General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

Brown, Emery N.; Purdon, Patrick L.; Dort, Christa J. Van

doi:10.1146/annurev-neuro-060909-153200

Cited by 438 publications

(420 citation statements)

References 174 publications

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“…A similar feature has been observed during burst suppression induced by isoflurane general anesthesia, in which slow-wave and delta activity persists during the burst epochs (11). The propofol-induced alpha is thought to involve potentiation of gamma aminobutyric acid (GABA) inhibitory currents in thalamocortical loops (20,21). The recovery of these mechanisms during bursts suggests that a more global dynamic perturbation, (i.e., not simply an increase in GABA, must be responsible for creating the epochs of suppression).…”

Section: Additional Data and Constraintsmentioning

confidence: 57%

A neurophysiological–metabolic model for burst suppression

Ching

Purdon

Vijayan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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249

326

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Burst suppression is an electroencepholagram (EEG) pattern in which high-voltage activity alternates with isoelectric quiescence. It is characteristic of an inactivated brain and is commonly observed at deep levels of general anesthesia, hypothermia, and in pathological conditions such as coma and early infantile encephalopathy. We propose a unifying mechanism for burst suppression that accounts for all of these conditions. By constructing a biophysical computational model, we show how the prevailing features of burst suppression may arise through the interaction between neuronal dynamics and brain metabolism. In each condition, the model suggests that a decrease in cerebral metabolic rate, coupled with the stabilizing properties of ATP-gated potassium channels, leads to the characteristic epochs of suppression. Consequently, the model makes a number of specific predictions of experimental and clinical relevance.B urst suppression-an electroencephalogram (EEG) pattern in which high voltage activity (burst) and flatline (suppression) periods alternate systematically but quasiperiodically (almost periodic but with variations in inter-and intra-burst duration) (1)-is a state of profound brain inactivation. It is frequently observed in deep general anesthesia (2). It is also observed in a range of pathological conditions including hypothermia (3-5), hypoxic-ischemic trauma/coma (6), and the so-called Ohtahara syndrome (7,8), a type of early infantile encephalopathy. These etiologies indicate that the burst suppression pattern represents a low-order dynamic mechanism that persists in the absence of higher-level brain activity. Indeed, the fact that many different conditions produce similar brain activity suggests that there may be a common pathway to the state of brain inactivation and may indicate fundamental properties of the brain's arousal circuits (2).The basic features of the burst suppression phenomenon have been established through a variety of EEG studies that are reviewed in ref. 9. The two most notable of these features are the spatial homogeneity of bursts and the quasi-periodic nature of the suppression. Later research has been directed at describing the phenomenon in vivo and in the specific context of general anesthesia. In particular, the early work of Steriade et al. (10) helped establish the neural correlates of burst suppression, including the differential participation of cortical and subcortical cell types. More recent studies (11,12) have suggested that burst suppression is associated with enhanced excitability in cortical networks. These studies implicate extracellular calcium as a correlate for the switches between burst and suppression.Despite the findings of these studies, a unifying mechanism for burst suppression-one that explains its prevailing features and also accounts for its range of etiologies-has not been proposed. Indeed, the existing characterizations of burst suppression in pathological situations are highly limited. Computational models offer a means of synthesizing the availabl...

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Section: Additional Data and Constraintsmentioning

confidence: 57%

A neurophysiological–metabolic model for burst suppression

Ching

Purdon

Vijayan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

249

326

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“…This presynaptic selectivity was not due to an intrinsic difference in the Ca 2+ sensitivity of exocytosis between glutamatergic and GABAergic terminals, which were in fact similar in control conditions. These findings elucidate fundamental synaptic mechanisms that lead to neurotransmitter-selective effects that are critical to understanding the actions of anesthetics on sensitive neuronal networks (13,14).…”

Section: Discussionmentioning

confidence: 87%

“…Sensitivity of SV exocytosis to isoflurane is therefore determined by presynaptic targets upstream of exocytosis that determine the magnitude of action potential-evoked Ca 2+ influx. Identification of neurotransmitter-selective effects of anesthetics on SV exocytosis is critical for understanding their pathway specific effects on neuronal interactions (13,14). …”

mentioning

confidence: 99%

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

Baumgart

Zhou

Hara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

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Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca 2+ influx without significantly altering the Ca 2+ sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca 2+ ] i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca 2+ ([Ca 2+ ] e ). Lowering external Ca 2+ to match the isoflurane-induced reduction in Ca 2+ entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca 2+ entry without significant direct effects on Ca 2+ -exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca 2+ influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system. GCaMP3 | pHlourin | mechanisms of anesthesia | live cell imaging | presynaptic T he molecular and cellular mechanisms of anesthetic-induced amnesia, unconsciousness and immobilization are incompletely understood, particularly for the modern halogenated ether derivatives like isoflurane. General anesthetics, which are essential to both medical practice and experimental neuroscience, have potent and selective effects on neurotransmission (1), including both presynaptic actions (reduced neurotransmitter release) and postsynaptic actions (modulation of receptor function). These effects contribute to anesthetic-induced reductions in neuronal interactions, which are critical to information processing and consciousness (2-4). Knowledge of the fundamental synaptic effects of anesthetics is therefore essential to a molecular and physiological understanding of anesthetic mechanisms, and to development of more selective and safer anesthetics.Although postsynaptic electrophysiological effects of anesthetics can be assessed directly using whole cell recordings and heterologous expression of putative molecular targets, their presynaptic actions have been difficult to resolve by conventional approaches that do not clearly discriminate between presynaptic and postsynaptic contributions. Direct evidence for presynaptic effects of volatile anesthetics includes selective inhibition of glutamate release from isolated nerve terminals (5, 6) and of synaptic vesicle (SV) exocytosis in intact hippocampal neurons (7). However, it remains controversial whether these effects involve direct inhibition of SV exocytosis itself or of upstrea...

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“…Kaspar Meyer A Dendritic Signaling Hypothesis of Anesthesia obtained for the dissociative anesthetic ketamine and the gaseous agents xenon and nitrous oxide, but volatile agents, such as sevoflurane and desflurane, down-regulate NMDA receptors to varying extents as well. [47][48][49][50] Conceivably, NMDA antagonists will interfere with the generation of NMDA spikes that carry top-down signals from the peripheral tuft dendrites toward the calcium potential initiation zone ( fig. 4B).…”

Section: The Effects Of General Anesthetics On Apical Dendrites Of Pymentioning

confidence: 99%

The Role of Dendritic Signaling in the Anesthetic Suppression of Consciousness

Meyer

2015

Anesthesiology

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Despite considerable progress in the identification of the molecular targets of general anesthetics, it remains unclear how these drugs affect the brain at the systems level to suppress consciousness. According to recent proposals, anesthetics may achieve this feat by interfering with corticocortical topdown processes, that is, by interrupting information flow from association to early sensory cortices. Such a view entails two immediate questions. First, at which anatomical site, and by virtue of which physiological mechanism, do anesthetics interfere with top-down signals? Second, why does a breakdown of top-down signaling cause unconsciousness? While an answer to the first question can be gleaned from emerging neurophysiological evidence on dendritic signaling in cortical pyramidal neurons, a response to the second is offered by increasingly popular theoretical frameworks that place the element of prediction at the heart of conscious perception. Science magazine posed this question in a special section titled "What don't we know?," dedicated to the greatest challenges of contemporary science. 1 "Scientists are chipping away at the drugs' effects on individual neurons," the article reads, "but understanding how they render us unconscious will be a tougher nut to crack." This prediction proved correct: a decade later, we have expanded considerably our knowledge of the molecular targets of general anesthetics, but it remains enigmatic how these drugs affect the brain at the systems level. Why does the potentiation of γ-aminobutyric acid (GABA) receptors caused by propofol or desflurane cause unconsciousness? How are the brain's computational processes affected by this and other molecular mechanisms of anesthetics, so that patients undergoing surgery cease to experience their surrounds in terms of sight, sound, and touch? Anesthesiologists and cognitive neuroscientists alike have been captivated by these questions and have proposed a number of models in an attempt to answer them, such as Flohr's "information processing theory of anesthesia," 2 Alkire's "thalamic consciousness switch hypothesis," 3-6 Mashour's "cognitive unbinding paradigm," 7,8 John and Prichep's "anesthetic cascade," 9 or Hudetz's "forgotten present." 10,11 We shall return to some of these frameworks in a later section of the article.One recent development is particularly intriguing. Given that the most striking feature of general anesthesia is an interruption of the patient's ability to perceive the environment, it would appear intuitive for anesthetics to interfere primarily with bottom-up information flow along the sensory pathways, that is, with the signals that carry perceptual information from the thalamus to the primary sensory cortices and on to unimodal and multimodal association cortices. However, the very opposite appears to be the case. Several recent studies-carried out in both humans and animals, and using a variety of different anesthetic agents-have investigated differences in directional corticocortical connectivity bet...

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General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

Cited by 438 publications

References 174 publications

A neurophysiological–metabolic model for burst suppression

A neurophysiological–metabolic model for burst suppression

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

The Role of Dendritic Signaling in the Anesthetic Suppression of Consciousness

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General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

Cited by 438 publications

References 174 publications

A neurophysiological–metabolic model for burst suppression

A neurophysiological–metabolic model for burst suppression

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca 2+ influx, not Ca 2+ -exocytosis coupling

The Role of Dendritic Signaling in the Anesthetic Suppression of Consciousness

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Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling