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Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer's disease: PET study using parametric visual stimulation.

OBJECTIVE: The authors examined the interaction of Alzheimer's disease severity and visual stimulus complexity in relation to regional brain function. METHOD: Each subject had five positron emission tomography [15]H2O scans while wearing goggles containing a grid of red lights embedded into each lens. Regional cerebral blood flow (CBF) was measured at 0 Hz and while lights were flashed alternately into the two eyes at 1, 4, 7, and 14 Hz. Changes in regional CBF from the 0-Hz baseline were measured at each frequency in 19 healthy subjects (mean age = 65 years, SD = 11), 10 patients with mild Alzheimer's disease (mean age = 69, SD = 5; Mini-Mental State score > or = 20), and 11 patients with moderate to severe Alzheimer's disease (mean age = 73, SD = 12; Mini-Mental State score < or = 19). RESULTS: As pattern-flash frequency increased, CBF responses in the comparison group included biphasic rising then falling in the striate cortex, linear increase in visual association areas, linear decrease in many anterior areas, and a peak at 1 Hz in V5/MT. Despite equivalent resting CBF and CBF responses to low frequencies among all groups, the groups with Alzheimer's disease had significantly smaller CBF responses than the comparison group at the frequency producing the largest response in the comparison group in many brain regions. Also, patients with moderate/severe dementia had smaller responses at frequencies producing intermediate responses in comparison subjects. CONCLUSIONS: Functional failure was demonstrated in patients with mild dementia when large neural responses were required and in patients with moderate/severe dementia when large and intermediate responses were required.

Aged↗

Scale-free brain functional networks.

Functional magnetic resonance imaging is used to extract functional networks connecting correlated human brain sites. Analysis of the resulting networks in different tasks shows that (a) the distribution of functional connections, and the probability of finding a link versus distance are both scale-free, (b) the characteristic path length is small and comparable with those of equivalent random networks, and (c) the clustering coefficient is orders of magnitude larger than those of equivalent random networks. All these properties, typical of scale-free small-world networks, reflect important functional information about brain states.

Brain Mapping↗

Heritability of human brain functioning as assessed by electroencephalography.

To study the genetic and environmental contributions to individual differences in CNS functioning, the electroencephalogram (EEG) was measured in 213 twin pairs age 16 years. EEG was measured in 91 MZ and 122 DZ twins. To quantify sex differences in the genetic architecture, EEG was measured in female and male same-sex twins and in opposite-sex twins. EEG was recorded on 14 scalp positions during quiet resting with eyes closed. Spectral powers were calculated for four frequency bands: delta, theta, alpha, and beta. Twin correlations pointed toward high genetic influences for all these powers and scalp locations. Model fitting confirmed these findings; the largest part of the variance of the EEG is explained by additive genetic factors. The averaged heritabilites for the delta, theta, alpha and beta frequencies was 76%, 89%, 89%, and 86%, respectively. Multivariate analyses suggested that the same genes for EEG alpha rhythm were expressed in different brain areas in the left and right hemisphere. This study shows that brain functioning, as indexed by rhythmic brain-electrical activity, is one of the most heritable characteristics in humans.

Adolescent↗

Hyperventilation impairs brain function in acute cerebral air embolism in pigs.

OBJECTIVE: To evaluate, in a model of cerebral air embolism (CAE), the effects of ventilation-induced hypocapnia and hyperoxemia on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain oxygen (PbrO(2)), brain carbon dioxide (PbrCO(2)), brain pH (brpH) and levels of brain glucose and lactate. DESIGN AND SETTING: Prospective animal study in a university medical center. SUBJECTS: Fifteen Landrace/Yorkshire pigs. INTERVENTIONS: In 15 anesthetized pigs ICP, PbrO(2), PbrCO(2) and brpH were measured with multi-parameter sensors, and brain glucose and lactate by microdialysis. All these parameters were recorded for 2 h after injection of air into the internal carotid artery. Nine animals were hyperventilated (PaCO(2 )+/-25 mmHg) and hyperoxygenated (FiO(2) 1.0) and six animals were normoventilated (PaCO(2)()+/-40 mmHg with an FiO(2) 0.4) and served as controls. RESULTS. In the treatment group the ICP rose from 8+/-1 to 52+/-6 mmHg, which was similar to that in the control group (12+/-1 to 57+/-8 mmHg). At the end of the 2-h study period, there were no significant differences in PbrO(2), PbrCO(2) and brpH between the two groups. The decreased brain glucose and increased brain lactate reached severe pathological values in both groups by the end of the 2-h study period. CONCLUSIONS: Hypocapnia and hyperoxemia in acute CAE did not improve pathological functional brain parameters compared with normoventilated controls. Similarly, the pathological changes in brain glucose/lactate could also not be improved by hypocapnia and hyperoxemia.

Animals↗

Imaging of brain function using SPECT.

Single photon emission computed tomography (SPECT) is a technique widely used in nuclear medicine for the imaging of the many organs including the skeleton and heart, as well as for whole body imaging for the detection of tumors. The use of tracers of cerebral perfusion and more recently brain neurotransmitter systems has resulted in the development of a number of applications for brain SPECT in neurology and psychiatry. Indications have been established in cases of dementia, epilepsy, neurovascular disorders, Parkinsonism, and following minor head trauma. It also has the potential to be a valuable research tool for the study of in vivo brain function. In this paper an overview will be given of the principles underlying Brain SPECT, the performance of the procedure, and its applications as a diagnostic modality and research tool.

Brain Diseases↗

Cardiopulmonary bypass temperature and brain function.

A debate has emerged in recently published studies about the optimum cardiopulmonary bypass temperature for good neurological outcome - warm vs. cold, i.e. normothermic vs. hypothermic. Although many comparative studies have been performed, the results of these studies are inconclusive and are difficult to interpret. Brain function has been studied in terms of neurological and neuropsychological outcome, protein S100beta levels as a marker of brain damage, and cerebral oxygenation using jugular bulb oximetry and near-infrared spectroscopy. The studies produce no conclusive proof of the superiority of warm or cold cardiopulmonary bypass. However, it appears that any degree of bypass hypothermia (< 35 degrees C) may protect the brain. On the other hand, even a slight increase in bypass temperature to > 37 degrees C may cause marked brain injury.

Brain↗

Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.

Phenylalanine and tyrosine constitute the two initial steps in the biosynthesis of dopamine, which, in its turn, is the metabolic precursor of noradrenaline and adrenaline. The extracellular phenylalanine concentration influences brain function in phenylalanine deficiency (PHD) by decreased dopamine synthesis. It has been shown to induce EEG slowing, and prolonged the performance time on neuropsychological tests. The tyrosine concentration in the CNS is reduced in PHD, possibly implying insufficient substrate (= tyrosine) for catecholamine synthesis due to competition inhibition, for instance across the blood brain barrier. In experimental studies it has been shown that the synthesis and release of dopamine can be influenced by an increase in the availability of tyrosine. In PHD an extra dietary intake of three doses of tyrosine (160 mg/kg/24h) induced a shortening of reaction time and decreased variability, and in a double-blind crossover study a similar dose has been reported to induce an improvement on psychological tests. In a study with lower doses of tyrosine (110 mg/kg/24 h) no effect was found on reaction time tests. These findings need to be substantiated, and more detailed information should be obtained.

Brain Chemistry↗

Brain functional involvement by perfusion SPECT in systemic sclerosis and Behçet's disease.

Involvement of the central nervous system is frequent in systemic immune-mediated diseases, such as systemic lupus erythematosus, Behçet's disease (BD), and systemic sclerosis (SSc). Structural brain examinations, such as computed tomography and magnetic resonance imaging, may be useful in diagnosing and following-up these cerebral syndromes in some cases, but they are more often inconclusive. Single photon emission computed tomography (SPECT) with perfusion tracers is a powerful method that can disclose brain involvement in many clinical situations, even in patients with subtle neurological symptoms. In fact, perfusion tracers can disclose regional hypoperfusion caused by both ischemia due to vascular narrowing and neuronal metabolic derangement due to direct neuronal damage. The latter phenomenon occurs because the blood flow to the brain is strictly regulated by metabolic demands, so that hypometabolism is reflected by hypoperfusion in most instances. SPECT findings in 42 mainly neurologically asymptomatic patients with SSc and in eight mainly neurologically symptomatic patients with BD are reported. SPECT was shown to be very sensitive and disclosed brain functional deficits in approximately half of SSc patients without neurological complaints and in all patients with BD, who had various neurological symptoms but usually inconclusive structural brain examinations.

Aged↗

Functional brain asymmetry, handedness and age characteristics of climacterium in women.

A total of 1985 women aged between 55 and 65 were distributed into two groups (145 left-handers and 1840 right-handers). They were asked to complete a questionnaire on the appearance of menopause, duration of menopausal transition and age of menopause. In left-handed women a significantly earlier appearance of premenopause was established together with a shorter menopause transition and an earlier occurrence of menopause. These results give grounds for a correlation between handedness, functional brain asymmetry, respectively and the genetically determined fading away of ovary steroidogenesis associated with the appearance and progression of the climacterium. In light of the available literature we assume that progressive reduction in ovarian function during climacterium is coupled with possible specific functioning of the hypothalamo-pituitary-gonadal axis, dependent on the type of hemispheric asymmetry.

Aged↗

Steroid effects on brain functions: an example of the action of glucocorticoids on central dopaminergic and neurotensinergic systems.

It is now clearly established that steroid hormones released from peripheral endocrine glands may, through specific receptors in the brain, directly regulate brain function. These effects may be rapid or involve long-term modifications at the genomic level. Concerning the glucocorticoids, their receptors are found in most neuronal cells, an observation which can be related to their widespread effects on neuronal metabolism. Furthermore, glucocorticoids are often related to stress. We have previously demonstrated that neonatal handling of the rat prevented excessive endocrine response to stress. In adults, this action appeared to protect the animal from potential damaging effects of glucocorticoids and from related impairment of cognitive functions. The effects of glucocorticoids are thought to involve an interaction of several central neurotransmitter systems. One such neurotransmitter is neurotensin, a neuropeptide which was reported to be closely related to central dopaminergic system regulation. This paper presents a rapid overview of the central effects of glucocorticoids and possible evidence for the interrelationship between these steroids, dopamine and neurotensin systems in the regulation of the hypothalamo-pituitary-adrenal axis. It provides a new way to approach stress responses and to develop new substances that may become potential drugs in the treatment of some psychiatric disorders.

Adrenocorticotropic Hormone↗

Possible role of histamine in brain function: neurochemical, physiological, and pharmacological indications.

Recently accumulated neurochemical, physiological, and pharmacological evidence strongly supports a role for histamine as a central neurotransmitter. Neurochemical methods, which became available within the last years, allow determination of small amounts of histamine and its metabolites in the brain and make possible future studies of central histamine regulation. The demonstration of histamine H1 and H2 receptors in the brain of several species suggests a possible role for histamine in brain function. Microelectrophysiological studies on single central neurones suggest both excitatory and depressant effects of histamine which are receptor mediated. In addition, brain histamine has been demonstrated to be subject to cyclic variations, to play a role in hormonal regulation, and to be altered by stressful conditions. Several psychotropic drugs significantly affect brain histamine regulation and elicit inhibitory effects on central histamine receptors. These findings bring new approaches and stimulus to further research on the significance of brain histamine.

Animals↗

Effect of acute doses of controlled-release carbamazepine on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function.

The neurotoxic effect of acute doses of carbamazepine controlled-release (CBZ-CR) divitabs (800, 1,200, and 1,600 mg) was assessed on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function in 10 healthy volunteers in a double-blind, randomised, placebo-controlled, phase I study. Significant changes compared to placebo were demonstrated for the clinical scales, ataxia (AT), convergence of the near-point (CNP), peak saccadic velocity (PSV), critical flicker fusion (CFF), spectral analysis of the EEG, and brainstem auditory evoked potential (BAEP) tests. Digit repetition, digit symbol substitution, Sternberg memory scanning time, Sternberg choice reaction time, saccadic latency, and saccadic accuracy showed important negative findings. Significant clinical tolerance to side effects developed within 20 to 33 h after CBZ-CR dosage during a period in which the mean CBZ blood levels remained virtually unchanged. CBZ-CR, 800, 1,200, and 1,600 mg yielded low, medium, and high therapeutic blood levels, respectively, for +10 to +33 h after dosage without the development of severe clinical side effects.

Adult↗

Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals.

This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely to result in altered brain concentrations of the n-3 fatty acid docosahexaenoic acid (DHA) during the perinatal period of "brain growth spurt." Experimental designs reviewed include observational breastfeeding studies and randomized controlled trials in humans and studies in rodents and nonhuman primates. This review is based on a large number of expert reviews and commentaries and on some 50 recent studies in humans and animals that have not yet been included in published reviews. Expert opinion regarding the strengths and weaknesses of the major experimental systems and uncertainties associated with interpreting results is summarized. On the basis of our reading of this literature, we conclude that evidence from several types of studies, particularly studies in animals, suggests that, within the context of specific experimental designs, changes in brain concentrations of DHA are positively associated with changes in cognitive or behavioral performance. Additional experimental information required to conclude that a causal association exists is discussed, as are uncertainties associated with applying results from specific experimental designs to the question of whether infant formula should be supplemented with DHA.

Animals↗

Roles of diverse glutamate receptors in brain functions elucidated by subunit-specific and region-specific gene targeting.

Glutamate receptor (GluR) channels play a major role in fast excitatory synaptic transmission in vertebrate central nervous system. We revealed the molecular diversity of the GluR channel by molecular cloning and investigated their physiological roles by subunit-specific gene targeting. NMDA receptor GluRepsilon1 KO mice showed increase in thresholds for hippocampal long-term potentiation and hippocampus-dependent contextual learning. The mutant mice performed delay eyeblink conditioning, but failed to learn trace eyeblink conditioning. GluRepsilon1 mutant suffered less brain injury after focal cerebral ischemia. NMDA receptor GluRepsilon2 KO mice showed impairment of the whisker-related neural pattern formation and suckling response, and died shortly after birth. Heterozygous (+/-) GluRepsilon2 mutant mice were viable and showed enhanced startle response to acoustic stimuli. GluRdelta2, a member of novel GluR channel subfamily we found by molecular cloning, is selectively expressed in the Purkinje cells of the cerebellum. GluRdelta2 KO mice showed impairments of cerebellar synaptic plasticity and synapse stability. GluRdelta2 KO mice exhibited impairment in delay eyeblink conditioning, but learned normally trace eyeblink conditioning. The phenotypes of NMDA receptor subunits and GluRdelta2 mutant mice suggest that diverse GluR subunits play differential roles in the brain functions.

Animals↗

Modulation of cerebral blood oxygenation by indomethacin: MRI at rest and functional brain activation.

The modulation of blood oxygenation level-dependent (BOLD) cerebral MRI contrast by the vasoconstrictive drug indomethacin (i.v. 0.2 mg/kg b.w.) was investigated in 10 healthy young adults without and with functional challenge (repetitive and sustained visual activation). For comparison, isotonic saline (placebo, 20 mL) and acetylsalicylate (i.v. 500 mg) were investigated as well, each in separate sessions using identical protocols. After indomethacin, dynamic T2*-weighted echo-planar MRI at 2.0 T revealed a rapid decrease in MRI signal intensity by 2.1%-2.6% in different gray matter regions (P < or = 0.001 compared to placebo), which was not observed for acetylsalicylate and the placebo condition. Regional signal differences were not significant within gray matter, but all gray matter regions differed significantly from the signal decrease of only 1.2% +/- 0.7% observed in white matter (P = 0.001). For the experimental parameters used, a 1% MRI signal decrease in response to indomethacin was estimated to correlate with a decrease of the cerebral blood flow by about 12 ml/100 g/minute, and an increase of the oxygen extraction fraction by about 15%. Responses to visual activation were not affected by saline or acetylsalicylate, and yielded 5.0%-5.5% BOLD MRI signal increases both before and after drug application. In contrast, indomethacin reduced the initial response strength to 82%-85% of that obtained without the drug. The steady-state response during sustained activation reached only 47% of the corresponding pre-drug level (P < 0.01). During repetitive activation the BOLD contrast was reduced to 66% of that observed for control conditions (P < 0.001). In conclusion, indomethacin attenuates the vasodilatory force at functional brain activation, indicating different mechanisms governing neurovascular coupling.

Adult↗