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Introduction: UMHealthResearch is the University of Michigan's digital health research recruitment platform. It allows health researchers to connect efficiently with potentially eligible volunteers., Methods: In 2013, the UMHealthResearch team strategically adapted a consumer behavior model, the buying funnel, to create the Digital Health Research Participation Funnel. The Digital Health Research Participation Funnel was then used to design a more active way for potential participants to volunteer for research studies through UMHealthResearch., Results: In the 5 years before the redesign (2007-2012), an average of 1844 new accounts were created every year, whereas in the completed years after the redesign (2013-2016) the annual average improved to 3906, an increase of 111%., Conclusion: Although a randomized design was not possible in this instance, these preintervention and postintervention data suggest that the focus on user experience is an effective strategy for improving web-based research recruitment platforms.

Background: Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults., Methods: The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988., Findings: Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups., Interpretation: A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences., Funding: National Institutes of Health and Cancer Center Support., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Previous studies have demonstrated inconsistent neurophysiologic effects of ketamine, although discrepant findings might relate to differences in doses studied, brain regions analyzed, coadministration of other anesthetic medications, and resolution of the electroencephalograph. The objective of this study was to characterize the dose-dependent effects of ketamine on cortical oscillations and functional connectivity., Methods: Ten healthy human volunteers were recruited for study participation. The data were recorded using a 128-channel electroencephalograph during baseline consciousness, subanesthetic dosing (0.5 mg/kg over 40 min), anesthetic dosing (1.5 mg/kg bolus), and recovery. No other sedative or anesthetic medications were administered. Spectrograms, topomaps, and functional connectivity (weighted and directed phase lag index) were computed and analyzed., Results: Frontal theta bandwidth power increased most dramatically during ketamine anesthesia (mean power ± SD, 4.25 ± 1.90 dB) compared to the baseline (0.64 ± 0.28 dB), subanesthetic (0.60 ± 0.30 dB), and recovery (0.68 ± 0.41 dB) states; P < 0.001. Gamma power also increased during ketamine anesthesia. Weighted phase lag index demonstrated theta phase locking within anterior regions (0.2349 ± 0.1170, P < 0.001) and between anterior and posterior regions (0.2159 ± 0.1538, P < 0.01) during ketamine anesthesia. Alpha power gradually decreased with subanesthetic ketamine, and anterior-to-posterior directed connectivity was maximally reduced (0.0282 ± 0.0772) during ketamine anesthesia compared to all other states (P < 0.05)., Conclusions: Ketamine anesthesia correlates most clearly with distinct changes in the theta bandwidth, including increased power and functional connectivity. Anterior-to-posterior connectivity in the alpha bandwidth becomes maximally depressed with anesthetic ketamine administration, suggesting a dose-dependent effect.

How the brain reconstitutes consciousness and cognition after a major perturbation like general anesthesia is an important question with significant neuroscientific and clinical implications. Recent empirical studies in animals and humans suggest that the recovery of consciousness after anesthesia is not random but ordered. Emergence patterns have been classified as progressive and abrupt transitions from anesthesia to consciousness, with associated differences in duration and electroencephalogram (EEG) properties. We hypothesized that the progressive and abrupt emergence patterns from the unconscious state are associated with, respectively, continuous and discontinuous synchronization transitions in functional brain networks. The discontinuous transition is explainable with the concept of explosive synchronization, which has been studied almost exclusively in network science. We used the Kuramato model, a simple oscillatory network model, to simulate progressive and abrupt transitions in anatomical human brain networks acquired from diffusion tensor imaging (DTI) of 82 brain regions. To facilitate explosive synchronization, distinct frequencies for hub nodes with a large frequency disassortativity (i.e., higher frequency nodes linking with lower frequency nodes, or vice versa) were applied to the brain network. In this simulation study, we demonstrated that both progressive and abrupt transitions follow distinct synchronization processes at the individual node, cluster, and global network levels. The characteristic synchronization patterns of brain regions that are "progressive and earlier" or "abrupt but delayed" account for previously reported behavioral responses of gradual and abrupt emergence from the unconscious state. The characteristic network synchronization processes observed at different scales provide new insights into how regional brain functions are reconstituted during progressive and abrupt emergence from the unconscious state. This theoretical approach also offers a principled explanation of how the brain reconstitutes consciousness and cognitive functions after physiologic (sleep), pharmacologic (anesthesia), and pathologic (coma) perturbations.

Recent studies have investigated local oscillations, long-range connectivity, and global network patterns to identify neural changes associated with anesthetic-induced unconsciousness. These studies typically employ anesthetic protocols that either just cross the threshold of unconsciousness, or induce deep unconsciousness for a brief period of time-neither of which models general anesthesia for major surgery. To study neural patterns of unconsciousness and recovery in a clinically-relevant context, we used a realistic anesthetic regimen to induce and maintain unconsciousness in eight healthy participants for 3 h. High-density electroencephalogram (EEG) was acquired throughout and for another 3 h after emergence. Seven epochs of 5-min eyes-closed resting states were extracted from the data at baseline as well as 30, 60, 90, 120, 150, and 180-min post-emergence. Additionally, 5-min epochs were extracted during induction, unconsciousness, and immediately prior to recovery of consciousness, for a total of 10 analysis epochs. The EEG data in each epoch were analyzed using source-localized spectral analysis, phase-lag index, and graph theoretical techniques. Posterior alpha power was significantly depressed during unconsciousness, and gradually approached baseline levels over the 3 h recovery period. Phase-lag index did not distinguish between states of consciousness or stages of recovery. Network efficiency was significantly depressed and network clustering coefficient was significantly increased during unconsciousness; these graph theoretical measures returned to baseline during the 3 h recovery period. Posterior alpha power may be a potential biomarker for normal recovery of functional brain networks after general anesthesia.

There has been controversy regarding the precise mechanisms of anesthetic-induced unconsciousness, with two salient approaches that have emerged within systems neuroscience. One prominent approach is the "bottom up" paradigm, which argues that anesthetics suppress consciousness by modulating sleep-wake nuclei and neural circuits in the brainstem and diencephalon that have evolved to control arousal states. Another approach is the "top-down" paradigm, which argues that anesthetics suppress consciousness by modulating the cortical and thalamocortical circuits involved in the integration of neural information. In this article, we synthesize these approaches by mapping bottom-up and top-down mechanisms of general anesthetics to two distinct but inter-related dimensions of consciousness: level and content. We show how this explains certain empirical observations regarding the diversity of anesthetic drug effects. We conclude with a more nuanced discussion of how levels and contents of consciousness interact to generate subjective experience and what this implies for the mechanisms of anesthetic-induced unconsciousness.

Studies from human and non-human species have demonstrated a breakdown of functional corticocortical connectivity during general anesthesia induced by anesthetics with diverse molecular, neurophysiological, and pharmacological profiles. Recent studies have demonstrated that changes in long-range neural communication, and by corollary, functional connectivity, might be influenced by cross-frequency coupling (CFC) between the phase of slow oscillations and the amplitude of local fast oscillations. Phase-amplitude coupling (PAC) between slow oscillations and alpha rhythm during general anesthesia reveal distinct patterns depending on the anesthetic. In this study, we analyzed the effect of three clinically used anesthetics (propofol: n = 6, sevoflurane: n = 10, and ketamine: n = 8) with distinct molecular mechanisms on changes in PAC in the frontal cortex of rat. The loss of righting reflex was used as a surrogate for unconsciousness. PAC was calculated using the modulation index (MI) algorithm between delta (1-4 Hz), theta (4-10 Hz), low gamma (25-55 Hz), and high gamma (65-125 Hz) bands. A linear mixed model with fixed effects was used for statistical comparisons between waking, anesthetized, and post-anesthesia recovery epochs. All three anesthetics increased the coupling between delta and low gamma ( p < 0.0001) as well as between theta and low gamma ( p < 0.0001) oscillations, which returned to baseline waking levels during the post-anesthetic recovery period. In addition, a reversible reduction in high gamma power ( p < 0.0001) was a consistent change during anesthesia induced by all three agents. The changes in delta-high gamma and theta-high gamma PAC as well as power spectral changes in delta, theta, and low gamma bandwidths did not show a uniform response across the three anesthetics. These results encourage the study of alternative PAC patterns as drug-invariant markers of general anesthesia in humans.

Important scientific and clinical questions persist about general anesthesia despite the ubiquitous clinical use of anesthetic drugs in humans since their discovery. For example, it is not known how the brain reconstitutes consciousness and cognition after the profound functional perturbation of the anesthetized state, nor has a specific pattern of functional recovery been characterized. To date, there has been a lack of detailed investigation into rates of recovery and the potential orderly return of attention, sensorimotor function, memory, reasoning and logic, abstract thinking, and processing speed. Moreover, whether such neurobehavioral functions display an invariant sequence of return across individuals is similarly unknown. To address these questions, we designed a study of healthy volunteers undergoing general anesthesia with electroencephalography and serial testing of cognitive functions (NCT01911195). The aims of this study are to characterize the temporal patterns of neurobehavioral recovery over the first several hours following termination of a deep inhaled isoflurane general anesthetic and to identify common patterns of cognitive function recovery. Additionally, we will conduct spectral analysis and reconstruct functional networks from electroencephalographic data to identify any neural correlates (e.g., connectivity patterns, graph-theoretical variables) of cognitive recovery after the perturbation of general anesthesia. To accomplish these objectives, we will enroll a total of 60 consenting adults aged 20-40 across the three participating sites. Half of the study subjects will receive general anesthesia slowly titrated to loss of consciousness (LOC) with an intravenous infusion of propofol and thereafter be maintained for 3 h with 1.3 age adjusted minimum alveolar concentration of isoflurane, while the other half of subjects serves as awake controls to gauge effects of repeated neurobehavioral testing, spontaneous fatigue and endogenous rest-activity patterns.

Introduction: Changes in neural activity induce changes in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) signal. Commonly, increases in BOLD signal are ascribed to cellular excitation., Objective: The relationship between electrical activity and BOLD signal in the human brain was probed on the basis of burst suppression EEG. This condition includes two distinct states of high and low electrical activity., Methods: Resting-state simultaneous EEG and BOLD measurements were acquired during deep sevoflurane anesthesia with burst suppression EEG in nineteen healthy volunteers. Afterwards, fMRI volumes were assigned to one of the two states (burst or suppression) as defined by the EEG., Results: In the frontal, parietal and temporal lobes as well as in the basal ganglia, BOLD signal increased after burst onset in the EEG and decreased after onset of EEG suppression. In contrast, BOLD signal in the occipital lobe was anticorrelated to electrical activity. This finding was obtained consistently in a general linear model and in raw data., Conclusions: In human brains exhibiting burst suppression EEG induced by sevoflurane, the positive correlation between BOLD signal and electrical brain activity could be confirmed in most gray matter. The exceptional behavior of the occipital lobe with an anticorrelation of BOLD signal and electrical activity might be due to specific neurovascular coupling mechanisms that are pronounced in the deeply anesthetized brain.

Identifying how spatially distributed information becomes integrated in the brain is essential to understanding higher cognitive functions. Previous computational and empirical studies suggest a significant influence of brain network structure on brain network function. However, there have been few analytical approaches to explain the role of network structure in shaping regional activities and directionality patterns. In this study, analytical methods are applied to a coupled oscillator model implemented in inhomogeneous networks. We first derive a mathematical principle that explains the emergence of directionality from the underlying brain network structure. We then apply the analytical methods to the anatomical brain networks of human, macaque, and mouse, successfully predicting simulation and empirical electroencephalographic data. The results demonstrate that the global directionality patterns in resting state brain networks can be predicted solely by their unique network structures. This study forms a foundation for a more comprehensive understanding of how neural information is directed and integrated in complex brain networks.

Introduction: Previous studies have examined the impact of Clinical and Translational Science Awards programs on other outcomes, but not on grant seeking. The authors examined the effects on grant seeking of the Michigan Institute for Clinical & Health Research (MICHR), a Clinical and Translational Science Awards institute at the University of Michigan., Methods: We assessed over 63,000 grant proposals submitted at the University of Michigan in the years 2002-2012 using data from the university and MICHR's Tracking Metrics and Reporting System. We used a retrospective, observational study of the dynamics of grant-seeking success and award funding. Heckman selection models were run to assess MICHR's relationship with a proposal's success (selection), and subsequently the award's size (outcome). Models were run for all proposals and for clinical and translational research (CTR) proposals alone. Other covariates included proposal classification, type of grant award, academic unit, and year., Results: MICHR had a positive and statistically significant relationship with success for both proposal types. For all grants, MICHR was associated with a 29.6% increase in award size. For CTR grants, MICHR had a statistically nonsignificant relationship with award size., Conclusions: MICHR's infrastructure, created to enable and enhance CTR, has also created positive spillovers for a broader spectrum of research and grant seeking., Competing Interests: Declaration of Interest NIH had no role in study design, writing, or decisions to submit this report for publication.

Recent data from our laboratory demonstrate that high-frequency gamma connectivity across the cortex is present during consciousness and depressed during unconsciousness. However, these data were derived from static and well-defined states of arousal rather than during transitions that would suggest functional relevance. We also recently found that subanesthetic ketamine administered during isoflurane anesthesia accelerates recovery upon discontinuation of the primary anesthetic and increases gamma power during emergence. In the current study we re-analyzed electroencephalogram (EEG) data to test the hypothesis that functional cortical connectivity between anterior and posterior cortical regions would be increased during accelerated recovery induced by ketamine when compared to saline-treated controls. Rodents were instrumented with intracranial EEG electrodes and general anesthesia was induced with isoflurane anesthesia. After 37.5 min of continuous isoflurane anesthesia, a subanesthetic dose of ketamine (25 mg/kg intraperitoneal) was administered, with evidence of a 44% reduction in emergence time. In this study, we analyzed gamma and theta coherence (measure of undirected functional connectivity) and normalized symbolic transfer entropy (measure of directed functional connectivity) between frontal and parietal cortices during various levels of consciousness, with a focus on emergence from isoflurane anesthesia. During accelerated emergence in the ketamine-treated group, there was increased frontal-parietal coherence { p = 0.005, 0.05-0.23 [95% confidence interval (CI)]} and normalized symbolic transfer entropy [frontal to parietal: p < 0.001, 0.010-0.026 (95% CI); parietal to frontal: p < 0.001, 0.009-0.025 (95% CI)] in high-frequency gamma bandwidth as compared with the saline-treated group. Surrogates of cortical information exchange in high-frequency gamma are increased in association with accelerated recovery from anesthesia. This finding adds evidence suggesting a functional significance of high-gamma information transfer in consciousness.

Background: Promoting arousal by manipulating certain brain regions and/or neurotransmitters has been a recent research focus, with the goal of trying to improve recovery from general anesthesia. The current study tested the hypothesis that a single subanesthetic dose of ketamine during isoflurane anesthesia would increase cholinergic tone in the prefrontal cortex and accelerate recovery., Methods: Adult male rats were implanted with electroencephalography electrodes (frontal, parietal, and occipital cortex) and a microdialysis guide cannula targeted for the prefrontal cortex. After establishing general anesthesia with isoflurane, animals were randomly assigned to receive a saline control or ketamine injection. When isoflurane was discontinued nearly 90 min after drug or saline administration, recovery from anesthesia was measured by experimenters and blinded observers. During the entire experiment, electrophysiologic signals were recorded and acetylcholine was quantified by high-performance liquid chromatography with electrochemical detection., Results: A single dose of subanesthetic ketamine caused an initial 125% increase in burst suppression ratio (last isoflurane sample: 37.48 ± 24.11% vs. isoflurane after ketamine injection: 84.36 ± 8.95%; P < 0.0001), but also a significant 44% reduction in emergence time (saline: 877 ± 335 s vs. ketamine: 494 ± 108 s; P = 0.0005; n = 10 per treatment). Furthermore, ketamine caused a significant 317% increase in cortical acetylcholine release (mean after ketamine injection: 0.18 ± 0.16 pmol vs. ketamine recovery: 0.75 ± 0.41 pmol; P = 0.0002) after isoflurane anesthesia was discontinued., Conclusions: Administration of subanesthetic doses of ketamine during isoflurane anesthesia increases anesthetic depth but-paradoxically-accelerates the recovery of consciousness, possibly through cholinergic mechanisms., Competing Interests: The authors declare no conflicts of interest

Background: The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice., Methods: Two hundred sixty adult patients were recruited at six sites into a prospective cohort study of the isolated forearm technique after intubation. Demographic, anesthetic, and intubation data, plus postoperative questionnaires, were collected. Univariate statistics, followed by bivariate logistic regression models for age plus variable, were conducted., Results: The incidence of isolated forearm technique responsiveness after intubation was 4.6% (12/260); 5 of 12 responders reported pain through a second hand squeeze. Responders were younger than nonresponders (39 ± 17 vs. 51 ± 16 yr old; P = 0.01) with more frequent signs of sympathetic activation (50% vs. 2.4%; P = 0.03). No participant had explicit recall of intraoperative events when questioned after surgery (n = 253). Across groups, depth of anesthesia monitoring values showed a wide range; however, values were higher for responders before (54 ± 20 vs. 42 ± 14; P = 0.02) and after (52 ± 16 vs. 43 ± 16; P = 0.02) intubation. In patients not receiving total intravenous anesthesia, exposure to volatile anesthetics before intubation reduced the odds of responding (odds ratio, 0.2 [0.1 to 0.8]; P = 0.02) after adjustment for age., Conclusions: Intraoperative connected consciousness occurred frequently, although the rate is up to 10-times lower than anticipated. This should be considered a conservative estimate of intraoperative connected consciousness.

Consciousness has been linked to the repertoire of brain states at various spatiotemporal scales. Anesthesia is thought to modify consciousness by altering information integration in cortical and thalamocortical circuits. At a mesoscopic scale, neuronal populations in the cortex form synchronized ensembles whose characteristics are presumably state-dependent but this has not been rigorously tested. In this study, spontaneous neuronal activity was recorded with 64-contact microelectrode arrays in primary visual cortex of chronically instrumented, unrestrained rats under stepwise decreasing levels of desflurane anesthesia (8%, 6%, 4%, and 2% inhaled concentrations) and wakefulness (0% concentration). Negative phases of the local field potentials formed compact, spatially contiguous activity patterns (CAPs) that were not due to chance. The number of CAPs was 120% higher in wakefulness and deep anesthesia associated with burst-suppression than at intermediate levels of consciousness. The frequency distribution of CAP sizes followed a power-law with slope -1.5 in relatively deep anesthesia (8-6%) but deviated from that at the lighter levels. Temporal variance and entropy of CAP sizes were lowest in wakefulness (76% and 24% lower at 0% than at 8% desflurane, respectively) but changed little during recovery of consciousness. CAPs categorized by K-means clustering were conserved at all anesthesia levels and wakefulness, although their proportion changed in a state-dependent manner. These observations yield new knowledge about the dynamic landscape of ongoing population activity in sensory cortex at graded levels of anesthesia. The repertoire of population activity and self-organized criticality at the mesoscopic scale do not appear to contribute to anesthetic suppression of consciousness, which may instead depend on large-scale effects, more subtle dynamic properties, or changes outside of primary sensory cortex., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Significant advances have been made in our understanding of subcortical processes related to anesthetic- and sleep-induced unconsciousness, but the associated changes in cortical connectivity and cortical neurochemistry have yet to be fully clarified., Methods: Male Sprague-Dawley rats were instrumented for simultaneous measurement of cortical acetylcholine and electroencephalographic indices of corticocortical connectivity-coherence and symbolic transfer entropy-before, during, and after general anesthesia (propofol, n = 11; sevoflurane, n = 13). In another group of rats (n = 7), these electroencephalographic indices were analyzed during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep., Results: Compared to wakefulness, anesthetic-induced unconsciousness was characterized by a significant decrease in cortical acetylcholine that recovered to preanesthesia levels during recovery wakefulness. Corticocortical coherence and frontal-parietal symbolic transfer entropy in high γ band (85 to 155 Hz) were decreased during anesthetic-induced unconsciousness and returned to preanesthesia levels during recovery wakefulness. Sleep-wake states showed a state-dependent change in coherence and transfer entropy in high γ bandwidth, which correlated with behavioral arousal: high during wakefulness, low during SWS, and lowest during REM sleep. By contrast, frontal-parietal θ connectivity during sleep-wake states was not correlated with behavioral arousal but showed an association with well-established changes in cortical acetylcholine: high during wakefulness and REM sleep and low during SWS., Conclusions: Corticocortical coherence and frontal-parietal connectivity in high γ bandwidth correlates with behavioral arousal and is not mediated by cholinergic mechanisms, while θ connectivity correlates with cortical acetylcholine levels.

Background: The neural correlates of anesthetic-induced unconsciousness have yet to be fully elucidated. Sedative and anesthetic states induced by propofol have been studied extensively, consistently revealing a decrease of frontoparietal and thalamocortical connectivity. There is, however, less understanding of the effects of halogenated ethers on functional brain networks., Methods: The authors recorded simultaneous resting-state functional magnetic resonance imaging and electroencephalography in 16 artificially ventilated volunteers during sevoflurane anesthesia at burst suppression and 3 and 2 vol% steady-state concentrations for 700 s each to assess functional connectivity changes compared to wakefulness. Electroencephalographic data were analyzed using symbolic transfer entropy (surrogate of information transfer) and permutation entropy (surrogate of cortical information processing). Functional magnetic resonance imaging data were analyzed by an independent component analysis and a region-of-interest-based analysis., Results: Electroencephalographic analysis showed a significant reduction of anterior-to-posterior symbolic transfer entropy and global permutation entropy. At 2 vol% sevoflurane concentrations, frontal and thalamic networks identified by independent component analysis showed significantly reduced within-network connectivity. Primary sensory networks did not show a significant change. At burst suppression, all cortical networks showed significantly reduced functional connectivity. Region-of-interest-based thalamic connectivity at 2 vol% was significantly reduced to frontoparietal and posterior cingulate cortices but not to sensory areas., Conclusions: Sevoflurane decreased frontal and thalamocortical connectivity. The changes in blood oxygenation level dependent connectivity were consistent with reduced anterior-to-posterior directed connectivity and reduced cortical information processing. These data advance the understanding of sevoflurane-induced unconsciousness and contribute to a neural basis of electroencephalographic measures that hold promise for intraoperative anesthesia monitoring., Competing Interests: All other authors have no conflicts of interest.

A quest for a systems-level neuroscientific basis of anesthetic-induced loss and return of consciousness has been in the forefront of research for the past 2 decades. Recent advances toward the discovery of underlying mechanisms have been achieved using experimental electrophysiology, multichannel electroencephalography, magnetoencephalography, and functional magnetic resonance imaging. By the careful dosing of various volatile and IV anesthetic agents to the level of behavioral unresponsiveness, both specific and common changes in functional and effective connectivity across large-scale brain networks have been discovered and interpreted in the context of how the synthesis of neural information might be affected during anesthesia. The results of most investigations to date converge toward the conclusion that a common neural correlate of anesthetic-induced unresponsiveness is a consistent depression or functional disconnection of lateral frontoparietal networks, which are thought to be critical for consciousness of the environment. A reduction in the repertoire of brain states may contribute to the anesthetic disruption of large-scale information integration leading to unconsciousness. In future investigations, a systematic delineation of connectivity changes with multiple anesthetics using the same experimental design, and the same analytical method will be desirable. The critical neural events that account for the transition between responsive and unresponsive states should be assessed at similar anesthetic doses just below and above the loss or return of responsiveness. There will also be a need to identify a robust, sensitive, and reliable measure of information transfer. Ultimately, finding a behavior-independent measure of subjective experience that can track covert cognition in unresponsive subjects and a delineation of causal factors versus correlated events will be essential to understand the neuronal basis of human consciousness and unconsciousness., Competing Interests: The authors declare no conflicts of interest.

We sought to characterize stroke management and outcomes in a postoperative population. By using the electronic medical records, we identified 39 patients suffering perioperative stroke after noncardiac and nonneurosurgical procedures for whom documentation of management and outcomes was available. Thirty-three strokes occurred during admission, whereas 6 occurred after discharge and were recognized upon return to the hospital. Perioperative stroke was associated with delayed recognition, infrequent intervention, and significant rates of morbidity and mortality, suggesting the need for improved screening and more rapid treatment. There may be disparities in care and outcomes between in-hospital and out-of hospital stroke patients, though further study is warranted.

The neural mechanisms of anesthetic-induced unconsciousness have yet to be fully elucidated, in part because of the diverse molecular targets of anesthetic agents. We demonstrate, using intracortical recordings in macaque monkeys, that information transfer between structurally connected cortical regions is disrupted during ketamine anesthesia, despite preserved primary sensory representation. Furthermore, transfer entropy, an information-theoretic measure of directed connectivity, decreases significantly between neuronal units in the anesthetized state. This is the first direct demonstration of a general anesthetic disrupting corticocortical information transfer in the primate brain. Given past studies showing that more commonly used GABAergic drugs inhibit surrogate measures of cortical communication, this finding suggests the potential for a common network-level mechanism of anesthetic-induced unconsciousness., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Achieving a smooth and rapid emergence from general anesthesia is of particular importance for neurosurgical patients and is a clinical goal for neuroanesthesiologists. Recent data suggest that the process of emergence is not simply the mirror image of induction, but rather controlled by distinct neural circuits. In this narrative review, we discuss (1) hysteresis, (2) the concept of neural inertia, (3) the asymmetry between the neurobiology of induction and emergence, and (4) recent attempts at actively inducing emergence.

Up to 40% of individuals with unresponsive wakefulness syndrome (UWS) actually might be conscious. Recent attempts to detect covert consciousness in behaviorally unresponsive patients via neurophysiological patterns are limited by the need to compare data from brain-injured patients to healthy controls. In this report, we pilot an alternative within-subject approach by using propofol to perturb the brain state of a patient diagnosed with UWS. An auditory stimulation series was presented to the patient before, during, and after exposure to propofol while high-density electroencephalograph (EEG) was recorded. Baseline analysis revealed residual markers in the continuous EEG and event-related potentials (ERPs) that have been associated with conscious processing. However, these markers were significantly distorted by the patient's pathology, challenging the interpretation of their functional significance. Upon exposure to propofol, changes in EEG characteristics were similar to what is seen in healthy individuals and ERPs associated with conscious processing disappeared. At the 1-month follow up, the patient had regained consciousness. We offer three alternative explanations for these results: (1) the patient was covertly consciousness, and was anesthetized by propofol administration; (2) the patient was unconscious, and the observed EEG changes were a propofol-specific phenomenon; and (3) the patient was unconscious, but his brain networks responded normally in a way that heralded the possibility of recovery. These alternatives will be tested in a larger study, and raise the intriguing possibility of using a general anesthetic as a probe of brain states in behaviorally unresponsive patients.

Purpose: Perioperative stroke is associated with significant morbidity and mortality, with an incidence that may be underappreciated. In this review, we examine the significance, pathophysiology, risk factors, and evidence-based recommendations for the prevention and management of perioperative stroke., Source: This is a narrative review based on literature from the PubMed database regarding perioperative stroke across a broad surgical population. The Society for Neuroscience in Anesthesiology and Critical Care recently published evidence-based recommendations for perioperative management of patients at high risk for stroke; these recommendations were analyzed and incorporated into this review., Principal Findings: The incidence of overt perioperative stroke is highest in patients presenting for cardiac and major vascular surgery, although preliminary data suggest that the incidence of covert stroke may be as high as 10% in non-cardiac surgery patients. The pathophysiology of perioperative stroke involves different pathways. Thrombotic stroke can result from increased inflammation and hypercoagulability; cardioembolic stroke can result from disease states such as atrial fibrillation, and tissue hypoxia from anemia can result from the combination of anemia and beta-blockade. Across large-scale database studies, common risk factors for perioperative stroke include advanced age, history of cerebrovascular disease, ischemic heart disease, congestive heart failure, atrial fibrillation, and renal disease. Recommendations for prevention and management of perioperative stroke are evolving, though further work is needed to clarify the role of proposed modifiable risk factors such as perioperative anticoagulation, antiplatelet therapy, appropriate transfusion thresholds, and perioperative beta-blockade., Conclusions: Perioperative stroke carries a significant clinical burden. The incidence of perioperative stroke may be higher than previously recognized, and there are diverse pathophysiologic mechanisms. There are many opportunities for further investigation of the pathophysiology, prevention, and management of perioperative stroke.

Sleep, anesthesia, and coma share a number of neural features but the recovery profiles are radically different. To understand the mechanisms of reversibility of unconsciousness at the network level, we studied the conditions for gradual and abrupt transitions in conscious and anesthetized states. We hypothesized that the conditions for explosive synchronization (ES) in human brain networks would be present in the anesthetized brain just over the threshold of unconsciousness. To test this hypothesis, functional brain networks were constructed from multi-channel electroencephalogram (EEG) recordings in seven healthy subjects across conscious, unconscious, and recovery states. We analyzed four variables that are involved in facilitating ES in generic, non-biological networks: (1) correlation between node degree and frequency, (2) disassortativity (i.e., the tendency of highly-connected nodes to link with less-connected nodes, or vice versa), (3) frequency difference of coupled nodes, and (4) an inequality relationship between local and global network properties, which is referred to as the suppressive rule. We observed that the four network conditions for ES were satisfied in the unconscious state. Conditions for ES in the human brain suggest a potential mechanism for rapid recovery from the lightly-anesthetized state. This study demonstrates for the first time that the network conditions for ES, formerly shown in generic networks only, are present in empirically-derived functional brain networks. Further investigations with deep anesthesia, sleep, and coma could provide insight into the underlying causes of variability in recovery profiles of these unconscious states.

Background: Beach chair positioning during general anesthesia is associated with cerebral oxygen desaturation. Changes in cerebral oxygenation resulting from the interaction of inspired oxygen fraction (FIO2), end-tidal carbon dioxide (PETCO2), and anesthetic choice have not been fully evaluated in anesthetized patients in the beach chair position., Methods: This is a prospective interventional within-group study of patients undergoing shoulder surgery in the beach chair position that incorporated a randomized comparison between two anesthetics. Fifty-six patients were randomized to receive desflurane or total intravenous anesthesia with propofol. Following induction of anesthesia and positioning, FIO2 and minute ventilation were sequentially adjusted for all patients. Regional cerebral oxygenation (rSO2) was the primary outcome and was recorded at each of five set points., Results: While maintaining FIO2 at 0.3 and PETCO2 at 30 mmHg, there was a decrease in rSO2 from 68% (SD, 12) to 61% (SD, 12) (P < 0.001) following beach chair positioning. The combined interventions of increasing FIO2 to 1.0 and increasing PETCO2 to 45 mmHg resulted in a 14% point improvement in rSO2 to 75% (SD, 12) (P <0.001) for patients anesthetized in the beach chair position. There was no significant interaction effect of the anesthetic at the study intervention points., Conclusions: Increasing FIO2 and PETCO2 resulted in a significant increase in rSO2 that overcomes desaturation in patients anesthetized in the beach chair position and that appears independent of anesthetic choice.

Nav1.6 is a major voltage-gated sodium channel in the central and peripheral nervous systems. Within neurons, the channel protein is concentrated at the axon initial segment and nodes of Ranvier, where it functions in initiation and propagation of action potentials. We examined the role of Nav1.6 in general anesthesia using two mouse mutants with reduced activity of Nav1.6, Scn8amedJ/medJ and Scn8a9J/9J. The mice were exposed to the general anesthetics isoflurane and sevoflurane in step-wise increments; the concentration required to produce loss of righting reflex, a surrogate for anesthetic-induced unconsciousness in rodents, was determined. Mice homozygous for these mutations exhibited increased sensitivity to both isoflurane and sevoflurane. The increased sensitivity was observed during induction of unconsciousness but not during the recovery phase, suggesting that the effect is not attributable to compromised systemic physiology. Electroencephalographic theta power during baseline waking was lower in mutants, suggesting decreased arousal and reduced neuronal excitability. This is the first report linking reduced activity of a specific voltage-gated sodium channel to increased sensitivity to general anesthetics in vivo.

This article was published by mistake in the June issue of BJA due to an administrative error. It was supposed to go into this special issue on Memory and Awareness in Anaesthesia. The article can be accessed free of charge at the following link: http://bja.oxfordjournals.org/lookup/doi/10.1093/bja/aev095 The Publisher apologizes for the error.

Intraoperative awareness, with or without recall, continues to be a topic of clinical significance and neurobiological interest. In this article, we review evidence pertaining to the incidence, sequelae, and prevention of intraoperative awareness. We also assess which aspects of the complication are well understood (i.e. non-controversial) and which require further research for clarification (i.e. controversial)., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Awareness during general anaesthesia is a source of concern for patients and anaesthetists, with potential for psychological and medicolegal sequelae. We used a registry to evaluate unintended awareness from the patient's perspective with an emphasis on their experiences and healthcare provider responses., Methods: English-speaking subjects self-reported explicit recall of events during anaesthesia to the Anesthesia Awareness Registry of the ASA, completed a survey, and submitted copies of medical records. Anaesthesia awareness was defined as explicit recall of events during induction or maintenance of general anaesthesia. Patient experiences, satisfaction, and desired practitioner responses to explicit recall were based on survey responses., Results: Most of the 68 respondents meeting inclusion criteria (75%) were dissatisfied with the manner in which their concerns were addressed by their healthcare providers, and many reported long-term harm. Half (51%) of respondents reported that neither the anaesthesia provider nor surgeon expressed concern about their experience. Few were offered an apology (10%) or referral for counseling (15%). Patient preferences for responses after an awareness episode included validation of their experience (37%), an explanation (28%), and discussion or follow-up to the episode (26%)., Conclusions: Data from this registry confirm the serious impact of anaesthesia awareness for some patients, and suggest that patients need more systematic responses and follow-up by healthcare providers., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Intraoperative awareness with explicit recall is a potentially devastating complication of surgery that has been attributed to low anaesthetic concentrations in the vast majority of cases. Past studies have proposed the determination of an adequate dose for general anaesthetics that could be used to alert providers of potentially insufficient anaesthesia. However, there have been no systematic analyses of appropriate thresholds to develop population-based alerting algorithms for preventing intraoperative awareness., Objective: To identify a threshold for intraoperative alerting that could be applied for the prevention of awareness with explicit recall., Design: Secondary analysis of a randomised controlled trial (Michigan Awareness Control Study)., Setting: Three hospitals at a tertiary care centre in the USA., Patients: Unselected patients presenting for surgery under general anaesthesia., Interventions: Alerts based on end-tidal anaesthetic concentration or bispectral index values., Main Outcome Measures: Using case and outcomes data from the primary study, end-tidal anaesthetic concentration and bispectral index values were analysed using Youden's index and c-statistics derived from a receiver operating characteristic curve to determine a specific alerting threshold for the prevention of awareness., Results: No single population-based threshold that maximises sensitivity and specificity could be identified for the prevention of intraoperative awareness, using either anaesthetic concentration or bispectral index values. The c-statistic for anaesthetic concentration was 0.431 ± 0.046, and 0.491 ± 0.056 for bispectral index values., Conclusion: We could not derive a single population-based alerting threshold for the prevention of intraoperative awareness using either anaesthetic concentration or bispectral index values. These data indicate a need to move towards individualised alerting strategies in the prevention of intraoperative awareness., Trial Registration: Primary trial registration (Michigan Awareness Control Study) ClinicalTrials.gov identifier: NCT00689091.

The balance of global integration and functional specialization is a critical feature of efficient brain networks, but the relationship of global topology, local node dynamics and information flow across networks has yet to be identified. One critical step in elucidating this relationship is the identification of governing principles underlying the directionality of interactions between nodes. Here, we demonstrate such principles through analytical solutions based on the phase lead/lag relationships of general oscillator models in networks. We confirm analytical results with computational simulations using general model networks and anatomical brain networks, as well as high-density electroencephalography collected from humans in the conscious and anesthetized states. Analytical, computational, and empirical results demonstrate that network nodes with more connections (i.e., higher degrees) have larger amplitudes and are directional targets (phase lag) rather than sources (phase lead). The relationship of node degree and directionality therefore appears to be a fundamental property of networks, with direct applicability to brain function. These results provide a foundation for a principled understanding of information transfer across networks and also demonstrate that changes in directionality patterns across states of human consciousness are driven by alterations of brain network topology.

Purpose: The red-hair phenotype, which is often produced by mutations in the melanocortin-1 receptor gene, has been associated with an increase in sedative, anesthetic, and analgesic requirements in both animal and human studies. Nevertheless, the clinical implications of this phenomenon in red-haired patients undergoing surgery are currently unknown., Methods: In a secondary analysis of a prospective trial of intraoperative awareness, red-haired patients were identified and matched with five control patients, and the relative risk for intraoperative awareness was determined. Overall anesthetic management between groups was compared using Hotelling's T(2) statistic. Inhaled anesthetic requirements were compared between cohorts by evaluating the relationship between end-tidal anesthetic concentration and the bispectral index with a linear mixed-effects model. Time to recovery was compared using Kaplan-Meier analysis, and differences in postoperative pain and nausea/vomiting were evaluated with Chi square tests., Results: A cohort of 319 red-haired patients was matched with 1,595 control patients for a sample size of 1,914. There were no significant differences in the relative risk of intraoperative awareness (relative risk = 1.67; 95% confidence interval 0.34 to 8.22), anesthetic management, recovery times, or postoperative pain between red-haired patients and control patients. The relationship between pharmacokinetically stable volatile anesthetic concentrations and bispectral index values differed significantly between red-haired patients and controls (P < 0.001), but without clinical implications., Conclusion: There were no demonstrable differences between red-haired patients and controls in response to anesthetic and analgesic agents or in recovery parameters. These findings suggest that perioperative anesthetic and analgesic management should not be altered based on self-reported red-hair phenotype.

'Covert consciousness' is a state in which consciousness is present without the capacity for behavioural response, and it can occur in patients with intraoperative awareness or unresponsive wakefulness syndrome. To detect and prevent this undesirable state, it is critical to develop a reliable neurobiological assessment of an individual's level of consciousness that is independent of behaviour. One such approach that shows potential is measuring surrogates of cortical communication in the brain using electroencephalography (EEG). EEG is practicable in clinical application, but involves many fundamental signal processing problems, including signal-to-noise ratio and high dimensional complexity. Symbolic analysis of EEG can mitigate these problems, improving the measurement of brain connectivity and the ability to successfully assess levels of consciousness. In this article, we review the problem of covert consciousness, basic neurobiological principles of consciousness, current methods of measuring brain connectivity and the advantages of symbolic processing, with a focus on symbolic transfer entropy (STE). Finally, we discuss recent advances and clinical applications of STE and other symbolic analyses to assess levels of consciousness., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

Background: Recent studies of anesthetic-induced unconsciousness in humans have focused predominantly on the intravenous drug propofol and have identified anterior dominance of alpha rhythms and frontal phase-amplitude coupling patterns as neurophysiological markers. However, it is unclear whether the correlates of propofol-induced unconsciousness are generalizable to inhaled anesthetics, which have distinct molecular targets and which are used more commonly in clinical practice., Methods: The authors recorded 64-channel electroencephalograms in healthy human participants during consciousness, sevoflurane-induced unconsciousness, and recovery (n = 10; n = 7 suitable for analysis). Spectrograms and scalp distributions of low-frequency (1 Hz) and alpha (10 Hz) power were analyzed, and phase-amplitude modulation between these two frequencies was calculated in frontal and parietal regions. Phase lag index was used to assess phase relationships across the cortex., Results: At concentrations sufficient for unconsciousness, sevoflurane did not result in a consistent anteriorization of alpha power; the relationship between low-frequency phase and alpha amplitude in the frontal cortex did not undergo characteristic transitions. By contrast, there was significant cross-frequency coupling in the parietal region during consciousness that was not observed after loss of consciousness. Furthermore, a reversible disruption of anterior-posterior phase relationships in the alpha bandwidth was identified as a correlate of sevoflurane-induced unconsciousness., Conclusion: In humans, sevoflurane-induced unconsciousness is not correlated with anteriorization of alpha and related cross-frequency patterns, but rather by a disruption of phase-amplitude coupling in the parietal region and phase-phase relationships across the cortex.

Injury to the central and peripheral nervous systems is often permanent. As such, adverse neurological outcomes of surgery and anaesthesia can be devastating for patients and their families. In this article, we review the incidence, risk factors, outcomes, prevention, and treatment of a number of important neurological complications in the perioperative period., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Elective surgery can have long-term psychological sequelae, especially for patients who experience intraoperative awareness. However, risk factors, other than awareness, for symptoms of posttraumatic stress disorder (PTSD) after surgery are poorly defined, and practical screening methods have not been applied to a broad population of surgical patients., Methods: The Psychological Sequelae of Surgery study was a prospective cohort study of patients previously enrolled in the United States and Canada in 3 trials for the prevention of intraoperative awareness. The 68 patients who experienced definite or possible awareness were matched with 418 patients who denied awareness based on age, sex, surgery type, and awareness risk. Participants completed the PTSD Checklist-Specific (PCL-S) and/or a modified Mini-International Neuropsychiatric Interview telephone assessment to identify symptoms of PTSD and symptom complexes consistent with a PTSD diagnosis. We then used structural equation modeling to produce a composite PTSD score and examined potential risk factors., Results: One hundred forty patients were unreachable; of those contacted, 303 (88%) participated a median of 2 years postoperatively. Forty-four of the 219 patients (20.1%) who completed the PCL-S exceeded the civilian screening cutoff score for PTSD symptoms resulting from their surgery (15 of 35 [43%] with awareness and 29 of 184 [16%] without). Nineteen patients (8.7%; 5 of 35 [14%] with awareness and 14 of 184 [7.6%] without) both exceeded the cutoff and endorsed a breadth of symptoms consistent with the Diagnostic and Statistical Manual Fourth Edition diagnosis of PTSD attributable to their surgery. Factors independently associated with PTSD symptoms were poor social support, previous PTSD symptoms, previous mental health treatment, dissociation related to surgery, perceiving that one's life was threatened during surgery, and intraoperative awareness (all P ≤ 0.017). Perioperative dissociation was identified as a potential mediator for perioperative PTSD symptoms., Conclusions: Events in the perioperative period can precipitate psychological symptoms consistent with subsyndromal and syndromal PTSD. We not only confirmed the high rate of postoperative PTSD in awareness patients but also identified a significant rate in matched nonawareness controls. Screening surgical patients, especially those with potentially mediating risk factors such as intraoperative awareness or perioperative dissociation, for postoperative PTSD symptoms with the PCL-S is practical and could promote early referral, evaluation, and treatment.

Perioperative stroke can be a catastrophic outcome for surgical patients and is associated with increased morbidity and mortality. This consensus statement from the Society for Neuroscience in Anesthesiology and Critical Care provides evidence-based recommendations and opinions regarding the preoperative, intraoperative, and postoperative care of patients at high risk for the complication.

Introduction: Postoperative delirium is one of the most common complications of major surgery, affecting 10-70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial., Methods: The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report., Ethics and Dissemination: The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media., Registration Details: The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS)., Trial Registration Number: NCT01690988 (last updated December 2013)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Recent studies of propofol-induced unconsciousness have identified characteristic properties of electroencephalographic alpha rhythms that may be mediated by drug activity at γ-aminobutyric acid (GABA) receptors in the thalamus. However, the effect of ketamine (a primarily non-GABAergic anesthetic drug) on alpha oscillations has not been systematically evaluated. We analyzed the electroencephalogram of 28 surgical patients during consciousness and ketamine-induced unconsciousness with a focus on frontal power, frontal cross-frequency coupling, frontal-parietal functional connectivity (measured by coherence and phase lag index), and frontal-to-parietal directional connectivity (measured by directed phase lag index) in the alpha bandwidth. Unlike past studies of propofol, ketamine-induced unconsciousness was not associated with increases in the power of frontal alpha rhythms, characteristic cross-frequency coupling patterns of frontal alpha power and slow-oscillation phase, or decreases in coherence in the alpha bandwidth. Like past studies of propofol using undirected and directed phase lag index, ketamine reduced frontal-parietal (functional) and frontal-to-parietal (directional) connectivity in the alpha bandwidth. These results suggest that directional connectivity changes in the alpha bandwidth may be state-related markers of unconsciousness induced by both GABAergic and non-GABAergic anesthetics.

The question of how structurally and pharmacologically diverse general anesthetics disrupt consciousness has persisted since the nineteenth century. There has traditionally been a significant focus on "bottom-up" mechanisms of anesthetic action, in terms of sensory processing, arousal systems, and structural scales. However, recent evidence suggests that the neural mechanisms of anesthetic-induced unconsciousness may involve a "top-down" process, which parallels current perspectives on the neurobiology of conscious experience itself. This article considers various arguments for top-down mechanisms of anesthetic-induced unconsciousness, with a focus on sensory processing and sleep-wake networks. Furthermore, recent theoretical work is discussed to highlight the possibility that top-down explanations may be causally sufficient, even assuming critical bottom-up events.