Ketamine is an anesthetic drug that was introduced into clinical practice in the 1960s (Corssen and Domino, 1966) and is currently used for the induction of unconsciousness and, at subanesthetic doses, the prevention of acute pain or the treatment of depression. Ketamine is unique in the class of general anesthetics for a number of reasons. At the molecular level, the γ-aminobutyric acid (GABA)_A receptor is not the primary target for ketamine, unlike many drugs used for the induction and maintenance of general anesthesia. Rather, ketamine is thought to act by antagonizing glutamatergic N-methyl-D-aspartate (NMDA) receptors (like the related anesthetics nitrous oxide and xenon) and/or hyperpolarization-activated cyclic-nucleotide gated (HCN)1 channels (Yamamura et al., 1990; Chen et al., 2009; Zhou et al., 2013). At the neurochemical level, ketamine is unique because it increases cortical acetylcholine levels and appears to depend on noradrenergic signaling for its effects, in contrast to a number of GABAergic anesthetics (Kikuchi et al., 1997; Kushikata et al., 2011). At the systems neuroscience level, ketamine is also distinct because it does not metabolically activate the ventrolateral preoptic nucleus, a sleep-promoting nucleus in the hypothalamus that is activated by commonly-used anesthetics such as propofol and isoflurane; instead, it activates the wake-promoting locus coeruleus (Lu et al., 2008). Furthermore, in contrast to virtually all other anesthetic and sedative drugs, ketamine does not appear to metabolically depress the thalamus (Långsjö et al., 2005). Finally, at the neurophysiologic level, ketamine tends to increase the power of high-frequency electroencephalographic activity, whereas most anesthetics depress this bandwidth (Maksimow et al., 2006). Ketamine therefore fails to conform to virtually all mechanistic frameworks of anesthetic-induced unconsciousness.

Despite the many unique characteristics of ketamine, we recently demonstrated that anesthetic doses of ketamine selectively inhibit frontal-to-parietal directed connectivity, as measured by symbolic transfer entropy in electroencephalographic signals (Lee et al., 2013b). This finding was notable because selective inhibition of effective and directional connectivity from frontal to parietal regions has been demonstrated for two commonly-used anesthetics that act (at least in part) through GABA receptors: propofol [demonstrated with symbolic transfer entropy, evolution map approach, dynamic causal modeling, directed phase lag index (dPLI)] and sevoflurane (demonstrated with symbolic transfer entropy, evolution map approach) (Lee et al., 2009, 2013a; Ku et al., 2011; Boly et al., 2012). Given the proposed role of top-down reentrant processing and frontal-parietal networks in the conscious perception of environmental stimuli (Dehaene and Changeux, 2011; Demertzi et al., 2013), this finding suggests the exciting possibility of a common neurobiology underlying anesthetic-induced unconsciousness.

In the current study, we further characterized the effects of ketamine on the electroencephalogram, with a focus on alpha rhythms (8–14 Hz). Alpha oscillations have been an active area of research into anesthetic-induced unconsciousness because of a characteristic process referred to as anteriorization. In the resting/eyes-closed state in humans, the electroencephalographic power of alpha is dominant over the occipital cortex. However, at the point of propofol-induced unconsciousness, the power of alpha is dominant over the frontal cortex (Feshchenko et al., 2004; Purdon et al., 2013). Computational models that account for the observed posterior-to-anterior shift of alpha rhythms are based on propofol's agonism of GABA_A receptors in the thalamus (Ching et al., 2010; Vijayan et al., 2013; Ching and Brown, 2014). The anteriorization of alpha at the point of propofol-induced unconsciousness also appears to relate to a characteristic cross-frequency coupling pattern between the amplitude of alpha and the phase of slow oscillations. During transitions into and out of propofol-induced unconsciousness, there is a trough-max relationship, i.e., the maximal alpha amplitude is coupled to the trough of the slow oscillation. During deeper levels of propofol-induced unconsciousness, however, this coupling shifts to a peak-max relationship (Purdon et al., 2013; Mukamel et al., 2014). These coupling patterns have not been investigated during unconsciousness induced by ketamine or other non-GABAergic anesthetics.

The propofol-induced shift to hypersynchronous alpha in the frontal cortex has been posited to impair flexible corticocortical communication (Supp et al., 2011), a process thought to be critical for consciousness. This hypothesis is supported by our recent work demonstrating that propofol-induced unconsciousness is characterized by a depression of anterior-to-posterior corticocortical connectivity (as measured by dPLI) that is found only in the alpha bandwidth (Lee et al., 2013a). dPLI is a measure of directional connectivity that appears to be closely related to alpha, since neural mass models of the human brain demonstrate an anterior-to-posterior flow of dPLI in the alpha bandwidth (Stam and van Straaten, 2012). This finding has been confirmed empirically by our previous study of dPLI in the resting state of conscious human volunteers (Lee et al., 2013a).

The potential dependence of anteriorized alpha rhythms on GABA_A effects in the thalamus leads to the prediction that a non-GABAergic drug like ketamine would differ significantly from propofol and not increase the power of frontal alpha rhythms in association with the induction of unconsciousness. Similarly, we would not predict any characteristic cross-frequency coupling patterns around the time of unconsciousness, since these relationships appear to depend on increases in the frontal power of alpha. However, if the unconscious states induced by ketamine and propofol nonetheless share an underlying neurobiology, we would predict that the directional connectivity measure of dPLI would be inhibited by ketamine (as is observed with propofol), both in terms of the specificity of the alpha bandwidth and the anterior-to-posterior directionality. We tested these predictions regarding the effects of ketamine on alpha oscillations by re-analyzing electroencephalographic data acquired during consciousness and ketamine-induced unconsciousness in human surgical patients.

This study of ketamine and alpha oscillations revealed both drug-related and state-related effects in association with the induction of unconsciousness. Unlike propofol, ketamine does not increase frontal alpha power or induce characteristic cross-frequency coupling patterns between the power of alpha and the phase of slow-wave oscillations. Functional connectivity in the alpha bandwidth was preserved between states when measured by coherence, but decreased upon unconsciousness when measured by PLI. The discrepancy between these two functional connectivity metrics indicates that while the correlation between electroencephalogram signals in frontal and parietal regions remains unchanged in aggregate, their specific phase-relationship is disrupted upon loss of consciousness. Directional connectivity in the alpha bandwidth (as measured by dPLI) was inhibited across the frontoparietal network by ketamine, a finding consistent with our past study of propofol-induced unconsciousness (Lee et al., 2013a). The identification of shared neural features between the unconscious states induced by GABAergic and non-GABAergic anesthetics has been a longstanding problem in the study of both anesthetic mechanisms and anesthetic monitoring. The current findings support the hypothesis that anesthetic-induced unconsciousness has a common neurobiology related to disrupted functional relationships across cortical or thalamocortical networks.

Activity and connectivity of lateral frontal and posterior parietal cortices have been hypothesized to be critical for consciousness of environmental stimuli (Boly et al., 2007; Demertzi et al., 2013). As such, the finding that a variety of general anesthetic drugs suppresses both activity and connectivity in these regions appears relevant to the proximate cause of anesthetic-induced unconsciousness. Prior preclinical studies of anterior-posterior connectivity in rat brain identified a selective inhibition of frontal-to-posterior transfer entropy in the gamma bandwidth in association with isoflurane-induced unconsciousness (Imas et al., 2005). Our laboratory first demonstrated anesthetic inhibition of frontal-to-parietal connectivity in human volunteers (Lee et al., 2009) and surgical patients (Ku et al., 2011); inhibition of functional, directional, and effective connectivity in frontal-parietal networks in association with propofol-induced unconsciousness has been identified by studies from multiple research groups using multiple analytic methods (Boveroux et al., 2010; Schrouff et al., 2011; Boly et al., 2012; Jordan et al., 2013). Of note, the recent study of Jordan et al used combined electroencephalography and functional magnetic resonance imaging with no a priori assumptions regarding connectivity and found that the selective loss of frontal-to-parietal connectivity (as measured by symbolic transfer entropy) was the best discriminator between consciousness and propofol-induced unconsciousness (Jordan et al., 2013). However, most studies of directional/effective connectivity in frontal-parietal networks have focused on propofol, a prototypical GABA_A agonist. Recently, our laboratory demonstrated a similar and selective inhibition of frontal-to-parietal connectivity during unconsciousness induced by the diverse anesthetics ketamine, propofol, and sevoflurane (Lee et al., 2013b). This study was the first to identify a common network-level disruption induced by both GABAergic and non-GABAergic anesthetics. The current study builds on this work by using alternative connectivity measures to support the hypothesis that anesthetic-induced unconsciousness is characterized by interrupted directed connectivity from frontal to parietal regions. Impaired connectivity is of relevance to the mechanism of anesthetic-induced unconsciousness because it reduces the likelihood of achieving the neural information synthesis thought to be necessary for conscious perception (Tononi, 2011). Furthermore, by comparing ketamine's effects on the alpha bandwidth to past studies of propofol, we are now able to distinguish between drug-related and state-related effects on the electroencephalogram. Despite the divergent spectral effects on alpha oscillations induced by ketamine in this study and those reported in past studies of propofol, disruption of functional (PLI) and directional (dPLI) connectivity in the alpha bandwidth appears common to the state of unconsciousness induced by both drugs. It should be noted that changes in dPLI were reversed upon recovery from propofol; given the current study design we were not able to assess recovery of directional connectivity for ketamine.

This study has numerous limitations. First, we reanalyzed electroencephalographic data from a prior study of ketamine-induced unconsciousness (Lee et al., 2013b). It might be argued that the current findings could have been predicted from our past methodology using symbolic transfer entropy. However, this is not necessarily the case, since analysis of the same electroencephalographic dataset (Murphy et al., 2011) with dynamic causal modeling (Boly et al., 2012) and Granger causality (Barrett et al., 2012) yielded discrepant results regarding directionality across frontal and parietal cortices. Second, we used low-resolution electroencephalography given the clinical nature of the original study; thus, source-localized signals could not be analyzed. Third, there was no recording from occipital electrodes, which precluded topographic analysis that would allow comparison of alpha power in posterior and anterior structures. Fourth, it could be argued that the state of ketamine-induced unconsciousness is substantially distinct from the state of propofol-induced unconsciousness, which renders any comparisons questionable. Although it is true that ketamine-based anesthetics can be associated with conscious states such as dreaming or hallucinations (Grace, 2003), the same could be argued—albeit to a lesser degree—for propofol (Leslie et al., 2007). Furthermore, from the functional perspective, both ketamine and propofol can be used to induce unconsciousness in clinical settings; this functional similarity motivates the search for common mechanisms. Fifth, it one could argue that the reduction in PLI and dPLI we observed in the alpha bandwidth during induction/unconsciousness can be attributed to the dramatic decrease in power upon loss of consciousness. However, we have demonstrated that PLI and dPLI values calculated for surrogate datasets that have the same spectral characteristics are not significantly different. Furthermore, the fact that coherence values are not significantly different between states demonstrates that the change in PLI and dPLI values cannot be attributed to reduced power in the alpha bandwidth. Finally, we used loss of responsiveness as a surrogate for loss of consciousness; it is well known that consciousness and responsiveness are dissociable. However, this is a limitation common to all studies of anesthetic-induced unconsciousness. Although, as noted, loss of responsiveness induced by ketamine may still be associated with conscious states such as dreams, it is the connection to the environment that is likely of primary clinical relevance (Sanders et al., 2012).

Despite these limitations, this analysis of ketamine's effects on spectral changes, cross-frequency coupling, and connectivity in the alpha bandwidth provides insight into the neurobiology of ketamine-induced unconsciousness. In comparison with past studies of propofol, the distinct effects of ketamine suggest that the ability to induce anteriorized alpha and cross-frequency coupling varies across anesthetic drugs. By contrast, disrupted directional connectivity in the frontal-parietal network may be a common state-related feature—and, potentially, a common mechanism—of anesthetic-induced unconsciousness.

Supported by departmental and institutional funds.