BACKGROUND:Anesthetics like propofol increase electroencephalography (EEG) power in delta frequencies (0.1-4 Hz), with a decrease of power in bandwidths >30 Hz. Propofol is nonselective for gamma amino butyric acid type A receptor subtypes (GABA A R) as it enhances all 3 GABA A R subtypes (slow, fast, and tonic). Our newly developed anesthetic class selectively targets GABA A R-slow synapses to depress brain responsiveness. We hypothesized that a selective GABA A R-slow agonist, KSEB 01-S2, would produce a different EEG signature compared to the broad-spectrum GABA A R agonist (propofol), and tested this using rat EEG recordings. METHODS:Male rats were studied after Institutional Animal Care and Use Committees (IACUC) approval from the US Army Medical Research Institute of Chemical Defense and the University of Michigan. Rats were anesthetized using isoflurane (3%-5% induction, 1%-3% maintenance) with oxygen at 0.5 to 1.0 L/min. Stainless steel screws were placed in the skull and used to record subcranial cortical EEG signals. After recovery, either propofol or KSEB 01-S2 was administered and effects on EEG signals were analyzed. RESULTS:As previously reported, propofol produced increased power in delta frequencies (0.1-4 Hz) compared to predrug recordings and produced a decrease in EEG power >30 Hz but no significant changes were seen within ±20 seconds of losing the righting reflex. By contrast, KSEB 01-S2 produced a significant increase in theta frequency percent power (median 14.7%, 16.2/13.8, 75/25 confidence interval; to 34.7%, 35/31.8; P < .015) and a significant decrease in low gamma frequency percent power (16.9%, 18.6/15.8; to 5.45%, 5.5/5.39; P < .015) for all rats at ± 20 seconds of loss of consciousness (LOC). Both anesthetics produced a flattening of chaotic attractor plots from nonlinear dynamic analyses, like that produced by volatile and dissociative anesthetics at LOC. CONCLUSIONS:KSEB 01-S2 produced a markedly different EEG pattern, with a selective increase observed in the theta frequency range. KSEB 01-S2 also differs markedly in its activity at the GABA A R-slow receptor subtype, suggesting a possible mechanistic link between receptor subtype specificity and EEG frequency band signatures. Increased theta together with depressed gamma frequencies is interesting because GABA A R slow synapses have previously been suggested to underlie theta frequency oscillations, while fast synapses control gamma activity. These reciprocal effects support a previous model for theta and nested gamma oscillations based on inhibitory connections between GABA A R fast and slow interneurons. Although each anesthetic produced a unique EEG response, propofol and KSEB 01-S2 both increased slow wave activity and flattened chaotic attractor plots at the point of LOC.

Background: Maintaining an appropriate depth of anaesthesia is important for avoiding adverse effects from undermedication or overmedication during surgery. Electroencephalography (EEG) has become increasingly used to achieve this balance. Investigating the predictive power of intracranial EEG (iEEG) and scalp EEG for different levels of sedation could increase the utility of EEG monitoring. Methods: Simultaneous iEEG, scalp EEG, and Observer's Assessment of Alertness/Sedation (OAA/S) scores were recorded during emergence from anaesthesia in seven patients undergoing placement of intracranial electrodes for medically refractory epilepsy. A deep learning model was constructed to predict an OAA/S score of 0-2 vs 3-5 using iEEG, scalp EEG, and their combination. An additional five patients with only scalp EEG data were used for independent validation. Models were evaluated using the area under the receiver-operating characteristic curve (AUC). Results: Combining scalp EEG and iEEG yielded significantly better prediction (AUC=0.795, P<0.001) compared with iEEG only (AUC=0.750, P=0.02) or scalp EEG only (AUC=0.764, P<0.001). The validation scalp EEG only data resulted in an AUC of 0.844. Combining the two modalities appeared to capture spatiotemporal advantages from both modalities. Conclusions: The combination of iEEG and scalp EEG better predicted sedation level than either modality alone. The scalp EEG only model achieved a similar AUC to the combined model and maintained its performance in additional patients, suggesting that scalp EEG models are likely sufficient for real-time monitoring. Deep learning approaches using multiple leads to capture a wider area of brain activity may help augment existing EEG monitors for prediction of sedation.

Introduction:Dexmedetomidine is one of the anesthetics of choice for drug induced sleep endoscopy (DISE), with advantages including limited respiratory depression, analgesia, and decreased incidence of emergence delirium. However, challenges with determining sedation levels and prolonged recovery have limited its usage. An improved understanding of the effect of dexmedetomidine on the level of sedation and the corresponding electroencephalographic (EEG) changes could help overcome these barriers. Methods:Fifty-one patients received dexmedetomidine sedation with Richmond Agitation-Sedation Scale (RASS) score assessment and continuous EEG monitoring via SedLine for DISE. We constructed a pharmacokinetic model to determine continuous dexmedetomidine blood concentration. From the SedLine, we extracted the patient state index (PSI), and from the EEG we calculated the spectral edge frequency 95% (SEF95) and the correlation dimension (CD), a type of fractal dimension used to assess the complexity of a system. These metrics were subsequently compared against one another and with the dexmedetomidine concentration. Results:Our pharmacokinetic model yielded a two-compartment model with volumes of 51.8 L and 106.2 L, with clearances of 69.5 and 168.9 L/h, respectively, and a time to effect of 9 min, similar to prior studies. Based on this model, decreasing RASS score, SEF95, CD, and PSI were all significantly associated with increasing dexmedetomidine concentration (p < 0.001, p = 0.006, p < 0.001 respectively). The CD, SEF95, and PSI better captured the effects of increasing dexmedetomidine concentration as compared to the RASS score. Simulating dexmedetomidine concentration based on titration to target levels derived from CD and PSI confirmed commonly used dexmedetomidine infusion dosages. Conclusion:Dexmedetomidine use for DISE confirmed previous pharmacokinetic models seen with dexmedetomidine. Complex EEG metrics such as PSI and CD, as compared to RASS score and SEF95, better captured changes in brain state from dexmedetomidine and have potential to improve the monitoring of dexmedetomidine sedation.

INTRODUCTION: The dynamic interplay between several large-scale brain networks is thought to underlie human consciousness. The default mode network (DMN) governs internal thought during rest, the central executive network (CEN) drives goal-directed problem solving, and the salience network (SN) detects and integrates new stimuli during the transition between resting and cognitively active states. While scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have elucidated much about these networks in steady states, intracranial EEG (iEEG) dynamics during state transitions remain largely unclear. METHODS: Seven patients with medically refractory epilepsy underwent robot-assisted stereotactic placement of depth electrodes for epileptic focus localization. Recordings from 422 total iEEG contacts representing 49 distinct cognitive network nodes were obtained during anesthesia emergence. Local-field dynamics and Observer’s Assessment of Alertness/Sedation (OAAS) scale state were analyzed in 20s clips for complexity, functional connectivity (FC), and graph communicability metrics. RESULTS: Signal complexity as represented by mean multiscale sample entropy (MSE) of SN and DMN nodes increases significantly during emergence from anesthesia (P < 0.05), driven by a shift from low- to mid-frequency power in key nodes. Intermediate consciousness states demonstrated higher mean MSE and participation coefficient, representing early integrative network behavior, before reaching an optimal balance of segregation and integration at wakefulness. During emergence, between-network FC increased most strongly between SN and CEN nodes. Communicability of SN nodes increased during emergence, driven predominately by increasing communicability of right anterior insula. CONCLUSIONS: Intracranial electroencephalographic recording of brain activity during anesthesia emergence demonstrates a complex but quantifiable interplay of default mode, central executive, and salience network hubs. There may be a greater than previously understood role of right anterior insula in gating transitions in consciousness states.

Multiple electroencephalographic (EEG) monitors and their associated EEG markers have been developed to aid in assessing the level of sedation in the operating room. While many studies have assessed the response of these markers to propofol sedation and anesthetic gases, few studies have compared these markers when using dexmedetomidine, an alpha-2 agonist. Fiftyone patients underwent drug induced sleep endoscopy with dexmedetomidine sedation. Continuous EEG was captured using SedLine (Masimo, Inc), and a playback system was used to extract the bispectral index (BIS) (Medtronic Inc), the patient state index (PSI) (Masimo, Inc), the state and response Entropy (GE Healthcare), and calculate the spectral edge frequency 95% (SEF95). Richmond Agitation-Sedation Scale (RASS) scores were assessed continually throughout the procedure and in recovery. We assessed the correlation between EEG markers and constructed ordinal logistic regression models to predict the RASS score and compare EEG markers. All three commercial EEG metrics were significantly associated with the RASS score (p < 0.001 for all metrics) whereas SEF95 alone was insufficient at characterizing dexmedetomidine sedation. PSI and Entropy achieved higher accuracy at predicing deeper levels of sedation as compared to BIS (PSI: 58.3%, Entropy: 58.3%, BIS: 44.4%). Lightening secondary to RASS score assessment is significantly captured by all three commercial EEG metrics (p < 0.001). Commercial EEG monitors can capture changes in the brain state associated with the RASS score during dexmedetomidine sedation. PSI and Entropy were highly correlated and may be better suited for assessing deeper levels of sedation.

Merker, Williford, and Rudrauf make several arguments against the integrated information theory of consciousness; whereas some have merit, their conclusion that the theory should be discarded is premature. Coming years promise advances in the empirical study of consciousness, and only after theories are independently tested with shared data can they be ruled in or out. We propose future research directions.

Background: Several devices record and interpret patient brain activity via electroencephalogram (EEG) to aid physician assessment of anaesthetic effect. Few studies have compared EEG monitors on data from the same patient. Here, we describe a set-up to simultaneously compare the performance of three processed EEG monitors using pre-recorded EEG signals from older surgical patients. Methods: A playback system was designed to replay EEG signals into three different commercially available EEG monitors. We could then simultaneously calculate indices from the SedLine (R) Root (Masimo Inc., Irvine, CA, USA; patient state index [PSI]), bilateral BIS VISTA (TM) (Medtronic Inc., Minneapolis, MN, USA; bispectral index [BIS]), and Datex Ohmeda S/5 monitor with the Entropy (TM) Module (GE Healthcare, Chicago, IL, USA; E-entropy index [Entropy]). We tested the ability of each system to distinguish activity before anaesthesia administration (pre-med) and before/after loss of responsiveness (LOR), and to detect suppression incidences in EEG recorded from older surgical patients receiving beta-adrenergic blockers. We show examples of processed EEG monitor output tested on 29 EEG recordings from older surgical patients. Results: All monitors showed significantly different indices and high effect sizes between comparisons pre-med to after LOR and before/after LOR. Both PSI and BIS showed the highest percentage of deeply anaesthetised indices during periods with suppression ratios (SRs) > 25%. We observed significant negative correlations between percentage of suppression and indices for all monitors (at SR >5%). Conclusions: All monitors distinguished EEG changes occurring before anaesthesia administration and during LOR. The PSI and BIS best detected suppressed periods. Our results suggest that the PSI and BIS monitors might be preferable for older patients with risk factors for intraoperative awareness or increased sensitivity to anaesthesia.

Anesthetic agents cause unique electroencephalogram (EEG) activity resulting from actions on their diverse molecular targets. Typically to produce balanced anesthesia in the clinical setting, several anesthetic and adjuvant agents are combined. This creates challenges for the clinical use of intraoperative EEG monitoring, because computational approaches are mostly limited to spectral analyses and different agents and combinations produce different EEG responses. Thus, testing of many combinations of agents is needed to generate accurate, protocol independent analyses. Additionally, most studies to develop new computational approaches take place in young, healthy adults and electrophysiological responses to anesthetics vary widely at the extremes of age, due to physiological brain differences. Below, we discuss the challenges associated with EEG biomarker identification for anesthetic depth based on the diversity of molecular targets. We suggest that by focusing on the generalized effects of anesthetic agents on network activity, we can create paths for improved universal analyses.

One influential view in neuroscience is that pairwise cell interactions explain the firing patterns of large populations. Despite its prevalence, this view originates from studies in the retina and visual cortex of anesthetized animals. Whether pairwise interactions predict the firing patterns of neurons across multiple brain areas in behaving animals remains unknown. Here, we performed multi-area electrical recordings to find that 2nd-order interactions explain a high fraction of entropy of the population response in macaque cortical areas V1 and V4. Surprisingly, despite the brain-state modulation of neuronal responses, the model based on pairwise interactions captured ∼90% of the spiking activity structure during wakefulness and sleep. However, regardless of brain state, pairwise interactions fail to explain experimentally observed entropy in neural populations from the prefrontal cortex. Thus, while simple pairwise interactions explain the collective behavior of visual cortical networks across brain states, explaining the population dynamics in downstream areas involves higher-order interactions.

The complete characterization of the activity of a neural population is a challenging task that is complicated by the number of potential interactions that grows exponentially as the size of the population increases. One influential view that has emerged several decades ago is that simple pairwise interactions between neurons can account for the observed firing patterns of large networks. However, despite its prevalence, this view originates from computational and electrophysiological studies in the retina and the primary visual cortex (V1) of anesthetized animals. Therefore, whether or not pairwise interactions predict the observed distribution of firing patterns across multiple brain areas in behaving animals remains unknown. Here we performed multi-electrode recordings from 3 cortical areas to report that second-order neuronal interactions can explain a high fraction of the entropy of the population response in early and mid-level visual cortex (areas V1 and V4) while providing a good approximation of the probability of spiking for groups of neurons. Surprisingly, despite the fact the firing pattern of neurons is controlled by brain state, the model based on pairwise interactions captures more than 90% of the structure in the detailed patterns of spiking observed during wakefulness and sleep. In contrast, regardless of brain state, pairwise interactions fail to explain experimentally observed entropy in neural populations from executive brain areas, such as the dorsolateral prefrontal cortex (dlPFC). These results indicate that higher-order interactions explain the population dynamics in downstream, executive areas, whereas simple pairwise interactions account for the dynamic behavior of neuronal networks in sensory cortical areas.

Anaesthetic depth changes spontaneously over the course of an anaesthetic for pharmacological and physiological reasons. Traditional methods for determining the efficacy of anaesthetic agents in individuals rely on population statistics, which limits progress towards precision anaesthesia for each individual. The laboratories of Proekt and Kelz have begun to quantify this variability in anaesthesia in mice, both at the level of the individual mouse1McKinstry-Wu A.R. Wasilczuk A.Z. Harrison B.A. et al.Analysis of stochastic fluctuations in responsiveness is a critical step toward personalized anesthesia.Elife. 2019; 8e50143Crossref PubMed Scopus (9) Google Scholar, 2Wasilczuk A. Harrison B. Kwasniewska P. et al.Resistance to state transitions is differentially modulated by different volatile anaesthetics.Br J Anaesth. 2020; (BJA-2020-00152-HH102.R1)Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, and also regarding differences between specific anaesthetic agents.2Wasilczuk A. Harrison B. Kwasniewska P. et al.Resistance to state transitions is differentially modulated by different volatile anaesthetics.Br J Anaesth. 2020; (BJA-2020-00152-HH102.R1)Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar In a study from their groups published by Wasilczuk and colleagues2Wasilczuk A. Harrison B. Kwasniewska P. et al.Resistance to state transitions is differentially modulated by different volatile anaesthetics.Br J Anaesth. 2020; (BJA-2020-00152-HH102.R1)Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar in this issue of British Journal of Anaesthesia, three volatile anaesthetics (isoflurane, sevoflurane, and halothane) were quantitatively assessed with regard to stability over time of the loss of righting reflex, a surrogate measure of loss of consciousness in rodents.3Frank G.B. Jhamandas K. Effects of drugs acting alone and in combination on the motor activity of intact mice.Br J Pharmacol. 1970; 39: 696-706Crossref PubMed Scopus (18) Google Scholar Steady-state concentrations at the minimum alveolar concentration dose for each agent were administered, and the ability to right was determined at 3-min intervals in each mouse over 2 h. Although the responses of the population of mice resulted in a calculable half maximal effective concentration (EC50) for each anaesthetic, the response dynamics of each individual mouse were highly variable. Over the 2-h measurement period, some mice exhibited the righting reflex on a majority of trials, while other mice failed to right on a majority of trials. The majority of the mice, however, exhibited seemingly random fluctuations between responsiveness and unresponsiveness during anaesthetic administration. The authors quantified this as a resistance to state transitions (Rst) using models of stochastic processes (Fig. 1). Interestingly, different volatile agents exhibited differing degrees of Rst. Halothane produced the most stable behavioural responses during anaesthesia (highest Rst), whereas sevoflurane, and more so isoflurane, produced lower resistances (i.e. higher fluctuations between response and no-response trials). Wasilczuk and colleagues2Wasilczuk A. Harrison B. Kwasniewska P. et al.Resistance to state transitions is differentially modulated by different volatile anaesthetics.Br J Anaesth. 2020; (BJA-2020-00152-HH102.R1)Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar argue that pharmacokinetic factors could not have played a role since animals were held at fixed inhaled concentrations for more than 2 h before behavioural measures commenced. Thirty minutes would be more than sufficient time for complete concentration equilibration at anaesthetic effect sites. Resistance to state transition provides a new measure of anaesthetic effect stability and provides a further example of agent-selective effects produced by different volatile anaesthetics.4MacIver M.B. Roth S.H. Anesthetics produce differential actions on the discharge activity of a single neuron.Eur J Pharmacol. 1987; 139: 43-52Crossref PubMed Scopus (14) Google Scholar, 5MacIver M.B. Roth S.H. Inhalation anaesthetics exhibit pathway-specific and differential actions on hippocampal synaptic responses in vitro.Br J Anaesth. 1988; 60: 680-691Abstract Full Text PDF PubMed Scopus (81) Google Scholar, 6Nishikawa K. MacIver M.B. Agent-selective effects of volatile anesthetics on GABAA receptor-mediated synaptic inhibition in hippocampal interneurons.Anesthesiology. 2001; 94: 340-347Crossref PubMed Scopus (91) Google Scholar, 7MacIver M.B. Anesthetic agent-specific effects on synaptic inhibition.Anesth Analg. 2014; 119: 558-569Crossref PubMed Scopus (31) Google Scholar Results from this study do not provide an explanation for the mechanism underlying the observed individual biological variability in anaesthetic effect between mice, nor do they probe the mechanisms accounting for observed differences in Rst between agents. However, they do show that the variability can be individually measured, providing a way forward for more detailed studies of these phenomena. Future research should include incorporating these measures into experimental paradigms where the resistance to state transitions metrics are quantified for mice of different genotypes. Wasilczuk and colleagues2Wasilczuk A. Harrison B. Kwasniewska P. et al.Resistance to state transitions is differentially modulated by different volatile anaesthetics.Br J Anaesth. 2020; (BJA-2020-00152-HH102.R1)Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar hypothesise that differences in brain structure and function must exist between mice, and that these differences must lead to differentially distributed anaesthetic target sites of action that each anaesthetic can act upon. It remains to be seen what these target sites might be, or even how many sites might be involved in producing the differential actions for each anaesthetic.4MacIver M.B. Roth S.H. Anesthetics produce differential actions on the discharge activity of a single neuron.Eur J Pharmacol. 1987; 139: 43-52Crossref PubMed Scopus (14) Google Scholar Growing evidence suggests that multiple sites of action contribute to anaesthesia, including some types of sodium,8Hemmings H.C. Sodium channels and the synaptic mechanisms of inhaled anaesthetics.Br J Anaesth. 2009; 103: 61-69Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar calcium,9Koyanagi Y. Torturo C.L. Cook D.C. Zhou Z. Hemmings H.C. Role of specific presynaptic calcium channel subtypes in isoflurane inhibition of synaptic vesicle exocytosis in rat hippocampal neurones.Br J Anaesth. 2019; 123: 219-227Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar and potassium10Westphalen R.I. Krivitski M. Amarosa A. Guy N. Hemmings H.C. Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1.Br J Pharmacol. 2007; 152: 939-945Crossref PubMed Scopus (25) Google Scholar channels, many ligand-gated channels,11Hemmings H.C. Akabas M.H. Goldstein P.A. Trudell J.R. Orser B.A. Harrison N.L. et al.Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar including channels gated by acetylcholine,12Forman S.A. Chiara D.C. Miller K.W. Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors.Neuropharmacology. 2015; 96: 169-177Crossref PubMed Scopus (29) Google Scholar catecholamines, glutamate,13Nishikawa K. MacIver M.B. Membrane and synaptic actions of halothane on rat hippocampal pyramidal neurons and inhibitory interneurons.J Neurosci. 2000; 20: 5915-5923Crossref PubMed Google Scholar,14Nishikawa K. MacIver M.B. Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to isoflurane than are non-NMDA receptor-mediated responses.Anesthesiology. 2000; 92: 228-236Crossref PubMed Scopus (95) Google Scholar and GABA,6Nishikawa K. MacIver M.B. Agent-selective effects of volatile anesthetics on GABAA receptor-mediated synaptic inhibition in hippocampal interneurons.Anesthesiology. 2001; 94: 340-347Crossref PubMed Scopus (91) Google Scholar,15Nicoll R.A. The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb.J Physiol (Lond). 1972; 223: 803-814Crossref Scopus (174) Google Scholar, 16Li X. Pearce R.A. Effects of halothane on GABA(A) receptor kinetics: evidence for slowed agonist unbinding.J Neurosci. 2000; 20: 899-907Crossref PubMed Google Scholar, 17Perouansky M. Pearce R.A. Is anesthesia caused by potentiation of synaptic or intrinsic inhibition? Recent insights into the mechanisms of volatile anesthetics.J Basic Clin Physiol Pharmacol. 2000; 11: 83-107Crossref PubMed Scopus (6) Google Scholar, 18Lecker I. Yin Y. Wang D.S. Orser B.A. Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists.Br J Anaesth. 2013; 110: i73-i81Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar and presynaptic neurotransmitter release proteins.19Xie Z. McMillan K. Pike C.M. et al.Interaction of anesthetics with neurotransmitter release machinery proteins.J Neurophysiol. 2013; 109: 758-767Crossref PubMed Scopus (26) Google Scholar, 20Herring B.E. McMillan K. Pike C.M. Marks J. Fox A.P. Xie Z. Etomidate and propofol inhibit the neurotransmitter release machinery at different sites.J Physiol. 2011; 589: 1103-1115Crossref PubMed Scopus (31) Google Scholar, 21Herring B.E. Xie Z. Marks J. Fox A.P. Isoflurane inhibits the neurotransmitter release machinery.J Neurophysiol. 2009; 102: 1265-1273Crossref PubMed Scopus (47) Google Scholar Many additional protein targets remain to be explored, and thus there are potentially hundreds of anaesthetic sites of action contributing to the observed biological variability.22Hemmings Jr., H.C. Riegelhaupt P.R. Kelz M.B. et al.Towards a comprehensive understanding of anesthetic mechanisms of action: a decade of discovery.Trends Pharmacol Sci. 2019; 40: 464-481Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Making the connections from these molecular dynamics to the emergent behavioural dynamics remains a challenge for understanding the neurophysiology of general anaesthesia. Clinically, it is well known that anaesthetic depth changes over the course of administration, and anaesthesiologists must titrate doses of various agents to adjust for this. Often stimuli such as the pain of surgery or simply saying a patient's name can prompt changes in anaesthetic depth. This new study indicates that even when stimuli are held relatively constant, fluctuations in depth of anaesthesia occur, independent of arousing stimuli. In layman's terms, the depth of anaesthesia changes spontaneously through time. Thus, targeting anaesthetic concentrations to obtain an ideal state remains a moving target. Wrote the manuscript, designed the figure, and are solely responsible for the content: both authors. The authors declare that they have no conflicts of interest. Resistance to state transitions in responsiveness is differentially modulated by different volatile anaesthetics in male miceBritish Journal of AnaesthesiaVol. 125Issue 3PreviewRecent studies point to a fundamental distinction between population-based and individual-based anaesthetic pharmacology. At the population level, anaesthetic potency is defined as the relationship between drug concentration and the likelihood of response to a stimulus. At the individual level, even when the anaesthetic concentration is held constant, fluctuations between the responsive and unresponsive states are observed. Notably, these spontaneous fluctuations exhibit resistance to state transitions Rst. Full-Text PDF

Propofol is one of the most widely used anesthetics for routine surgical anesthesia. Propofol administration alone produces EEG spectral characteristics similar to most hypnotics; however, inter-individual variation can make spectral measures inconsistent. Complexity measures of EEG signals could offer universal measures to better capture anesthetic depth as brain activity exhibits nonlinear behavior at several scales. We tested the potential of nonlinear dynamics analyses to identify loss and recovery of consciousness at clinically relevant timepoints. Patients undergoing propofol general anesthesia for various surgical procedures were identified as having changes in states of consciousness by the loss and recovery of response to verbal stimuli after induction and upon cessation of anesthesia, respectively. Nonlinear dynamics analyses showed more significant differences between consciousness states than most spectral measures. Thus, complexity measures could provide a means for reliably capturing depth of consciousness based on subtle EEG changes at the beginning and end of anesthesia administration.

The information processing capability of the brain decreases during unconscious states. Capturing this decrease during anesthesia-induced unconsciousness has been attempted using standard spectral analyses as these correlate relatively well with breakdowns in corticothalamic networks. Much of this work has involved the use of propofol to perturb brain activity, as it is one of the most widely used anesthetics for routine surgical anesthesia. Propofol administration alone produces EEG spectral characteristics similar to most hypnotics; however, inter-individual and drug variation render spectral measures inconsistent. Complexity measures of EEG signals could offer better measures to distinguish brain states, because brain activity exhibits nonlinear behavior at several scales during transitions of consciousness. We tested the potential of complexity analyses from nonlinear dynamics to identify loss and recovery of consciousness at clinically relevant timepoints. Patients undergoing propofol general anesthesia for various surgical procedures were identified as having changes in states of consciousness by the loss and recovery of response to verbal stimuli after induction and upon cessation of anesthesia, respectively. We demonstrate that nonlinear dynamics analyses showed more significant differences between consciousness states than spectral measures. Notably, attractors in conscious and anesthesia-induced unconscious states exhibited significantly different shapes. These shapes have implications for network connectivity, information processing, and the total number of states available to the brain at these different levels. They also reflect some of our general understanding of the network effects of consciousness in a way that spectral measures cannot. Thus, complexity measures could provide a universal means for reliably capturing depth of consciousness based on EEG changes at the beginning and end of anesthesia administration.

One of the great challenges and opportunities in medicine is to link biological actions produced by anaesthetics with their ability to produce loss of consciousness. We can measure consciousness in humans by asking subjects to respond to verbal commands, and we can measure detailed anaesthetic effects on neural circuits in animals, at surrogate loss of consciousness behavioural endpoints, but how do we link the two? In this issue, Banks and colleagues1Banks M.I. Moran N.S. Krause B.M. Grady S.M. Uhlrich D.J. Manning K.A. Altered stimulus representation in auditory cortex is not causal for loss of consciousness under general anaesthesia.BJA. 2018; 121: 605-615Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar used a sophisticated approach to measure high-level cortical information processing related to consciousness in an animal model. They asked whether sounds that carry auditory information, and are processed in rat primary auditory cortex, can be used to probe neuronal circuit alterations produced by general anaesthetics. Do anaesthetics alter information processing by the primary auditory cortex? Can measurement of cortical discrimination of auditory stimuli using mutual information reveal universal circuit functions relevant to consciousness? Banks and colleagues1Banks M.I. Moran N.S. Krause B.M. Grady S.M. Uhlrich D.J. Manning K.A. Altered stimulus representation in auditory cortex is not causal for loss of consciousness under general anaesthesia.BJA. 2018; 121: 605-615Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar tested the hypothesis that mutual information measures in primary auditory cortex reveal systematic changes occurring at loss of consciousness produced by anaesthetics. In their study, anaesthetic concentrations were carefully adjusted to reach loss of consciousness so that signal comparisons could be made between sedated and loss of consciousness brain states to allow detailed comparisons with earlier animal2MacIver M.B. Bland B.H. Chaos analysis of EEG during isoflurane-induced loss of righting in rats.Front Syst Neurosci. 2014; 8: 1Crossref PubMed Scopus (39) Google Scholar and human research.3Eagleman S.L. Drover C.M. Drover D.R. Ouellette N.T. MacIver M.B. Remifentanil and nitrous oxide anesthesia produces a unique pattern of EEG activity during loss and recovery of response.Front Hum Neurosci. 2018; 12: 173Crossref PubMed Scopus (9) Google Scholar They also tested cortical responses to three different anaesthetic agents—propofol, isoflurane, and dexmedetomidine—each of which has distinct molecular mechanisms of action.4Hemmings H.C. Akabas M.H. Goldstein P.A. Trudell J.R. Orser B.A. Harrison N.L. Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar They report that information processing in primary auditory cortex did not change in a systematic way with these three agents, so depressed information flow in this brain area did not appear to contribute to loss of consciousness. Interestingly, the three anaesthetic agents produced different effects at loss of righting reflex (a measure of loss of consciousness for rats), so there was no straightforward relationship between changes in neuronal activity at loss of consciousness across agents. Instead, information decreased for sedation with isoflurane and propofol, but increased with dexmedetomidine. No further information decrease was seen for propofol or isoflurane in the transition from sedation to loss of consciousness. In contrast, information increased again from sedation to loss of consciousness produced by dexmedetomidine. These results fit well with findings from previous research by Sarasso and colleagues5Sarasso S. Boly M. Napolitani M. et al.Consciousness and complexity during unresponsiveness induced by propofol, xenon, and ketamine.Curr Biol. 2015; 25: 3099-3105Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar and Alkire and colleagues6Alkire M.T. Hudetz A.G. Tononi G. Consciousness and anesthesia.Science. 2008; 322: 876-880Crossref PubMed Scopus (842) Google Scholar for other anaesthetics and cortical regions, and support a multisite agent specific mechanism of anaesthesia.4Hemmings H.C. Akabas M.H. Goldstein P.A. Trudell J.R. Orser B.A. Harrison N.L. Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 7MacIver M.B. Roth S.H. Inhalation anaesthetics exhibit pathway-specific and differential actions on hippocampal synaptic responses in vitro.Br J Anaesth. 1988; 60: 680-691Abstract Full Text PDF PubMed Scopus (85) Google Scholar, 8MacIver M.B. Anesthetic agent-specific effects on synaptic inhibition.Anesth Analg. 2014; 119: 558-569Crossref PubMed Scopus (36) Google Scholar Brain circuits appear to be altered in unique ways by various anaesthetic agents, working through multiple, often overlapping, mechanisms at a cellular level.8MacIver M.B. Anesthetic agent-specific effects on synaptic inhibition.Anesth Analg. 2014; 119: 558-569Crossref PubMed Scopus (36) Google Scholar, 9MacIver M.B. Mind and brain: consciousness in unresponsive subjects.Curr Biol. 2015; 25: R1140-R1142Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Each agent also produces unique EEG effects in animals and humans, and differences can be seen even between individuals using the same agent(s).10Purdon P.L. Sampson A. Pavone K.J. Brown E.N. Clinical electroencephalography for anesthesiologists: part I: background and basic signatures.Anesthesiology. 2015; 123: 937-960Crossref PubMed Scopus (387) Google Scholar, 11Purdon P.L. Pavone K.J. Akeju O. et al.The ageing brain: age-dependent changes in the electroencephalogram during propofol and sevoflurane general anaesthesia.BJA. 2015; 115: i46-i57Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 12Chander D. García P.S. MacColl J.N. Illing S. Sleigh J.W. Electroencephalographic variation during end maintenance and emergence from surgical anesthesia.PLoS One. 2014; 9 (e106291)Crossref Scopus (66) Google Scholar Thus, many sites of action exist that can be explored to produce a more targeted, safer way to produce general anaesthesia.4Hemmings H.C. Akabas M.H. Goldstein P.A. Trudell J.R. Orser B.A. Harrison N.L. Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 8MacIver M.B. Anesthetic agent-specific effects on synaptic inhibition.Anesth Analg. 2014; 119: 558-569Crossref PubMed Scopus (36) Google Scholar More emphasis could have been placed on a contributory role that primary sensory cortex plays together with accumulating effects on secondary, tertiary, and higher nodes of this hierarchical system for auditory consciousness.13Mashour G.A. Hudetz A.G. Neural correlates of unconsciousness in large-scale brain networks.Trends Neurosci. 2018; 41: 150-160Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Auditory consciousness has been well studied in humans (as loss of response to verbal command using EEG and functional MRI), as has auditory cortical neuronal processing using animal models. A variety of measures have shown that anaesthetics produce concentration-dependent alterations in auditory signalling from the brainstem to higher cortical regions across many sites. Excitatory inputs from higher cortical regions into primary auditory cortex are more sensitive to anaesthetic-induced depression than are ascending thalamocortical inputs,14Raz A. Grady S.M. Krause B.M. Uhlrich D.J. Manning K.A. Banks M.I. Preferential effect of isoflurane on top-down vs. bottom-up pathways in sensory cortex.Front Syst Neurosci. 2014; 8: 191Crossref PubMed Scopus (58) Google Scholar supporting a top-down depression of signalling at loss of consciousness.13Mashour G.A. Hudetz A.G. Neural correlates of unconsciousness in large-scale brain networks.Trends Neurosci. 2018; 41: 150-160Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar It should be noted that reciprocal thalamic and cortical connections would impose cortical effects onto ascending thalamocortical inputs, and vice versa.15Plourde G. Arseneau F. Absalom A.R. Attenuation of high-frequency (30–200 Hz) thalamocortical EEG rhythms as correlate of anaesthetic action: evidence from dexmedetomidine.Br J Anaesth. 2017; 119: 1150-1160Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar It should also be noted that bottom-up and top-down anaesthetic mechanisms are likely to occur together, probably simultaneously.16Mashour G.A. Hudetz A.G. Bottom-up and top-down mechanisms of general anesthetics modulate different dimensions of consciousness.Front Neural Circuits. 2017; 11: 44Crossref PubMed Scopus (69) Google Scholar But signalling across brain regions is not the same as understanding meaning in speech, and for this our brains need to be conscious. Banks and colleagues1Banks M.I. Moran N.S. Krause B.M. Grady S.M. Uhlrich D.J. Manning K.A. Altered stimulus representation in auditory cortex is not causal for loss of consciousness under general anaesthesia.BJA. 2018; 121: 605-615Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar used a sophisticated analytic approach to measure ‘meaning’ in information flow, to determine whether this high-level coding was altered in primary auditory cortex when rats lost consciousness. Interestingly, they found that high-level coding was not significantly altered in primary auditory cortex at loss of consciousness. The same has been reported for primary somatosensory and visual cortex,17Schroeder K.E. Irwin Z.T. Gaidica M. et al.Disruption of corticocortical information transfer during ketamine anesthesia in the primate brain.Neuroimage. 2016; 134: 459-465Crossref PubMed Scopus (58) Google Scholar, 18Lamme V.A. Zipser K. Spekreijse H. Figure-ground activity in primary visual cortex is suppressed by anesthesia.Proc Natl Acad Sci USA. 1998; 95: 3263-3268Crossref PubMed Scopus (231) Google Scholar demonstrating that early stages of cortical processing clearly remain intact at loss of consciousness. (Fig. 1) It may prove difficult to identify the brain level at which loss of consciousness to verbal stimuli pertains, because loss of consciousness likely results from cumulative changes in information flow across a hierarchical network of brain regions.16Mashour G.A. Hudetz A.G. Bottom-up and top-down mechanisms of general anesthetics modulate different dimensions of consciousness.Front Neural Circuits. 2017; 11: 44Crossref PubMed Scopus (69) Google Scholar, 19Lee M. Sanders R.D. Yeom S.-K. et al.Network properties in transitions of consciousness during propofol-induced sedation.Sci Rep. 2017; 7: 16791Crossref PubMed Scopus (79) Google Scholar The approach taken in the Banks study provides a detailed view of cortical regions and connections that need to be altered to disrupt sound and speech. This approach has already ruled out the central core auditory cortical area, because information flow is largely unaffected in this primary sensory area at loss of consciousness. Measuring mutual information with multielectrode recordings from frontal cortical areas, especially Broca's area and Wernike's area (the homologues in rodent cortex), could be a logical next step. Future research might compare similar measures at differing depths across a cortical layer, simultaneous recordings from multiple cortical locations, and a comparison of mutual information during up and down states. This new paper by Banks and colleagues1Banks M.I. Moran N.S. Krause B.M. Grady S.M. Uhlrich D.J. Manning K.A. Altered stimulus representation in auditory cortex is not causal for loss of consciousness under general anaesthesia.BJA. 2018; 121: 605-615Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar makes it clear that anaesthetic-induced changes in primary auditory cortical processing are not directly linked to loss of consciousness. Contributed equally to writing, reviewing, and proofing this editorial: both authors. Altered stimulus representation in rat auditory cortex is not causal for loss of consciousness under general anaesthesiaBritish Journal of AnaesthesiaVol. 121Issue 3PreviewCurrent concepts suggest that impaired representation of information in cortical networks contributes to loss of consciousness under anaesthesia. We tested this idea in rat auditory cortex using information theory analysis of multiunit responses recorded under three anaesthetic agents with different molecular targets: isoflurane, propofol, and dexmedetomidine. We reasoned that if changes in the representation of sensory stimuli are causal for loss of consciousness, they should occur regardless of the specific anaesthetic agent. Full-Text PDF Open Archive

Nitrous oxide (N2O) and remifentanil (remi) are used along with other anesthetic and adjuvant agents for routine surgical anesthesia, yet the electroencephalogram (EEG) changes produced by this combination are poorly described. N2O administered alone produces EEG spectral characteristics that are distinct from most hypnotics. Furthermore, EEG frequency-derived trends before and after clinically relevant time points vary depending on N2O concentration. Remifentanil typically increases low frequency and decreases high frequency activity in the EEG, but how it influences N2O's EEG effect is not known. Previous attempts to characterize EEG signals of patients anesthetized with N2O using frequency-derived measures have shown conflicts and inconsistencies. Thus, in addition to determining the spectral characteristics of this unique combination, we also test whether a newly proposed characterization of time-delayed embeddings of the EEG signal tracks loss and recovery of consciousness significantly at clinically relevant time points. We retrospectively investigated the effects of remi and N2O on EEG signals recorded from 32 surgical patients receiving anesthesia for elective abdominal surgeries. Remifentanil and N2O (66%) were co-administered during the procedures. Patients were tested for loss and recovery of response (ROR) to verbal stimuli after induction and upon cessation of anesthesia, respectively. We found that the addition of remifentanil to N2O anesthesia improves the ability of traditional frequency-derived measures, including the Bispectral Index (BIS), to discriminate between loss and ROR. Finally, we found that a novel analysis of EEG using nonlinear dynamics showed more significant differences between states than most spectral measures.