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The effects of anesthetics on brain activity and cognitive function.

PURPOSE OF THIS REVIEW: This review presents an overview of recent findings related to changes in brain activity with increasing anesthesia mainly obtained with brain imaging and electrophysiological techniques in humans. RECENT FINDINGS: Recent studies have revealed that the brain as a whole is not affected to the same degree by anesthetics, but that specific brain regions (and particular cognitive processes mediated by these regions) are more sensitive to anesthesia and sedation than others. Inhibition of activity in multimodal association cortices (such as parietal and prefrontal association cortices) by sedative concentrations of anesthetics produces amnesia and attention deficits, whereas activity in unimodal cortices and in the thalamus remains largely unaffected by low doses of anesthetics. Activity in the midbrain reticular formation, thalamus, and unimodal cortices appears to be suppressed only by anesthetic concentrations causing unconsciousness. Besides those regional suppressive effects, anesthetics impair functional connections between neurons in distributed cortical and thalamocortical networks, which also contributes to the state of anesthesia. SUMMARY: Anesthetics produce changes in the patient's behavioral state by interacting with brain activity via at least two mechanisms: the dose-dependent global and regionally specific suppression of neuronal activity and the disruption of functional interactivity within distributed neural networks.

Journal Article↗

Effects of N,N'-bisdimethyl-1,2-ethanediamine dichloride, a double-chain surfactant, on membrane-related functions in human erythrocytes.

The effects of N,N'-bisdimethyl-1,2-ethanediamine dichloride (dioctyldiQAS), a double chain surfactant with two positive charges in the polar head, on the erythrocyte membrane were studied. At sublytic concentrations dioctyldiQAS protected erythrocytes against hypotonic hemolysis, induced the formation of sphero-echinocytes, increased passive fluxes of potassium through the membrane, decreased the activity of the Na(+)-K(+)-pump and decreased the efflux of phosphate. The alterations in membrane-connected functions induced by dioctyldiQAS are qualitatively similar to those induced by its single-chain close analogue decyltrimethylammonium bromide. DioctyldiQAS, however, exhibited these effects at considerably lower concentrations than decyltrimethylammonium bromide. This is most likely due to a higher extent of partitioning into the membrane by dioctyldiQAS.

Erythrocyte Membrane↗

Effects of gangliosides on the development of selective afferent connections within fetal mouse spinal cord explants.

Monosynaptic evoked responses were used to localize dorsal root ganglion (DRG) afferent terminals within organotypic fetal mouse spinal cord explants which had been chronically exposed to purified bovine gangliosides during early development. Ganglioside grown cultures showed a highly significant increase in dorsal cord innervation preferences in comparison with control cultures. The amount of evoked activity was significantly lower than was observed in controls, suggesting that the formation of 'incorrect' functional connections was blocked by specific chemical factors. Exposure to N-acetylgalactosamine, a major ganglioside amino sugar, also resulted in an increased dorsal cord innervation preference by the DRG afferents.

Acetylgalactosamine↗

A long-range cortical network emerging with theta oscillation in a mental task.

Human scalp EEG has demonstrated that global coherence among distant areas increases during cognitive tasks, suggesting that oscillating neural activities work to generate global neuronal assemblies for cognitive functions. The theta oscillation in a frequency range of 4-8 Hz with large amplitudes which emerges during mental tasks around the frontal midline region is called fm theta. If theta oscillation concerns the global neuronal assemblies, fm theta should be associated with regional activities that depend on task conditions. In the present study, we examine the EEG-related brain activities by developing simultaneous EEG and fMRI during a mental calculation task. EEG-related negative BOLD was dominant over anterior medial regions, suggesting a major contribution of negative BOLD to fm theta. Negative and positive BOLD were found over distant regions. Functional connectivity analyses revealed that the connectivity varied remarkably according to mental conditions. In the rest condition, the connectivity was localized, whereas in the task condition, a long-range coherent network was formed by the anterior midline, posterior cingulate and right middle temporal cortices with linking between the right middle temporal and left lateral cortices during numerical processing. Further EEG analyses indicate that the long-range coherent network executing cognitive functions is coordinated in the time window of theta oscillations.

Action Potentials↗

Behavioral and neurochemical alterations following intracerebroventricular administration of anti-serotonin antibodies in adult Balb/c mice.

The effects of intracerebroventricular injections of serotonin (5-HT) antibodies were studied for changes in 5-HT, dopamine (DA), their metabolites and norepinephrine (NE) as well as 5-HT mediated behavior in adult mice. While nociceptive thresholds (tail-flick latency) were inhibited in antibody treated animals, tremor response to 5-methoxy-N,N-dimethyl tryptamine administration was increased. 5-HT and DA in the nucleus raphe dorsalis (NRD), substantia nigra (SN), nucleus caudatus putamen (NCP) and in the substantia grisea centralis, and NE in the former two nuclei were significantly decreased in these animals. 5-Hydroxyindoleacetic acid was unaffected in all nuclei except NRD, where it was inhibited. Homovanillic acid and 3,4-dihydroxyphenylacetic acid were inhibited in all nuclei except in NCP. The brunt of insult was more evident in NRD and SN where all neurotransmitters were inhibited for a longer period. 5-HT turnover was increased in all the nuclei, however only SN showed increased DA turnover. It may be assumed that the observed neurochemical and behavioral changes were the consequence of the antibodies binding to 5-HT, which in turn influenced the anatomically and functionally connected neurotransmitters. While the study contributes to the existing understanding of central neurotransmitter control on behavior, it fails to delineate the underlying mechanism. The possibility of developing a useful, drug-free 5-HT deficient animal model for studying clinical disorders, as well as for solving some of the basic questions related to the physiological functions of 5-HT in adult animals are envisaged from the study.

Animals↗

The insular lobe of Reil--its anatamico-functional, behavioural and neuropsychiatric attributes in humans--a review.

There is considerable clinical and experimental research to explore the anatamico-functional correlations of the limbic lobe to establish its relevance in modern neuroscience. The insula being a pivotal structure in the concept of the greater limbic lobe, we have attempted to highlight in this review the topographical anatomy and development, the remarkable heterogeneity of the insular cortical architecture, the widespread multifaceted spectrum of functional connectivity patterns and how this is translated to its behavioural specialisation in humans. The insula serves as an intergration cortex for multimodal convergence of distributed neural networks such as the somesthetic-limbic, insulo-limbic, insulo-orbito-temporal and the prefrontal-striato-pallidal-basal forebrain. This provides the conceptual framework to facilitate functional and clinical considerations relevant to the various behavioural and neuropsychiatric disorders outlined in this review. The functional role of the insula in these disorders with particular reference to the current functional neuroimaging data has been also reviewed in this article.

Cerebral Cortex↗

Ion exchanges through respiratory and chloride cells in freshwater- and seawater-adapted teleosteans.

The present study discusses the respective roles of the chloride and respiratory cells in branchial ion exchange in freshwater- and seawater-adapted teleosts. In the gill, two distinct epithelia are defined according to their blood irrigation and cellular characteristics: the primary lamellar epithelium containing mostly chloride cells is functionally connected to the venous compartment; the secondary lamellar epithelium consisting of respiratory cells is irrigated by the arterioarterial circulation. The fundamental reorganization occurring in the chloride cells during adaptation to seawater consists of the appearance of leaky ultrastructure related to an increase in the ionic and nonelectrolyte permeabilities of the primary lamellar epithelium. The physiological functions of respiration, excretion, and the maintenance of acid-base balance occur through the secondary lamellar epithelium both in freshwater and seawater fish. The increase of the exchange diffusion across the secondary lamellar epithelium on seawater adaptation is directly related to the increase in the external salinity. The study of adrenergic control in the teleost gill emphasizes the functional advantage to the fish during adaptation to seawater of the anatomic separation of the osmoregulatory primary lamellar epithelium.

Adaptation, Physiological↗

Analysis of neural interactions explains the activation of occipital cortex by an auditory stimulus.

Analysis of neural interactions explains the activation of occipital cortex by an auditory stimulus. J. Neurophysiol. 80: 2790-2796, 1998. Large-scale neural interactions were characterized in human subjects as they learned that an auditory stimulus signaled a visual event. Once learned, activation of left dorsal occipital cortex (increased regional cerebral blood flow) was observed when the auditory stimulus was presented alone. Partial least-squares analysis of the interregional correlations (functional connectivity) between the occipital area and the rest of the brain identified a pattern of covariation with four dominant brain areas that could have mediated this activation: prefrontal cortex (near Brodmann area 10, A10), premotor cortex (A6), superior temporal cortex (A41/42), and contralateral occipital cortex (A18). Interactions among these regions and the occipital area were quantified with structural equation modeling to identify the strongest sources of the effect on left occipital activity (effective connectivity). Learning-related changes in feedback effects from A10 and A41/42 appeared to account for this change in occipital activity. Influences from these areas on the occipital area were initially suppressive, or negative, becoming facilitory, or positive, as the association between the auditory and visual stimuli was acquired. Evaluating the total effects within the functional models showed positive influences throughout the network, suggesting enhanced interactions may have primed the system for the now-expected visual discrimination. By characterizing both changes in activity and the interactions underlying sensory associative learning, we demonstrated how parts of the nervous system operate as a cohesive network in learning about and responding to the environment.

Acoustic Stimulation↗

Biochemistry and turnover of lung interstitium.

The lung contains a host of extracellular matrix components that comprise the supporting and adhesive elements of conducting airways, alveoli and the vascular tree. While none of these components is unique to the lung, their peculiar distribution determines the architecture and function of this gas exchange organ. Cells and tissues of the lung interact with the matrix through a variety of surface receptors, especially the integrins and adhesive molecules, some of which may play important roles in lung injury and repair. Collagen type I is the predominant determinant of tensile strength, but as many as 11 other genetic types of collagen with specialized adhesive and connecting functions can be found in various lung structures, including cartilage and basement membranes. Excessive matrix accumulation in the lung is the result of a complex set of influences on gene regulation, part of which may be due to the presence of inflammatory cytokines that directly stimulate matrix synthesis. However, degradation and turnover of the matrix are also critical processes influenced by many of the same mediators. Collagenase and gelatinase (type IV collagenase) are tightly-regulated metalloenzymes that, together with a set of specific inhibitors of metalloproteinases, determine the net abundance and distribution of collagen. Elastases of several biochemical types are also under tight regulation by proteinase inhibitors. Elastin is essential to lung function at the level of alveolar wall resiliency and patency, and loss of elastin in emphysema appears to be due to uncontrolled degradation of the embryologically-established pattern of elastic fibres accompanied by nonfunctional replacement as a response to injury. Injury to the vascular endothelium of the lung, as well as other physiological insults that elevate pulmonary blood pressure, can lead to the excessive accumulation of collagen and elastin in the conductance and resistance arteries of the pulmonary circulation. Mechanical stress and endothelial injury may mediate the medial hypertrophy of these vessels. Extracellular matrix components are critically involved in every stage of lung biology: development, normal function and acute and chronic disease states. To date, only glucocorticoids, cross-linking inhibitors, and protease inhibitors have been used in a general attempt to suppress either excessive matrix accumulation or loss. More detailed understanding of the regulation and specific interactions of matrix components is central to the analysis of disease states and the development of appropriate therapeutic strategies.

Cell Adhesion Molecules↗

Neural representation of language: activation versus long-range connectivity.

Cognitive functions are thought to build on connectivity within large-scale neuronal networks, rather than on strictly localized processes. Yet, present understanding of neural mechanisms of language function, as derived from neuroimaging, is based on mapping brain areas that are more active during specific linguistic tasks than in control conditions. Connectivity can then be evaluated among those areas. However, network nodes should ideally be determined based on their correlated time series of activity. Recent developments in analysis methods now facilitate localization and characterization of functionally connected neural networks directly from real-time magnetoencephalography data. Analysis of long-range connectivity might clarify and expand the view provided by traditional neurophysiological and hemodynamic activation studies. Here, we use silent reading as the example process.

Brain↗

Consistent resting-state networks across healthy subjects.

Functional MRI (fMRI) can be applied to study the functional connectivity of the human brain. It has been suggested that fluctuations in the blood oxygenation level-dependent (BOLD) signal during rest reflect the neuronal baseline activity of the brain, representing the state of the human brain in the absence of goal-directed neuronal action and external input, and that these slow fluctuations correspond to functionally relevant resting-state networks. Several studies on resting fMRI have been conducted, reporting an apparent similarity between the identified patterns. The spatial consistency of these resting patterns, however, has not yet been evaluated and quantified. In this study, we apply a data analysis approach called tensor probabilistic independent component analysis to resting-state fMRI data to find coherencies that are consistent across subjects and sessions. We characterize and quantify the consistency of these effects by using a bootstrapping approach, and we estimate the BOLD amplitude modulation as well as the voxel-wise cross-subject variation. The analysis found 10 patterns with potential functional relevance, consisting of regions known to be involved in motor function, visual processing, executive functioning, auditory processing, memory, and the so-called default-mode network, each with BOLD signal changes up to 3%. In general, areas with a high mean percentage BOLD signal are consistent and show the least variation around the mean. These findings show that the baseline activity of the brain is consistent across subjects exhibiting significant temporal dynamics, with percentage BOLD signal change comparable with the signal changes found in task-related experiments.

Brain↗

Logistic patterning of brain activity.

Brain activity is a set of electrochemical events in the neural tissue during a specified period of time. Neural networks are the functionally connected and dynamically organized population of neurons and neuroglial cells, serving as a unified interface between environmental input and behavioral output at a specified time. They are patterned dynamically in neural space, time and intensity. It is proposed that 1. the electrophysiological patterning of brain activity follows the laws of logistic growth, decay and impulse response function and 2. that this process of logistic transform (LOGIT) of electrochemical processes is itself the general code of information transfer in the brain. A mathematical model of logistic transformation and new electrophysiological data based on the topographic mapping of event-related potentials (ERP) during selective auditory attentional tasks from nine healthy adults is presented. The N100-P200 and the N200-P300 segments of ERP's were analyzed at 20 ms intervals. Logarithmic latencies and voltages were highly correlated. Significant correlation was found between the mathematically estimated and actual values. The interpeak latencies also followed the logistic growth pattern and could be predicted by the model. A general equation of logistic transformation of brain activity, including variables of cortical voltage and frequency is proposed.

Adult↗

COG-2, a sox domain protein necessary for establishing a functional vulval-uterine connection in Caenorhabditis elegans.

In screens for mutants defective in vulval morphogenesis, multiple mutants were isolated in which the uterus and the vulva fail to make a proper connection. We describe five alleles that define the gene cog-2, for connection of gonad defective. To form a functional connection between the vulva and the uterus, the anchor cell must fuse with the multinucleate uterine seam cell, derived from uterine cells that adopt a (pi) lineage. In cog-2 mutants, the anchor cell does not fuse to the uterine seam cell and, instead, remains at the apex of the vulva, blocking the connection between the vulval and uterine lumens, resulting in an egg-laying defective phenotype. According to lineage analysis and expression assays for two (pi)-cell-specific markers, induction of the (pi) fate occurs normally in cog-2 mutants. We have cloned cog-2 and shown that it encodes a Sox family transcription factor that is expressed in the (pi) lineage. Thus, it appears that COG-2 is a transcription factor that regulates a late-stage aspect of uterine seam cell differentiation that specifically affects anchor cell-uterine seam cell fusion.

Amino Acid Sequence↗

Evaluation of a cross-validation stopping rule in MLE SPECT reconstruction.

One of the problems in the routine use of the maximum-likelihood estimator method-expectation maximization (MLE-EM) algorithm is to decide when the iterative process should be stopped. We studied a cross-validation stopping rule to assess its usefulness in SPECT. We tested this stopping rule criterion in the MLE-EM algorithm without acceleration as well as in two accelerating algorithms, the successive substitutions algorithm (SSA) and the additive algorithm (AA). Different values of an acceleration factor were tested in SSA and AA. Our results from numerical and physical phantoms show that the stopping rule based on the cross-validation ratio (CVR) takes into account the similarity of the reconstructed image to the ideal image, noise and the contrast of the image. CVR yields reconstructed images with balanced values of the figures of merit (FOM) employed to assess the image quality. The CVR criterion can be used in the original MLE-EM algorithm as well as in SSA and AA. The reconstructed images obtained with SSA and AA showed FOM values that were very similar. These results were justified by considering AA to be an approximate form of SSA. The range of validity for the acceleration factor in SSA and AA was found to be [1, 2]. In this range, an inverse function connects the acceleration factor to the number of iterations needed to attain prefixed values of FOMs.

Algorithms↗

Structure of the excitatory receptive fields of infragranular forelimb neurons in the rat primary somatosensory cortex responding to touch.

We quantitatively studied the excitatory receptive fields of 297 neurons recorded from the forelimb infragranular somatosensory cortex of the rat while touch stimuli were applied to discrete locations on the forelimbs. Receptive fields were highly heterogeneous, but they were regulated, on average, by an underlying spatio-temporal structure. We found the following. (i) Neurons responded with decreasing magnitude and increasing latency when the stimulus was moved from the primary location to secondary locations and to far ispilateral locations of their excitatory receptive fields, displaying smooth transitions from the primary location to secondary locations. (ii) Receptive field patterns revealed functional connectivity between the digits and ventral palm, which did not depend on whether the digits were stimulated dorsally or ventrally. (iii) The structure of the receptive fields (i.e. the neural responses to stimulation of secondary locations compared to the neural responses to stimulation of the primary location), reflected cortical (rather than body) distances. (iv) There was a functional separation between the forepaw and the rest of the forelimb. Namely: if the primary location was in the digits or palm, secondary locations were biased toward the digits and palm; if the primary location was in rest of the forelimb, secondary locations appeared equally distributed over forelimb, digits and palm. (v) More than 40% of neurons extended their receptive field to the ipsilateral forelimb, without any evident spatial organization. Overall, the stimuli evoked approximately 3 times more spikes from secondary responses than from primary responses. These results suggest that a rich repertoire of spatio-temporal responses is available for encoding tactile information. This highly distributed receptive field structure provides the electrophysiological architecture for studying organization and plasticity of cortical somatosensory processing.

Animals↗

[Functional relations of the adrenal cortex, thyroid and pineal body. II. Adrenal cortex reaction following epiphysectomy and administration of melatonin].

Histologic-cytological and morphometrical changes were investigated in the adrenal cortex of male Wistar-rats following pinealectomy and application of melatonin in eu-, hypo-, and hyperthyroid situations. A rat experiment (at an average of 45 d) to find a possible functional connection between the pineal gland and the adrenal cortex was carried out. In the literature, there are only a few of informations about the role of the pineal in regulating ACTH secretion. The results are very contrarily. We found that pinealectomy is connected with a progressive transformation and melatonin with a little regressive transformation in the adrenal cortex. But, it is not evident, that the glomerular zone is activated after both pinealectomy and application of melatonin. In our opinion, the glomerular zone and the secretion of aldosterone increased after as well pinealectomy as melatonin. Application of melatonin diminishes the function of the pineal gland (see group 4-pinealectomy plus melatonin-where was found a progressive transformation). Under these experimental conditions, one can speak of a "pharmacological pinealectomy" after application of melatonin alone. However, the effect of melatonin on the fascicular zone and the glomerular zone is different. The effects of pinealectomy or application of melatonin in combination with methylthiouracil or thyroxin are relatively unimportant.

Adrenal Cortex↗

[Neuroimaging in schizophrenia].

This overview is focused on functional neuroimaging including functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). Recent evidence for the "dopamine hypothesis of schizophrenia" is summarized including alterations of presynaptic dopamine metabolism and postsynaptic receptor binding potential. Emphasis is given to dopaminergic challenge studies using amphetamine and AMPT. Several PET and SPECT studies have shown a pronounced increase of amphetamine-induced dopamine release as well as decrease of AMPT-induced dopamine depletion in drug-naive schizophrenic patients, indicating a dysregulation of dopaminergic neurotransmission. Results of studies combining amphetamine challenge and the NMDA receptor antagonist ketamine are related to glutaminergic dysfunction and neurotransmitter interactions. FMRI and PET results demonstrating alterations in task-specific functional connectivity between brain areas are discussed with a focus on the prefrontal cortex and temporal structures. Increase of serotonin-1A receptor binding potential in prefrontal and mesotemporal cortex is related to the serotonin-dopamine interaction. Genetic neuroimaging techniques, including voxel-based morphometry (VBM) and fMRI, revealing significant effects of the dopamine metabolizing enzyme COMT on functional activation in prefrontal areas are also discussed. Functional neuroimaging based on challenge-paradigms in PET as well as task-specific state- or trait-dependent alterations of activation patterns in fMRI, seems to be a promising candidate for the development of biological marker tests for schizophrenia.

Brain↗

Twist-mediated activation of the NK-4 homeobox gene in the visceral mesoderm of Drosophila requires two distinct clusters of E-box regulatory elements.

NK-4, also called msh2 and tinman, encodes a homeodomain transcription factor that is required for the development of the dorsal mesoderm and its derivatives in the Drosophila embryo. Genetic analyses indicate that NK-4 resides downstream of the mesodermal determinant twist, which encodes a basic helix-loop-helix-type transcription factor. However, the regulation of NK-4 by twist remains poorly understood. Using expression assays in cultured cells and transgenic flies, we show that two distinct clusters of E-box regulatory sequences, present upstream of the NK-4 gene, mediate NK-4 expression in the visceral mesoderm. These elements are conserved between the Drosophila melanogaster and Drosophila virilis NK-4 genes and serve as binding sites for Twist (E1 cluster) and NK-4 (E2 cluster) proteins. In cultured cells, Twist and NK-4 binding results in activation of NK-4 gene expression. In transgenic animals, the E1 and E2 clusters are functionally connected, and both elements are required for NK-4 activation in cells of the visceral mesoderm and also for NK-4 repression in cells of the somatic musculature. These results demonstrate that NK-4 is a direct transcriptional target for Twist and its own gene product in visceral mesodermal cells, supporting the idea that twist and NK-4 function in the subdivision of the mesoderm during Drosophila embryogenesis.

Animals↗