implications for brain function.

The glutamate receptors mediate excitatory neurotransmission in the brain and are important in memory acquisition, learning, and some neurodegenerative disorders. This receptor family is classified in three groups: the N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate, and metabotropic receptors. Recent molecular studies have shown that many receptor subtypes exist in all three groups of the receptors and exhibit heterogeneity in function and expression patterns. This article reviews the molecular and functional diversity of the glutamate receptors and discusses their implications for integrative brain function.

Amino Acid Sequence↗

Nuclear magnetic resonance imaging and spectroscopy of human brain function.

The techniques of in vivo magnetic resonance (MR) imaging and spectroscopy have been established over the past two decades. Recent applications of these methods to study human brain function have become a rapidly growing area of research. The development of methods using standard MR contrast agents within the cerebral vasculature has allowed measurements of regional cerebral blood volume (rCBV), which are activity dependent. Subsequent investigations linked the MR relaxation properties of brain tissue to blood oxygenation levels which are also modulated by consumption and blood flow (rCBF). These methods have allowed mapping of brain activity in human visual and motor cortex as well as in areas of the frontal lobe involved in language. The methods have high enough spatial and temporal sensitivity to be used in individual subjects. MR spectroscopy of proton and carbon-13 nuclei has been used to measure rates of glucose transport and metabolism in the human brain. The steady-state measurements of brain glucose concentrations can be used to monitor the glycolytic flux, whereas subsequent glucose metabolism--i.e., the flux into the cerebral glutamate pool--can be used to measure tricarboxylic acid cycle flux. Under visual stimulation the concentration of lactate in the visual cortex has been shown to increase by MR spectroscopy. This increase is compatible with an increase of anaerobic glycolysis under these conditions as earlier proposed from positron emission tomography studies. It is shown how MR spectroscopy can extend this understanding of brain metabolism.

Brain↗

Order and disorder in the brain function.

The interest in studying the brain electrical activity as a function of the development of intelligence has been spurred by the need to understand how the brain responds to environmental information. The description of sleep in mentally retarded children reveals deviant patterns of the EEG-spindles and of the eye movement activity (REM sleep) when compared to normal children. The patterns may be considered as a valuable index of mental function. According to experimental evidence, the distribution of the eye movements of sleep appears either as random or ordered. The latter are altered in the mentally handicapped in whom the appearance out of chaos, of the order which is needed for intelligence and memory to function, is altered. The sleep signs are redundant as from birth. Their pattern is also related to the psychomotor development of the infant. If their distribution remains random, or appears in long uninterrupted sequences of waves as in epilepsy, intelligence does not develop. A similar strategy appears to function in the foetus when nature organizes the structures that will lead to the development of intelligence. The eye movement patterns of sleep change in the pregnant women as a function of term and resemble those of premature babies of a similar gestational age. They also change as a function of the menstrual cycle and more generally as a function of age. The hypothesis that attention is the diurnal equivalent of REM sleep is discussed. Attempts at modelling the eye movement patterns of REM sleep as a function of near zero gravity environments have been made. 1) By means of a Montecarlo simulation using the semi Markov model during the Spacelab 1 flight. 2) With the method of the single and multiple g-phase transition analysis of the strange attractor dimension (d) during parabolic flights. The implication of the latter for the neural processes involved in learning is that the central nervous system can preserve intact, from input to output, over a period of several days, all the information it receives 3) The relation between spindles and eye movements has also been viewed by a quantum approach which is another medium between the information and the way of describing it.

Aging↗

Nutrition, brain function and behavior.

Current food intake has been shown to directly affect neurotransmission, with resultant modification of behavior. The role of vitamin co-factors in brain function is discussed, with emphasis on changes in mood and neurological function with deficiency. The use of megadoses of vitamins for the treatment of psychiatric diseases has little scientific support at this time. Current research also does not substantiate the Feingold thesis of improvement in childhood hyperkinesis when an additive-free diet is consumed. The effects of medications used to moderate mood are related to changes in nutrient intake that in turn alters weight status. In addition, the effect of certain nutrients modifying the dose response to mood altering drugs has been discussed. Finally evidence for mood state directly affecting the capacity of the body to utilize nutrients is presented.

Adolescent↗

Cardiovascular, metabolic and fetal brain function observation following total cord occlusion.

The effect of total cord occlusion (TCO) on the time sequence of fetal oxygenation, metabolic and cardiovascular parameters and on brain function of the sheep fetus was studied. It was also of importance to differentiate between cardiovascular alteration following TCO due to hypoxia and baroreceptor response, respectively. The investigations were performed on 11 near term pregnant sheep with dated gestational age of 126--137 days. Catheters were placed in the fetal aorta for monitoring fetal arterial blood pressure (FA BP), fetal heart rate (FHR). Blood samples were drawn and analysed for pH, PCO2 and SO2. An electromagnetic flow probe was placed around the common umbilical vein. Fetal EEG was measured over the right hemisphere. All parameters were studied over a varying time of TCO.

Animals↗

Molecules of the mind: integrating synaptic biochemistry to understand brain function.

The focused meeting entitled 'Molecular Determinants of Synaptic Function: Molecules and Models' brought together several molecules and experimental models that are furthering our understanding of the biochemical basis of integrative brain function. Invited speakers and short communications from more junior scientists highlighted how individual molecules or protein networks underlie defined subcellular functions (e.g. transmitter release, receptor activation and transmitter uptake) can be used to unravel integrative function at cellular, systems and behavioural levels.

Animals↗

A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs.

Small-world properties have been demonstrated for many complex networks. Here, we applied the discrete wavelet transform to functional magnetic resonance imaging (fMRI) time series, acquired from healthy volunteers in the resting state, to estimate frequency-dependent correlation matrices characterizing functional connectivity between 90 cortical and subcortical regions. After thresholding the wavelet correlation matrices to create undirected graphs of brain functional networks, we found a small-world topology of sparse connections most salient in the low-frequency interval 0.03-0.06 Hz. Global mean path length (2.49) was approximately equivalent to a comparable random network, whereas clustering (0.53) was two times greater; similar parameters have been reported for the network of anatomical connections in the macaque cortex. The human functional network was dominated by a neocortical core of highly connected hubs and had an exponentially truncated power law degree distribution. Hubs included recently evolved regions of the heteromodal association cortex, with long-distance connections to other regions, and more cliquishly connected regions of the unimodal association and primary cortices; paralimbic and limbic regions were topologically more peripheral. The network was more resilient to targeted attack on its hubs than a comparable scale-free network, but about equally resilient to random error. We conclude that correlated, low-frequency oscillations in human fMRI data have a small-world architecture that probably reflects underlying anatomical connectivity of the cortex. Because the major hubs of this network are critical for cognition, its slow dynamics could provide a physiological substrate for segregated and distributed information processing.

Adult↗

Methadone effects on brain functioning and type A and B CNV shapes.

Twelve male outpatients participating in a methadone maintenance treatment program were evaluated for the effects of acute administration of methadone on brain functioning (contingent negative variation or CNV), attention performance (reaction time and continuous performance test), and psychophysiological activity (heart rate and eye blink rate). Individual differences in response to methadone were assessed by classifying patients into two groups on the basis of basal CNV shapes: Type A (quick rise time) and type B (slow rise time). Methadone produced a pattern of increased electrical brain activity (CNV) and enhanced attention performance in type B patients and elevated heart rate and lowered eye blink rate in type A subjects. Results are interpreted in terms of the distraction-arousal and the eye blink-hedonia hypotheses.

Adult↗

Binding in models of perception and brain function.

The development of the concept of feature binding as fundamental to neural dynamics has made possible recent advances in the modeling of difficult problems of perception and brain function. Major weaknesses of past neural modeling (most prominently its inability to work with natural stimuli and its 'learning-time' barrier) have been traced back to improper treatment of the binding issue. Signal synchrony is now seen as playing a major role in binding. Inclusion of temporal binding in neural models has led to recent breakthroughs in solving important perceptual problems. Among them is perceptual segmentation, invariant object recognition and natural language parsing, as well as overcoming the 'learning-time' barrier.

Animals↗

Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females.

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with APOE epsilon2 and epsilon3, APOE epsilon4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.

Age Factors↗

Anatomic standardization: linear scaling and nonlinear warping of functional brain images.

UNLABELLED: An automated method was proposed for anatomic standardization of PET scans in three dimensions, which enabled objective intersubject and cross-group comparisons of functional brain images. METHODS: The method involved linear scaling to correct an individual brain size and nonlinear warping to minimize regional anatomic variations among subjects. In the linear-scaling step, the anteroposterior length and width of the brain were measured on the PET images, and the brain height was estimated by a contour-matching procedure using the midsagittal plane. In the nonlinear warping step, individual gray matter locations were matched with those of a standard brain by maximizing correlation coefficients of regional profile curves determined between predefined stretching centers (predominantly in white matter) and the gray matter landmarks. RESULTS: The accuracy of the brain height estimation was compared with skull x-ray estimations, showing comparable accuracy and better reproducibility. Linear-scaling and nonlinear warping methods were validated using [18F]fluorodeoxyglucose and [15O]water images. Regional anatomic variability on the glucose images was reduced markedly. The statistical significance of activation foci in paired water images was improved in both vibratory and visual activation paradigms. A group versus group comparison following the proposed anatomic standardization revealed highly significant glucose metabolic alterations in the brains of patients with Alzheimer's disease compared with those of a normal control group. CONCLUSION: These results suggested that the method is well suited to both research and clinical settings and can facilitate pixel-by-pixel comparisons of PET images.

Algorithms↗

Probing emotion in the developing brain: functional neuroimaging in the assessment of the neural substrates of emotion in normal and disordered children and adolescents.

Virtually all developmental neuropsychiatric disorders involve some dysfunction or dysregulation of emotion. Moreover, many psychiatric disorders with adult onset have early subclinical manifestations in children. This essay selectively reviews the literature on the neuroimaging of affect and disorders of affect in children. Some critical definitional and conceptual issues are first addressed, including the distinctions between the perception and production of emotion and between emotional states and traits. Developmental changes in morphometric measures of brain structure are then discussed and the implications of such findings for studies of functional brain activity are considered. Data on functional neuroimaging and childhood depression are then reviewed. While the extant data in this area are meager, they are consistent with studies in adults that have observed decreased left-sided anterolateral prefrontal cortex activation in depression. Studies in children on the recognition of emotion and affective intent in faces using functional magnetic resonance imaging are then reviewed. These findings indicate that the amygdala plays an important role in such affective face processing in children, similar to the patterns of activation observed in adults. Moreover, one study has reported abnormalities in amygdala activation during a task requiring the judgment of affective intent from the eye region of the face in subjects with autism. Some of the methodological complexities of developmental research in this area are discussed, and directions for future research are suggested.

Adolescent↗

Impact of cannabis use on brain function in adolescents.

Cannabis is the most common illicit substance used by adolescents. This paper reports results of a pilot study using fMRI and a working memory task to compare brain function of adolescent cannabis users to that of two control groups, one matched for tobacco use and the other for nonsmokers.

Adolescent↗

Relationships between measures of brain functions and general intelligence.

Relationships between measures of general intelligence (Wechsler-Bellevue Verbal IQ, Performance IQ, and Full-scale IQ) and a measure designed to reflect adequacy of brain functions (Halstead Impairment Index) were studied using a control group and groups with left, right and generalized cerebral lesions. The results confirmed earlier findings of (1) differential levels of Verbal and Performance intelligence depending on damage of the left or right cerebral hemisphere; and (2) the greater general sensitivity of the Impairment Index than IQ values to brain damage. Comparative data suggested particularly that IQ values may underestimate brain-dependent adaptive abilities among non-brain-damaged subjects. A significant relationship between IQ values and the Impairment Index was present. This finding permitted evaluation of use of a differing cut-off Impairment Index, as an indicator of cerebral damage, depending on the subject's IQ level. The results suggested that increased accuracy in classifying subjects as brain-damaged might be achieved using a cutting Impairment Index of .4 or greater when the IQ value is 100 or more and .5 or greater when the IQ value is below 100.

Adult↗

Whole-brain functional mapping with isotropic MR imaging.

PURPOSE: To assess the reliability and sensitivity of gradient-echo, isotropic multisection echo-planar magnetic resonance (MR) imaging for within-subject whole-brain mapping. MATERIALS AND METHODS: Eight right-handed healthy volunteers underwent gradient-echo, echo-planar MR imaging while they performed a motor task on three occasions over 2-3 months. Ninety-six whole-brain volumes were acquired in 8 minutes 48 seconds. A rigorous statistical threshold for determining activation was set at P < .05 and was Bonferroni corrected for approximately 15,000 cortical voxels. RESULTS: In all subjects, reproducible activation was demonstrated in multiple cortical areas and in the cerebellum specific to the motor system. Of the activated voxels, 75%-78% were confined to the motor areas during all sessions. No statistically significant difference was found in the proportion of activated voxels in any motor region (relative to the total number of activated voxels in the whole brain) across the three sessions. The centers of mass of the activated areas were within 2.5 resolution elements of the image across the three sessions. CONCLUSION: Isotropic multisection echo-planar MR imaging, has the potential for noninvasive, reliable within-subject mapping of whole-brain functional anatomy.

Adult↗

In vivo multiparametric monitoring of brain functions under intracranial hypertension following mannitol administration.

OBJECTIVE: Over the last 20 years, mannitol has replaced other osmotic diuretics. Its beneficial effects on intracranial pressure (ICP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF) and brain metabolism are widely accepted. In the present study, we tested the effect of mannitol injection on brain hemodynamic, metabolic, ionic and electrical state in rats exposed to intracranial hypertension. METHODS: The parameters monitored simultaneously included ICP, CBF using the laser Doppler flowmetry, mitochondrial NADH redox state by the fluorometric technique, extracellular K(+) and H(+) levels, DC potential, ECoG, blood pressure and calculated CPP. ICP was elevated to 30 mmHg for 30 minutes and mannitol was injected 15 minutes post-ICP elevation. RESULTS: Our results showed that mannitol decreased ICP, and improved the levels of MAP, CPP and CBF. Moreover, mannitol completely prevented mortality following intracranial hypertension in rats. CONCLUSION: It seems that the multiparametric monitoring approach, used in intracranial hypertension models, is an important tool for brain functional state evaluation.

Animals↗

PET and the effects of aging and neurodegeneration on brain function: basic principles.

In the first part of a three-part series on the role of positron emission tomography (PET) in the study of neurodegeneration and aging in the human brain, the authors review the historical development of the in vivo measurement of brain function resulting in recent advances in PET technology. An overview is presented of the physical principles of PET scanning and the inherent limitations of this technology to set the basis for the critical interpretation of PET data presented in the second and third parts and in the ever-increasing number of PET studies on the brain in different physiological and pathological conditions. Finally, the authors describe the ability to measure in vivo regional cerebral glucose metabolism with [(18)F]-FDG PET, regional cerebral blood flow and the distribution and binding capacity of neuroreceptors. They conclude with future perspectives of PET technology and its relevance, especially for neuropsychiatric research.

Journal Article↗