Lack of Responsiveness during the Onset and Offset of Sevoflurane Anesthesia Is Associated with Decreased Awake-Alpha Oscillation Power.
Frontiers in systems neuroscience
Anesthetic drugs are typically administered to induce altered states of arousal that range from sedation to general anesthesia (GA). Systems neuroscience studies are currently being used to investigate the neural circuit mechanisms of anesthesia-induced altered arousal states. These studies suggest that by disrupting the oscillatory dynamics that are associated with arousal states, anesthesia-induced oscillations are a putative mechanism through which anesthetic drugs produce altered states of arousal. However, an empirical clinical observation is that even at relatively stable anesthetic doses, patients are sometimes intermittently responsive to verbal commands during states of light sedation. During these periods, prominent anesthesia-induced neural oscillations such as slow-delta (0.1-4 Hz) oscillations are notably absent. Neural correlates of intermittent responsiveness during light sedation have been insufficiently investigated. A principled understanding of the neural correlates of intermittent responsiveness may fundamentally advance our understanding of neural dynamics that are essential for maintaining arousal states, and how they are disrupted by anesthetics. Therefore, we performed a high-density (128 channels) electroencephalogram (EEG) study ( = 8) of sevoflurane-induced altered arousal in healthy volunteers. We administered temporally precise behavioral stimuli every 5 s to assess responsiveness. Here, we show that decreased eyes-closed, awake-alpha (8-12 Hz) oscillation power is associated with lack of responsiveness during sevoflurane effect-onset and -offset. We also show that anteriorization-the transition from occipitally dominant awake-alpha oscillations to frontally dominant anesthesia induced-alpha oscillations-is not a binary phenomenon. Rather, we suggest that periods, which were defined by lack of responsiveness, represent an intermediate brain state. We conclude that awake-alpha oscillation, previously thought to be an idling rhythm, is associated with responsiveness to behavioral stimuli.
10.3389/fnsys.2017.00038
Alterations in the coupling functions between cortical and cardio-respiratory oscillations due to anaesthesia with propofol and sevoflurane.
Stankovski Tomislav,Petkoski Spase,Raeder Johan,Smith Andrew F,McClintock Peter V E,Stefanovska Aneta
Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
The precise mechanisms underlying general anaesthesia pose important and still open questions. To address them, we have studied anaesthesia induced by the widely used (intravenous) propofol and (inhalational) sevoflurane anaesthetics, computing cross-frequency coupling functions between neuronal, cardiac and respiratory oscillations in order to determine their mutual interactions. The phase domain coupling function reveals the form of the function defining the mechanism of an interaction, as well as its coupling strength. Using a method based on dynamical Bayesian inference, we have thus identified and analysed the coupling functions for six relationships. By quantitative assessment of the forms and strengths of the couplings, we have revealed how these relationships are altered by anaesthesia, also showing that some of them are differently affected by propofol and sevoflurane. These findings, together with the novel coupling function analysis, offer a new direction in the assessment of general anaesthesia and neurophysiological interactions, in general.
10.1098/rsta.2015.0186
Enhanced wakefulness following lesions of a mesopontine locus essential for the induction of general anesthesia.
Lanir-Azaria Sa'ar,Meiri Guy,Avigdor Tamir,Minert Anne,Devor Marshall
Behavioural brain research
The induction of general anesthesia shares many features with the transition from wakefulness to non-rapid eye movement (NREM) sleep, suggesting that the two types of brain-state transition are orchestrated by a common neuronal mechanism. Previous studies revealed a brainstem locus, the mesopontine tegmental anesthesia area (MPTA), that is of singular importance for anesthetic induction. Microinjection of GABAergic anesthetics there induces rapid loss-of-consciousness and lesions render the animal relatively insensitive to anesthetics administered systemically. Here we show that MPTA lesions also alter the natural sleep-wake rhythm by increasing overall wake time at the expense of time asleep (NREM and REM sleep equally), with nearly all of the change occurring during the dark hours of the light-dark cycle. The effect was proportional to the extent of the lesion and was not seen after lesions just outside of the MPTA, or following sham lesions. Thus, MPTA neurons appear to play a role in natural bistable brain-state switching (sleep-wake) as well as in loss and recovery of consciousness induced pharmacologically.
10.1016/j.bbr.2017.12.035
Photoaffinity Ligand for the Inhalational Anesthetic Sevoflurane Allows Mechanistic Insight into Potassium Channel Modulation.
Woll Kellie A,Peng Wesley,Liang Qiansheng,Zhi Lianteng,Jacobs Jack A,Maciunas Lina,Bhanu Natarajan,Garcia Benjamin A,Covarrubias Manuel,Loll Patrick J,Dailey William P,Eckenhoff Roderic G
ACS chemical biology
Sevoflurane is a commonly used inhaled general anesthetic. Despite this, its mechanism of action remains largely elusive. Compared to other anesthetics, sevoflurane exhibits distinct functional activity. In particular, sevoflurane is a positive modulator of voltage-gated Shaker-related potassium channels (K1.x), which are key regulators of action potentials. Here, we report the synthesis and validation of azisevoflurane, a photoaffinity ligand for the direct identification of sevoflurane binding sites in the K1.2 channel. Azisevoflurane retains major sevoflurane protein binding interactions and pharmacological properties within in vivo models. Photoactivation of azisevoflurane induces adduction to amino acid residues that accurately reported sevoflurane protein binding sites in model proteins. Pharmacologically relevant concentrations of azisevoflurane analogously potentiated wild-type K1.2 and the established mutant K1.2 G329T. In wild-type K1.2 channels, azisevoflurane photolabeled Leu317 within the internal S4-S5 linker, a vital helix that couples the voltage sensor to the pore region. A residue lining the same binding cavity was photolabeled by azisevoflurane and protected by sevoflurane in the K1.2 G329T. Mutagenesis of Leu317 in WT K1.2 abolished sevoflurane voltage-dependent positive modulation. Azisevoflurane additionally photolabeled a second distinct site at Thr384 near the external selectivity filter in the K1.2 G329T mutant. The identified sevoflurane binding sites are located in critical regions involved in gating of K channels and related ion channels. Azisevoflurane has thus emerged as a new tool to discover inhaled anesthetic targets and binding sites and investigate contributions of these targets to general anesthesia.
10.1021/acschembio.7b00222
Breakdown of local information processing may underlie isoflurane anesthesia effects.
Wollstadt Patricia,Sellers Kristin K,Rudelt Lucas,Priesemann Viola,Hutt Axel,Fröhlich Flavio,Wibral Michael
PLoS computational biology
The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source-such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)-as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy-suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.
10.1371/journal.pcbi.1005511
GABAB receptor-mediated tonic inhibition of locus coeruleus neurons plays a role in deep anesthesia induced by isoflurane.
Hung Wei-Chen,Chu Yun-Lin,Tsai Meng-Li,Wong Shi-Bing,Min Ming-Yuan,Chen Ruei-Feng,Yang Hsui-Wen
Neuroreport
Noradrenergic neurons in the locus coeruleus referred to as locus coeruleus neurons, provide the major supply of norepinephrine to the forebrain and play important roles in behavior through regulation of wakefulness and arousal. In a previous study using brain slice preparations, we reported that locus coeruleus neurons are subject to tonic inhibition mediated by γ-aminobutyric acid B receptors (GABABRs) and that the extent of tonic inhibition varies with ambient GABA levels. Since ambient GABA in the locus coeruleus was reported to fluctuate during the sleep-wakefulness cycle, here we tested whether GABABR-mediated tonic inhibition of locus coeruleus neurons could be a mechanism underlying changes in brain arousal. We first demonstrated that GABABR-mediated tonic inhibition of locus coeruleus neurons also exists in vivo by showing that local infusion of CGP35348, a GABABR antagonist, into the locus coeruleus increased the firing rate of locus coeruleus neurons in anesthetized rats. We then showed that this manipulation accelerated the behavioral emergence of rats from deep anesthesia induced by isoflurane. Together, these observations show that GABABR-mediated tonic inhibition of locus coeruleus neurons occurs in vivo and support the idea that this effect may be important in regulating the functional state of the brain.
10.1097/WNR.0000000000001450
Restoring VTA DA neurons excitability accelerates emergence from sevoflurane general anesthesia of anxiety state.
Wang Hui,Yu Le,Qin Yuan-Jun,Chen Ming,Wang Xin,Luo Huo-Qing,Cong Pei-Lin,Wang Xiao-Li,Cai Hong-Miao,Zhang Ai-Lian,Juan-Guo ,Sun Xiao-Hui,Li Zhao,Xue Ming,Sun Na,Wang Qing-Xiu,Hu Ji
Biochemical and biophysical research communications
Preoperative anxiety is common and often comes with a higher probability of worse recovery. However, the neurological mechanism of the effect of preoperative anxiety on general anesthesia and subsequent awakening remains unknown. In this study, we report an anxious state results in delayed awakening in anxiety model mice from sevoflurane general anesthesia. More profound inhibition of DA neurons in the VTA contributes to delayed awakening. Optogenetic stimulation of VTA DA neurons can reverse the delay. The results indicate that VTA DA neurons may be involved in the delay in awakening from general anesthesia caused by anxiety.
10.1016/j.bbrc.2021.05.079
Effect of anesthetic structure on inhalation anesthesia: implications for the mechanism.
Abraham Michael H,Acree William E,Mintz Christina,Payne Stacy
Journal of pharmaceutical sciences
Many previous attempts (e.g., the Meyer-Overton hypothesis) to provide a single set of physical or chemical characteristics that accurately predict anesthetic potency have failed. A finding of a general predictive correlation would support the notion of a unitary theory of narcosis. Using the Abraham solvation parameter model, the minimum alveolar concentration, MAC, of 148 varied anesthetic agents can be fitted to a linear equation in log (1/MAC) with R(2) = 0.985 and a standard deviation, SD = 0.192 log units. Division of the 148 compounds into a training set and a test set shows that log (1/MAC) values can be predicted with no bias and with SD = 0.20 log units. The two main factors that determine MAC values are compound size and compound hydrogen bond acidity, both of which increase anesthetic activity. Shape has little or no effect on anesthetic activity. Our observations support a unitary theory of narcosis by inhalation anesthetics. A two-stage mechanism for inhalation anesthesia accounts for the observed structural effects of anesthetics. In this mechanism, the first main step is transfer of the anesthetic to the site of action, and the second step is interaction of the anesthetic with a receptor(s).
10.1002/jps.21150
Activation of Parabrachial Nucleus Glutamatergic Neurons Accelerates Reanimation from Sevoflurane Anesthesia in Mice.
Wang Tian-Xiao,Xiong Bo,Xu Wei,Wei Hao-Hua,Qu Wei-Min,Hong Zong-Yuan,Huang Zhi-Li
Anesthesiology
BACKGROUND:The parabrachial nucleus (PBN), which is a brainstem region containing glutamatergic neurons, is a key arousal nucleus. Injuries to the area often prevent patient reanimation. Some studies suggest that brain regions that control arousal and reanimation are a key part of the anesthesia recovery. Therefore, we hypothesize that the PBN may be involved in regulating emergence from anesthesia. METHODS:We investigated the effects of specific activation or inhibition of PBN glutamatergic neurons on sevoflurane general anesthesia using the chemogenetic "designer receptors exclusively activated by designer drugs" approach. Optogenetic methods combined with polysomnographic recordings were used to explore the effects of transient activation of PBN glutamatergic neuron on sevoflurane anesthesia. Immunohistochemical techniques are employed to reveal the mechanism by which PBN regulated sevoflurane anesthesia. RESULTS:Chemogenetic activation of PBN glutamatergic neurons by intraperitoneal injections of clozapine-N-oxide decreased emergence time (mean ± SD, control vs. clozapine-N-oxide, 55 ± 24 vs. 15 ± 9 s, P = 0.0002) caused by sevoflurane inhalation and prolonged induction time (70 ± 15 vs. 109 ± 38 s, n = 9, P = 0.012) as well as the ED50 of sevoflurane (1.48 vs. 1.60%, P = 0.0002), which was characterized by a rightward shift of the loss of righting reflex cumulative curve. In contrast, chemogenetic inhibition of PBN glutamatergic neurons slightly increased emergence time (56 ± 26 vs. 87 ± 26 s, n = 8, P = 0.034). Moreover, instantaneous activation of PBN glutamatergic neurons expressing channelrhodopsin-2 during steady-state general anesthesia with sevoflurane produced electroencephalogram evidence of cortical arousal. Immunohistochemical experiments showed that activation of PBN induced excitation of cortical and subcortical arousal nuclei during sevoflurane anesthesia. CONCLUSIONS:Activation of PBN glutamatergic neurons is helpful to accelerate the transition from general anesthesia to an arousal state, which may provide a new strategy in shortening the recovery time after sevoflurane anesthesia.
10.1097/ALN.0000000000002475
Studies on the mechanism of general anesthesia.
Pavel Mahmud Arif,Petersen E Nicholas,Wang Hao,Lerner Richard A,Hansen Scott B
Proceedings of the National Academy of Sciences of the United States of America
Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in whole-cell patch-clamp recordings. Localization of PLD2 renders the TRAAK channel sensitive, a channel that is otherwise anesthetic insensitive. General anesthetics, such as chloroform, isoflurane, diethyl ether, xenon, and propofol, disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and PLD flies resist anesthesia. Our results establish a membrane-mediated target of inhaled anesthesia and suggest PA helps set thresholds of anesthetic sensitivity in vivo.
10.1073/pnas.2004259117
Dorsal raphe serotonergic neurons promote arousal from isoflurane anesthesia.
Li Ao,Li Rui,Ouyang Pengrong,Li Huihui,Wang Sa,Zhang Xinxin,Wang Dan,Ran Mingzi,Zhao Guangchao,Yang Qianzi,Zhu Zhenghua,Dong Hailong,Zhang Haopeng
CNS neuroscience & therapeutics
AIMS:General anesthesia has been widely applied in surgical or nonsurgical medical procedures, but the mechanism behind remains elusive. Because of shared neural circuits of sleep and anesthesia, whether serotonergic system, which is highly implicated in modulation of sleep and wakefulness, regulates general anesthesia as well is worth investigating. METHODS:Immunostaining and fiber photometry were used to assess the neuronal activities. Electroencephalography spectra and burst-suppression ratio (BSR) were used to measure anesthetic depth and loss or recovery of righting reflex to indicate the induction or emergence time of general anesthesia. Regulation of serotonergic system was achieved through optogenetic, chemogenetic, or pharmacological methods. RESULTS:We found that both Fos expression and calcium activity were significantly decreased during general anesthesia. Activation of 5-HT neurons in the dorsal raphe nucleus (DRN) decreased the depth of anesthesia and facilitated the emergence from anesthesia, and inhibition deepened the anesthesia and prolonged the emergence time. Furthermore, agonism or antagonism of 5-HT 1A or 2C receptors mimicked the effect of manipulating DRN serotonergic neurons. CONCLUSION:Our results demonstrate that 5-HT neurons in the DRN play a regulative role of general anesthesia, and activation of serotonergic neurons could facilitate emergence from general anesthesia partly through 5-HT 1A and 2C receptors.
10.1111/cns.13656
Delta oscillations phase limit neural activity during sevoflurane anesthesia.
Communications biology
Understanding anesthetic mechanisms with the goal of producing anesthetic states with limited systemic side effects is a major objective of neuroscience research in anesthesiology. Coherent frontal alpha oscillations have been postulated as a mechanism of sevoflurane general anesthesia. This postulate remains unproven. Therefore, we performed a single-site, randomized, cross-over, high-density electroencephalogram study of sevoflurane and sevoflurane--ketamine general anesthesia in 12 healthy subjects. Data were analyzed with multitaper spectral, global coherence, cross-frequency coupling, and phase-dependent methods. Our results suggest that coherent alpha oscillations are not fundamental for maintaining sevoflurane general anesthesia. Taken together, our results suggest that subanesthetic and general anesthetic sevoflurane brain states emerge from impaired information processing instantiated by a delta-higher frequency phase-amplitude coupling syntax. These results provide fundamental new insights into the neural circuit mechanisms of sevoflurane anesthesia and suggest that anesthetic states may be produced by extracranial perturbations that cause delta-higher frequency phase-amplitude interactions.
10.1038/s42003-019-0664-3