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Background: The ability of current depth-of-anaesthesia monitors to differentiate subtle changes in the conscious state has not been well characterised. We examine the variability in bispectral index (BIS) scores associated with disconnected conscious and unconscious states as confirmed by a novel serial awakening paradigm., Methods: Seventy adult participants, given propofol or dexmedetomidine, had a cumulative 1381 electroencephalographic (EEG) recordings across two centres. Participants were awakened periodically, and their recent conscious experience interrogated by structured questioning. BIS were reconstructed from EEG using openibis, and the distribution of BIS scores were compared using linear mixed effects modelling. The predictive capacity of BIS across states of consciousness was also examined., Results: Reconstructed BIS scores correlated significantly with blood concentrations of propofol and dexmedetomidine (all P<0.001). However, while the average BIS was different between baseline wakefulness (mean BIS=95.1 [standard deviation=3.5]); connected consciousness with drug present (84.0 [10.9]); disconnected consciousness (70.0 [16.9]); and unconsciousness (68.1 [16.1]), the interquartile range of these states (3.6, 15.1, 23.3 and 26.8, respectively) indicated high degrees of overlap and individual variability. Connected consciousness could be differentiated from either disconnected consciousness or unconsciousness with 86% accuracy (i.e. 14% error rate), and disconnected consciousness differentiated from unconsciousness with 74% accuracy., Conclusions: These results agree with previous studies that BIS scores fail to reliably differentiate between states of consciousness, exacerbated by segregating connected, disconnected, and unconscious states. To develop a method that reliably identifies the conscious state of an individual (not an average), work is needed to establish the causal mechanisms of disconnection and unconsciousness., Competing Interests: Declaration of interest The authors declare that they have no conflicts of interest., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Understanding the neural correlates of consciousness has important ramifications for the theoretical understanding of consciousness and for clinical anaesthesia. A major limitation of prior studies is the use of responsiveness as an index of consciousness. We identified a collection of measures derived from unresponsive subjects and more specifically their association with consciousness (any subjective experience) or connectedness (specific experience of environmental stimuli). Using published data generated through the UNderstanding Consciousness Connectedness and Intra-Operative Unresponsiveness Study (NCT03284307), we evaluated 10 previously published resting-state EEG-based measures that were derived using unresponsiveness as a proxy for unconsciousness. Measures were tested across dexmedetomidine and propofol sedation and natural sleep. These markers represent the complexity, connectivity, cross-frequency coupling, graph theory, and power spectrum measures. Although many of the proposed markers were associated with consciousness per se (reported subjective experience), none were specific to consciousness alone; rather, each was also associated with connectedness (i.e. awareness of the environment). In addition, multiple markers showed no association with consciousness and were associated only with connectedness. Of the markers tested, loss of normalised-symbolic transfer entropy (front to back) was associated with connectedness across all three experimental conditions, whereas the transition from disconnected consciousness to unconsciousness was associated with significant decreases in permutation entropy and spectral exponent (P <0.05 for all conditions). None of the proposed EEG-based neural correlates of unresponsiveness corresponded solely to consciousness, highlighting the need for a more conservative use of the term (un)consciousness when assessing unresponsive participants. NCT03284307. [ABSTRACT FROM AUTHOR]

Sensory disconnection is a key feature of sleep and anaesthesia. We have proposed that predictive coding offers a framework for understanding the mechanisms of disconnection. Low doses of ketamine that do not induce disconnection should thus diminish predictive coding, but not abolish it. Ketamine was administered to 14 participants up to a blood concentration of 0.3 μg ml−1 Participants were played a series of tones comprising a roving oddball sequence while electroencephalography evoked response potentials were recorded. We fit a Bayesian observer model to the tone sequence, correlating neural activity with the prediction errors generated by the model using linear mixed effects models and cluster-based statistics. Ketamine modulated prediction errors associated with the transition of one tone to the next (transitional probability), but not how often tones changed (environmental volatility), of the system. Transitional probability was reduced when blood concentrations of ketamine were increased to 0.2–0.3 μg ml−1 (96–208 ms, P =0.003); however, correlates of prediction error were still evident in the electroencephalogram (124–168 ms, P =0.003). Prediction errors related to environmental volatility were associated with electroencephalographic activity before ketamine (224–284 ms, P =0.028) and during 0.2–0.3 μg ml−1 ketamine (108–248 ms, P =0.003). At this subanaesthetic dose, ketamine did not exert a dose-dependent modulation of prediction error. Subanaesthetic dosing of ketamine reduced correlates of predictive coding but did not eliminate them. Future studies should evaluate whether states of sensory disconnection, including anaesthetic doses of ketamine, are associated with a complete absence of predictive coding responses. NCT03284307. [ABSTRACT FROM AUTHOR]

Background: How conscious experience becomes disconnected from the environment, or disappears, across arousal states is unknown. We sought to identify the neural correlates of sensory disconnection and unconsciousness using a novel serial awakening paradigm.Methods: Volunteers were recruited for sedation with dexmedetomidine i.v., propofol i.v., or natural sleep with high-density EEG monitoring and serial awakenings to establish whether subjects were in states of disconnected consciousness or unconsciousness in the preceding 20 s. The primary outcome was classification of conscious states by occipital delta power (0.5-4 Hz). Secondary analyses included derivation (dexmedetomidine) and validation (sleep/propofol) studies of EEG signatures of conscious states.Results: Occipital delta power differentiated disconnected and unconscious states for dexmedetomidine (area under the curve [AUC] for receiver operating characteristic 0.605 [95% confidence interval {CI}: 0.516; 0.694]) but not for sleep/propofol (AUC 0.512 [95% CI: 0.380; 0.645]). Distinct source localised signatures of sensory disconnection (AUC 0.999 [95% CI: 0.9954; 1.0000]) and unconsciousness (AUC 0.972 [95% CI: 0.9507; 0.9879]) were identified using support vector machine classification of dexmedetomidine data. These findings generalised to sleep/propofol (validation data set: sensory disconnection [AUC 0.743 {95% CI: 0.6784; 0.8050}]) and unconsciousness (AUC 0.622 [95% CI: 0.5176; 0.7238]). We identified that sensory disconnection was associated with broad spatial and spectral changes. In contrast, unconsciousness was associated with focal decreases in activity in anterior and posterior cingulate cortices.Conclusions: These findings may enable novel monitors of the anaesthetic state that can distinguish sensory disconnection and unconsciousness, and these may provide novel insights into the biology of arousal.Clinical Trial Registration: NCT03284307. [ABSTRACT FROM AUTHOR]