Evaluation of putative signatures of consciousness using specific definitions of responsiveness, connectedness, and consciousness.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT03284307.

Subanaesthetic doses of ketamine reduce but do not eliminate predictive coding responses: implications for mechanisms of sensory disconnection.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT03284307.

Breathe-squeeze: pharmacodynamics of a stimulus-free behavioural paradigm to track conscious states during sedation☆.

BACKGROUND: Conscious states are typically inferred through responses to auditory tasks and noxious stimulation. We report the use of a stimulus-free behavioural paradigm to track state transitions in responsiveness during dexmedetomidine sedation. We hypothesised that estimated dexmedetomidine effect-site (Ce) concentrations would be higher at loss of responsiveness (LOR) compared with return of responsiveness (ROR), and both would be lower than comparable studies that used stimulus-based assessments. METHODS: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine data were analysed for secondary analysis. Fourteen healthy volunteers were asked to perform the breathe-squeeze task of gripping a dynamometer when inspiring and releasing it when expiring. LOR was defined as five inspirations without accompanied squeezes; ROR was defined as the return of five inspirations accompanied by squeezes. Brain states were monitored using 64-channel EEG. Dexmedetomidine was administered as a target-controlled infusion, with Ce estimated from a pharmacokinetic model. RESULTS: Counter to our hypothesis, mean estimated dexmedetomidine Ce was lower at LOR (0.92 ng ml-1; 95% confidence interval: 0.69-1.15) than at ROR (1.43 ng ml-1; 95% confidence interval: 1.27-1.58) (paired t-test; P=0.002). LOR was characterised by progressively increasing fronto-occipital EEG power in the 0.5-8 Hz band and loss of occipital alpha (8-12 Hz) and global beta (16-30 Hz) power. These EEG changes reverted at ROR. CONCLUSIONS: The breathe-squeeze task can effectively track changes in responsiveness during sedation without external stimuli and might be more sensitive to state changes than stimulus-based tasks. It should be considered when perturbation of brain states is undesirable. CLINICAL TRIAL REGISTRATION: NCT04206059.

Distinct EEG signatures differentiate unconsciousness and disconnection during anaesthesia and sleep.

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.

Human Rapid Eye Movement Sleep Shows Local Increases in Low-Frequency Oscillations and Global Decreases in High-Frequency Oscillations Compared to Resting Wakefulness.

It is often assumed that during rapid eye movement (REM) sleep the cerebral cortex homogenously shows electroencephalogram (EEG) activity highly similar to wakefulness. However, to date no studies have compared neural oscillatory activity in human REM sleep to resting wakefulness with high spatial sampling. In the current study, we evaluated high-resolution topographical changes in neural oscillatory power between both early and late naturalistic REM sleep and resting wakefulness in adult humans. All-night recordings with 256-channel high-density EEG (hd-EEG) were collected in healthy volunteers (N = 12). Topographic analysis revealed that, compared to wake, both the first and last cycle of REM sleep were associated with increased low-frequency oscillations in local central and occipital regions. In contrast, high-frequency activity in both α and ß bands (8-20 Hz) was globally decreased during both early and late REM sleep cycles compared to wakefulness. No significant differences in topographic power in any frequency band were observed between REM sleep cycles occurring early and late in the night. We replicated these findings in an independent dataset (N = 33). Together, our findings show that human REM sleep shows consistent topographical changes in oscillatory power across both early and late sleep cycles compared to resting wakefulness.