UnCheol Lee

Disruption of frontal-parietal communication by ketamine, propofol, and sevoflurane.

Introduction:Directional connectivity from anterior to posterior brain regions (or “feedback” connectivity) has been shown to be inhibited by propofol and sevoflurane. In this study the authors tested the hypothesis that ketamine would also inhibit cortical feedback connectivity in frontoparietal networks. Methods:Surgical patients (n = 30) were recruited for induction of anesthesia with intravenous ketamine (2 mg/kg); electroencephalography of the frontal and parietal regions was acquired. The authors used normalized symbolic transfer entropy, a computational method based on information theory, to measure directional connectivity across frontal and parietal regions. Statistical analysis of transfer entropy measures was performed with the permutation test and the time-shift test to exclude false-positive connectivity. For comparison, the authors used normalized symbolic transfer entropy to reanalyze electroencephalographic data gathered from surgical patients receiving either propofol (n = 9) or sevoflurane (n = 9) for anesthetic induction. Results:Ketamine reduced alpha power and increased gamma power, in contrast to both propofol and sevoflurane. During administration of ketamine, feedback connectivity gradually diminished and was significantly inhibited after loss of consciousness (mean ± SD of baseline and anesthesia: 0.0074 ± 0.003 and 0.0055 ± 0.0027; F(5, 179) = 7.785, P < 0.0001). By contrast, feedforward connectivity was preserved during exposure to ketamine (mean ± SD of baseline and anesthesia: 0.0041 ± 0.0015 and 0.0046 ± 0.0018; F(5, 179) = 2.07; P = 0.072). Like ketamine, propofol and sevoflurane selectively inhibited feedback connectivity after anesthetic induction. Conclusions:Diverse anesthetics disrupt frontal–parietal communication, despite molecular and neurophysiologic differences. Analysis of directional connectivity in frontal–parietal networks could provide a common metric of general anesthesia and insight into the cognitive neuroscience of anesthetic-induced unconsciousness.

Preferential Inhibition of Frontal-to-Parietal Feedback Connectivity Is a Neurophysiologic Correlate of General Anesthesia in Surgical Patients

Background The precise mechanism and optimal measure of anesthetic-induced unconsciousness has yet to be elucidated. Preferential inhibition of feedback connectivity from frontal to parietal brain networks is one potential neurophysiologic correlate, but has only been demonstrated in animals or under limited conditions in healthy volunteers. Methods and Findings We recruited eighteen patients presenting for surgery under general anesthesia; electroencephalography of the frontal and parietal regions was acquired during (i) baseline consciousness, (ii) anesthetic induction with propofol or sevoflurane, (iii) general anesthesia, (iv) recovery of consciousness, and (v) post-recovery states. We used two measures of effective connectivity, evolutional map approach and symbolic transfer entropy, to analyze causal interactions of the frontal and parietal regions. The dominant feedback connectivity of the baseline conscious state was inhibited after anesthetic induction and during general anesthesia, resulting in reduced asymmetry of feedback and feedforward connections in the frontoparietal network. Dominant feedback connectivity returned when patients recovered from anesthesia. Both analytic techniques and both classes of anesthetics demonstrated similar results in this heterogeneous population of surgical patients. Conclusions The disruption of dominant feedback connectivity in the frontoparietal network is a common neurophysiologic correlate of general anesthesia across two anesthetic classes and two analytic measures. This study represents a key translational step from the underlying cognitive neuroscience of consciousness to more sophisticated monitoring of anesthetic effects in human surgical patients.

The directionality and functional organization of frontoparietal connectivity during consciousness and anesthesia in humans

Frontoparietal connectivity has been suggested to be important in conscious processing and its interruption is thought to be one mechanism of general anesthesia. Data in animals demonstrate that feedforward processing of information may persist during the anesthetized state, while feedback processing is inhibited. We investigated the directionality and functional organization of frontoparietal connectivity in 10 human subjects anesthetized with propofol on two separate occasions. Multichannel electroencephalography and a computational method of assessing directed functional connectivity were employed. We demonstrate that directed feedback connectivity is diminished with loss of consciousness and returns with responsiveness to verbal command. We also applied the Dendrogram classification method to assess the global organization of directed functional connectivity during consciousness and anesthesia. We demonstrate a state-specific hierarchy and subject-specific subhierarchy in functional organization. These data support the hypothesis that specific states of human consciousness are defined by specific states of frontoparietal connectivity.

Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia.

The cognitive unbinding paradigm suggests that the synthesis of neural information is attenuated by general anesthesia. Here, we analyzed the functional organization of brain activities in the conscious and anesthetized states, based on functional segregation and integration. Electroencephalography (EEG) recordings were obtained from 14 subjects undergoing induction of general anesthesia with propofol. We quantified changes in mean information integration capacity in each band of the EEG. After induction with propofol, mean information integration capacity was reduced most prominently in the gamma band of the EEG (p=.0001). Furthermore, we demonstrate that loss of consciousness is reflected by the breakdown of the spatiotemporal organization of gamma waves. We conclude that induction of general anesthesia with propofol reduces the capacity for information integration in the brain. These data directly support the information integration theory of consciousness and the cognitive unbinding paradigm of general anesthesia.

Brain networks maintain a scale-free organization across consciousness, anesthesia, and recovery: evidence for adaptive reconfiguration.

Background:Loss of consciousness is an essential feature of general anesthesia. Although alterations of neural networks during anesthesia have been identified in the spatial domain, there has been relatively little study of temporal organization. Methods:Ten healthy male volunteers were anesthetized with an induction dose of propofol on two separate occasions. The duration of network connections in the brain was analyzed by multichannel electroencephalography and the minimum spanning tree method. Entropy of the connections was calculated based on Shannon entropy. The global temporal configuration of networks was investigated by constructing the cumulative distribution function of connection times in different frequency bands and different states of consciousness. Results:General anesthesia was associated with a significant reduction in the number of network connections, as well as significant alterations of their duration. These changes were most prominent in the &dgr; bandwidth and were also associated with a significant reduction in entropy of the connection matrix. Despite these and other changes, a global “scale-free” organization was consistently preserved across multiple subjects, anesthetic exposures, states of consciousness, and electroencephalogram frequencies. Conclusions:Our data suggest a fundamental principle of temporal organization of network connectivity that is maintained during consciousness and anesthesia, despite local changes. These findings are consistent with a process of adaptive reconfiguration during general anesthesia.

Reconfiguration of Network Hub Structure after Propofol-Induced Unconsciousness

Introduction:General anesthesia induces unconsciousness along with functional changes in brain networks. Considering the essential role of hub structures for efficient information transmission, the authors hypothesized that anesthetics have an effect on the hub structure of functional brain networks. Methods:Graph theoretical network analysis was carried out to study the network properties of 21-channel electroencephalogram data from 10 human volunteers anesthetized on two occasions. The functional brain network was defined by Phase Lag Index, a coherence measure, for three states: wakefulness, loss of consciousness induced by the anesthetic propofol, and recovery of consciousness. The hub nodes were determined by the largest centralities. The correlation between the altered hub organization and the phase relationship between electroencephalographic channels was investigated. Results:Topology rather than connection strength of functional networks correlated with states of consciousness. The average path length, clustering coefficient, and modularity significantly increased after administration of propofol, which disrupted long-range connections. In particular, the strength of hub nodes significantly decreased. The primary hub location shifted from the parietal to frontal region, in association with propofol-induced unconsciousness. The phase lead of frontal to parietal regions in the &agr; frequency band (8–13 Hz) observed during wakefulness reversed direction after propofol and returned during recovery. Conclusions:Propofol reconfigures network hub structure in the brain and reverses the phase relationship between frontal and parietal regions. Changes in network topology are more closely associated with states of consciousness than connectivity and may be the primary mechanism for the observed loss of frontal to parietal feedback during general anesthesia.

Dissociable network properties of anesthetic state transitions.

Background:It is still unknown whether anesthetic state transitions are continuous or binary. Mathematical graph theory is one method by which to assess whether brain networks change gradually or abruptly upon anesthetic induction and emergence. Methods:Twenty healthy males were anesthetized with an induction dose of propofol, with continuous measurement of 21-channel electroencephalogram at baseline, during anesthesia, and during recovery. From these electroencephalographic data a “genuine network” was reconstructed based on the surrogate data method. The effects of topologic structure and connection strength on information transfer through the network were measured independently across different states. Results:Loss of consciousness was consistently associated with a disruption of network topology. However, recovery of consciousness was associated with complex patterns of altered connection strength after the initial topologic structure had slowly recovered. In one group of subjects, there was a precipitous increase of connection strength that was associated with reduced variability of emergence time. Analysis of regional effects on brain networks demonstrated that the parietal network was significantly disrupted, whereas the frontal network was minimally affected. Conclusions:By dissociating the effects of network structure and connection strength, both continuous and discrete elements of anesthetic state transitions were identified. The study also supports a critical role of parietal networks as a target of general anesthetics.

Functional and Topological Conditions for Explosive Synchronization Develop in Human Brain Networks with the Onset of Anesthetic-Induced Unconsciousness

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.

Electroencephalographic effects of ketamine on power, cross-frequency coupling, and connectivity in the alpha bandwidth

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.

Isoflurane anesthesia does not satisfy the homeostatic need for rapid eye movement sleep.

BACKGROUND: Sleep and general anesthesia are distinct states of consciousness that share many traits. Prior studies suggest that propofol anesthesia facilitates recovery from rapid eye movement (REM) and non-REM (NREM) sleep deprivation, but the effects of inhaled anesthetics have not yet been studied. We tested the hypothesis that isoflurane anesthesia would also facilitate recovery from REM sleep deprivation. METHODS: Six rats were implanted with superficial cortical, deep hippocampal, and nuchal muscle electrodes. Animals were deprived of REM sleep for 24 hours and then (1) allowed to sleep ad libitum for 8 hours or (2) were immediately anesthetized with isoflurane for a 4-hour period followed by ad libitum sleep for 4 hours. The percentage of REM and NREM sleep after the protocols was compared with similar conditions without sleep deprivation. Hippocampal &thgr; activity during isoflurane anesthesia was also compared with &thgr; activity during REM sleep and active waking. RESULTS: Recovery after deprivation was associated with a 5.7-fold increase (P = 0.0005) in REM sleep in the first 2 hours and a 2.6-fold increase (P = 0.004) in the following 2 hours. Animals that underwent isoflurane anesthesia after deprivation demonstrated a 3.6-fold increase (P = 0.001) in REM sleep in the first 2 hours of recovery and a 2.2-fold increase (P = 0.003) in the second 2 hours. There were no significant differences in REM sleep rebound between the first 4 hours after deprivation and the first 4 hours after both deprivation and isoflurane anesthesia. Hippocampal &thgr; activity during isoflurane anesthesia was not affected by REM sleep deprivation, and the probability distribution of &thgr; events during anesthesia was more similar to that of waking than to REM sleep. CONCLUSION: Unlike propofol, isoflurane does not satisfy the homeostatic need for REM sleep. Furthermore, the regulation and organization of hippocampal &thgr; events during anesthesia are unlike sleep. We conclude that different anesthetics have distinct interfaces with sleep.