Protocol for the Reconstructing Consciousness and Cognition (ReCCognition) Study

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

Comparison of the qCON and qNOX indices for the assessment of unconsciousness level and noxious stimulation response during surgery

The objective of this work is to compare the performances of two electroencephalogram based indices for detecting loss of consciousness and loss of response to nociceptive stimulation. Specifically, their behaviour after drug induction and during recovery of consciousness was pointed out. Data was recorded from 140 patients scheduled for general anaesthesia with a combination of propofol and remifentanil. The qCON 2000 monitor (Quantium Medical, Barcelona, Spain) was used to calculate the qCON and qNOX. Loss of response to verbal command and loss of eye-lash reflex were assessed during the transition from awake to anesthetized, defining the state of loss of consciousness. Movement as a response to laryngeal mask (LMA) insertion was interpreted as the response to the nociceptive stimuli. The patients were classified as movers or non-movers. The values of qCON and qNOX were statistically compared. Their fall times and rise times defined at the start and at the end of the surgery were calculated and compared. The results showed that the qCON was able to predict loss of consciousness such as loss of verbal command and eyelash reflex better than qNOX, while the qNOX has a better predictive value for response to noxious stimulation such as LMA insertion. From the analysis of the fall and rise times, it was found that the qNOX fall time (median: 217 s) was significantly longer (p value <0.05) than the qCON fall time (median: 150 s). At the end of the surgery, the qNOX started to increase in median at 45 s before the first annotation related to response to stimuli or recovery of consciousness, while the qCON at 88 s after the first annotation related to response to stimuli or recovery of consciousness (p value <0.05). The indices qCON and qNOX showed different performances in the detection of loss of consciousness and loss of response to stimuli during induction and recovery of consciousness. Furthermore, the qCON showed faster decrease during induction. This behaviour is associated with the hypothesis that the loss of response to stimuli (analgesic effect) might be reached after the loss of consciousness (hypnotic effect). On the contrary, the qNOX showed a faster increase at the end of the surgery, associated with the hypothesis that a higher probability of response to stimuli might be reached before the recovery of consciousness.Postprint (author's final draft

Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia?

While geriatric patients have a high likelihood of requiring anesthesia, they carry an increased risk for adverse cognitive outcomes from its use. Previous work suggests this could be mitigated by better intraoperative monitoring using indexes defined by several processed electroencephalogram (EEG) measures. Unfortunately, inconsistencies between patients and anesthetic agents in current analysis techniques have limited the adoption of EEG as standard of care. In attempts to identify new analyses that discriminate clinically-relevant anesthesia timepoints, we tested 1/f frequency scaling as well as measures of complexity from nonlinear dynamics. Specifically, we tested whether analyses that characterize time-delayed embeddings, correlation dimension (CD), phase-space geometric analysis, and multiscale entropy (MSE) capture loss-of-consciousness changes in EEG activity. We performed these analyses on EEG activity collected from a traditionally hard-to-monitor patient population: geriatric patients on beta-adrenergic blockade who were anesthetized using a combination of fentanyl and propofol. We compared these analyses to traditional frequency-derived measures to test how well they discriminated EEG states before and after loss of response to verbal stimuli. We found spectral changes similar to those reported previously during loss of response. We also found significant changes in 1/f frequency scaling. Additionally, we found that our phase-space geometric characterization of time-delayed embeddings showed significant differences before and after loss of response, as did measures of MSE. Our results suggest that our new spectral and complexity measures are capable of capturing subtle differences in EEG activity with anesthesia administration-differences which future work may reveal to improve geriatric patient monitoring

EEG signals analysis using multiscale entropy for depth of anesthesia monitoring during surgery through artificial neural networks

In order to build a reliable index to monitor the depth of anesthesia (DOA), many algorithms have been proposed in recent years, one of which is sample entropy (SampEn), a commonly used and important tool to measure the regularity of data series. However, SampEn only estimates the complexity of signals on one time scale. In this study, a new approach is introduced using multiscale entropy (MSE) considering the structure information over different time scales. The entropy values over different time scales calculated through MSE are applied as the input data to train an artificial neural network (ANN) model using bispectral index (BIS) or expert assessment of conscious level (EACL) as the target. To test the performance of the new index's sensitivity to artifacts, we compared the results before and after filtration by multivariate empirical mode decomposition (MEMD). The new approach via ANN is utilized in real EEG signals collected from 26 patients before and after filtering by MEMD, respectively; the results show that is a higher correlation between index from the proposed approach and the gold standard compared with SampEn. Moreover, the proposed approach is more structurally robust to noise and artifacts which indicates that it can be used for monitoring the DOA more accurately.This research was financially supported by the Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan, which is sponsored by Ministry of Science and Technology (Grant no. MOST103-2911-I-008-001). Also, it was supported by National Chung-Shan Institute of Science & Technology in Taiwan (Grant nos. CSIST-095-V301 and CSIST-095-V302) and National Natural Science Foundation of China (Grant no. 51475342)

Modeling of Recovery Profiles in Mentally Disabled and Intact Patients after Sevoflurane Anesthesia; A Pharmacodynamic Analysis

PURPOSE: Mentally disabled patients show different recovery profiles compared to normal patients after general anesthesia. However, the relationship of dose-recovery profiles of mentally disabled patients has never been compared to that of normal patients. MATERIALS AND METHODS: Twenty patients (10 mentally disabled patients and 10 mentally intact patients) scheduled to dental surgery under general anesthesia was recruited. Sevoflurane was administered to maintain anesthesia during dental treatment. At the end of the surgery, sevoflurane was discontinued. End-tidal sevoflurane and recovery of consciousness (ROC) were recorded after sevoflurane discontinuation. The pharmacodynamic relation between the probability of ROC and end-tidal sevoflurane concentration was analyzed using NONMEM software (version VII). RESULTS: End-tidal sevoflurane concentration associated with 50% probability of ROC (C₅₀) and γ value were lower in the mentally disabled patients (C₅₀=0.37 vol %, γ=16.5 in mentally intact patients, C₅₀=0.19 vol %, γ=4.58 in mentally disabled patients). Mentality was a significant covariate of C₅₀ for ROC and γ value to pharmacodynamic model. CONCLUSION: A sigmoid Emanx model explains the pharmacodynamic relationship between end-tidal sevoflurane concentration and ROC. Mentally disabled patients may recover slower from anesthesia at lower sevoflurane concentration at ROC an compared to normal patients.ope

Bispectral index and their relation with consciousness of the patients who receive desflurane or sevoflurane anesthesia during wake-up test for spinal surgery for correction

Background: Wake-up tests may be necessary during surgery for kypho-scoliosis to ensure that spinal function remains intact. It is difficult to predict the time when patients can respond to a verbal command. We evaluated the effectiveness of the bispectral index (BIS) and its relation to patients&#39; levels of consciousness in wake-up tests during desflurane and sevoflurane anesthesia. Methods: Eighteen patients each were enrolled in the desflurane and sevoflurane groups for spinal correction surgery. We measured BIS values, blood pressure, heart rate, and consciousness state and time, at the points when patients responded during the wake-up test. Results: The BIS values when patients made fists upon a verbal command (T3) were 86.7 &plusmn; 7.5 for desflurane and 90.3 &plusmn; 5.4 for sevoflurane. Patients in the desflurane group had significantly shorter wake up delays than those in the sevoflurane group (6.9 &plusmn; 1.8 min vs. 11.8 &plusmn; 3.6 min). However, there was no difference between the groups in the time between the response to a verbal command and the time when a patient moved their toes in response to verbal commands. No recall of the wake-up tests occurred in either group. Conclusions: The values obtained using the BIS index could to some extent predict the time of a patient&#39;s and would be informative during desflurane and sevoflurane anesthesia. Moreover, desflurane permitted faster responses to verbal commands than sevoflurane, and allowed the wake-up test to be performed sooner

Sevoflurane Induces Coherent Slow-Delta Oscillations in Rats

Although general anesthetics are routinely administered to surgical patients to induce loss of consciousness, the mechanisms underlying anesthetic-induced unconsciousness are not fully understood. In rats, we characterized changes in the extradural EEG and intracranial local field potentials (LFPs) within the prefrontal cortex (PFC), parietal cortex (PC), and central thalamus (CT) in response to progressively higher doses of the inhaled anesthetic sevoflurane. During induction with a low dose of sevoflurane, beta/low gamma (12–40 Hz) power increased in the frontal EEG and PFC, PC and CT LFPs, and PFC–CT and PFC–PFC LFP beta/low gamma coherence increased. Loss of movement (LOM) coincided with an abrupt decrease in beta/low gamma PFC–CT LFP coherence. Following LOM, cortically coherent slow-delta (0.1–4 Hz) oscillations were observed in the frontal EEG and PFC, PC and CT LFPs. At higher doses of sevoflurane sufficient to induce loss of the righting reflex, coherent slow-delta oscillations were dominant in the frontal EEG and PFC, PC and CT LFPs. Dynamics similar to those observed during induction were observed as animals emerged from sevoflurane anesthesia. We conclude that the rat is a useful animal model for sevoflurane-induced EEG oscillations in humans, and that coherent slow-delta oscillations are a correlate of sevoflurane-induced behavioral arrest and loss of righting in rats.National Institutes of Health (U.S.) (Grant PO1-GM118269)National Institutes of Health (U.S.) (Grant TR01-GM104948

Subjective Experiences During Sedation Induced by Equipotent Dose of Dexmedetomidine, Propofol, Sevoflurane and S-ketamine

Studies conducted in clinical and experimental settings have shown that unresponsive persons undergoing anesthetic infusion often report subjective experiences, such as dreaming, when interviewed afterwards. The aim of the present study was to investigate the presence and quality of subjective experiences in healthy young participants sedated with dexmedetomidine, propofol, sevoflurane or S-ketamine. We addressed how participant’s responsiveness (measured as behavioral response to auditory stimulus) during sedation is related to reporting experiences. Further, we explored the differences between anesthetics in the prevalence and nature of subjective experiences. Participants received equisedative doses of either dexmedetomidine (n = 40), propofol (n = 40), sevoflurane (n = 41), or S-ketamine (n = 24) and were interviewed of their subjective experiences immediately after termination of anesthetic administration. The interview transcripts were content analyzed by two independent raters for dream-likeness, incorporations of the experimental setting, awareness of the research environment, and complexity and modalities of experiences. There were no differences in the prevalence or contents of experiences between those classified as unresponsive and responsive. Of all participants who could be interviewed, 49.0% reported subjective experiences, most frequently dreaming (98.0%). Incorporations of the experimental setting were also quite frequent (36.0%) while awareness of the environment was rare (4.1%). Participants receiving dexmedetomidine and S-ketamine reported subjective experiences most often and S-ketamine induced the most multimodal experiences. This study shows that unresponsiveness does not equal unconsciousness, and that participant’s responsiveness during sedation with equipotent dose is not associated with the likelihood of reporting subjective experiences. Subjective experiences are frequently reported after sedation and the subjective experiences may slightly differ between anesthetics administered in equipotent doses. Further studies should not consider responsiveness as an indicator of consciousness and should focus on how to distinguish unresponsive individuals who can experience external stimuli from those unresponsive individuals who cannot