What makes consciousness specifically sensitive to anesthetics? One suggestion is that the complexity of neuronal operations required to support conscious functions (Tononi, 2004
; Tononi and Edelman, 1998
) plays a role. The more extensive and complex the neuronal system is, the more sensitive it may be to the accumulation of locally disruptive effects. Polysynaptic pathways have been known to be vulnerable to anesthetics because of their cumulative effects along the signaling chain (Banoub et al., 2003
). According to the theory of Tononi, consciousness emerges from the dynamic interaction of large-scale networks of the brain that function to integrate information (Tononi, 2004
). These functional networks may bind information from endogenous and exogenous sources and make the computational result globally accessible across the brain (Baars, 2005
). Anesthesia may suppress consciousness by disrupting (Alkire et al., 2008
; Hudetz, 2006
) or unbinding (Mashour, 2005
) this integrative process.
In one of the first neuroimaging investigations on the subject, White and Alkire (2003
) analyzed PET CMR data obtained during isoflurane or halothane anesthesia and found an impairment of thalamocortical and corticocortical interactions that involved predominantly the primary motor and supplementary motor association cortices. These results were based on two measurements in each subject, one in the wakeful and one in the unconscious condition, and thus estimated functional interactions from the covariation of regional CMR across subjects. It took another 10 years after Biswal's discovery (Biswal et al., 1995
) to first examine the effect of anesthetics resting-state functional connectivity using the temporal correlation of low-frequency BOLD signals. Peltier and colleagues (2005
) studied the concentration-dependent effect of sevoflurane on functional connectivity on motor cortices. They used the original seed voxel-based approach of Biswal and found a dose-dependent reduction in the volume of bilaterally connected sensorimotor areas. Cross-hemispheric connectivity was fully suppressed at 2%, whereas intrahemispheric connectivity partially recovered at 1%. Kiviniemi and colleagues (2005
) administered midazolam at a sedative dose to children and found that the power and temporal synchrony of low-frequency BOLD fluctuations were actually increased within auditory and visual cortices. Together, these studies suggested that different effects might be expected with different agents, at least, at the lighter sedative hypnotic doses.
Subsequently, Vincent and colleagues (2007
) demonstrated using the same seed-based connectivity analysis that robust resting-state networks (RSNs) were present in the isoflurane-anesthetized macaque monkey (0.8%–1.5%) in the somatomotor, oculomotor, visual, and default-mode systems. These results were taken to imply that RSNs were anatomically defined, and they had little functional relevance for the state of consciousness. However, it remained unclear if the RSNs observed under anesthesia were altered relative to the normal conscious state. To determine if there was any critical change in RSN associated with the transition between consciousness and unconsciousness, required brain scans were performed at graded steady-state levels of anesthesia, including those just before and after loss of consciousness. Also, some of the scans in the study by Vincent and colleagues were performed at deep anesthetic levels corresponding to electroencephalogram (EEG)-burst suppression. Such undifferentiated, stereotypic neuronal activity does not support consciousness (Alkire et al., 2008
Subsequent investigations continued to test the hypothesis that specific RSN configurations were necessary to the state of consciousness. The DMN, already mentioned above, has been a focus of interest because of its proposed role in internally generated mental activity that may give rise to an ongoing endogeneous stream of consciousness (Boly et al., 2008
). One of the major hubs of the DMN is the PCC. Greicius and colleagues (2008
) found that midazolam in a sedative dose reduced functional connectivity of the PCC, while connectivity in the sensory-motor network was increased. They suggested that the reduction in PCC connectivity was a correlated with reduced consciousness.
However, the results were substantially different with sevoflurane (Deshpande et al.
). Sevoflurane at 1% (0.5 MAC) reduced medial and lateral prefrontal connectivity, while posterior parts of the DMN (posterior cingulate and inferior parietal cortex) were preserved. At 2% (1 MAC) sevoflurane, functional connectivity was reduced across the entire DMN. It remained unclear whether changes in prefrontal connectivity occurred at the time consciousness was lost, presumably somewhere between 1% and 2% sevoflurane. One should also note that the connectivity measure used in this study was different from that of Biswal and colleagues (1995
), as it assessed local, as opposed to long-range, correlations. Preclinical studies (Imas et al., 2005
) suggested that anesthetics disrupt long-range connectivity among distant brain regions (e.g., frontal and parietal), and this has been a focus of recent investigations in humans (Boly et al., 2012a
; Martuzzi et al., 2010
; Schrouff et al., 2011
; Stamatakis et al., 2010
). However, a change in local connectivity within a functional brain region may be equally important for either unimodal and multimodal information integration (Boveroux et al., 2010
In the same year, Martuzzi and colleagues (2010
) compared several RSNs between wakefulness and 1% (0.5 MAC) sevoflurane anesthesia using seed-based connectivity analysis. They showed that during sevoflurane administration, functional connectivity in the primary somatosensory, visual, and auditory cortices, and the DMN was preserved or even increased. At the same time, functional connectivity of higher-order networks for memory and pain, centered on the hippocampus and insula, was reduced. This observation appeared consistent with the amnesic and analgesic effects of light sevoflurane anesthesia, and the relative robustness of the early sensory systems and at least a significant part of the DMN. The significance of connectivity changes in the prefrontal regions for loss of consciousness remains to be confirmed.
The preservation of PCC connectivity was further supported by data (Stamatakis et al., 2010
) obtained during light-to-moderate sedation with propofol (0.27 and 0.67
μg/mL plasma), demonstrating increased connectivity of the PCC as a seed region with the anterior cingulate cortex, somatosensory, and motor cortex and parts of the reticular activating system in the pontine tegmentum. These connectivity patterns differ from the classical territory of the DMN as seen in wakefulness, and illustrate the involvement of PCC in additional networks during propofol sedation. It remains to be seen how the DMN may be altered during deep sedation or complete unconsciousness with propofol.
The importance of thalamocortical interactions for consciousness has already been indicated. So far, few studies have examined the anesthetic modulation of thalamocortical connectivity. In an early study, White and Alkire (2003
) used PET to determine the changes in effective connectivity in volunteers anesthetized by halothane or isoflurane to loss of responsiveness (0.7% and 0.5%, respectively). Using structural equation modeling, they found impaired thalamocortical (thalamus to supplementary motor association cortex, SMA) and corticocortical (SMA to primary motor cortex) connectivity. Obviously, due to the temporal limitations of PET, these results were not yet based on temporal correlation of signals. More recently, in the just-mentioned functional magnetic resonance imaging (fMRI) study by Stamatakis and colleagues (2010
), resting-state connectivity of the PCC with the anterior thalamus was increased in a linear relationship with propofol plasma concentration. Mhuircheartaigh and colleagues (2010
) also used fMRI and found that thalamocortical connectivity was preserved with propofol titrated to loss of verbal responsiveness. An interesting exception was the putamen, which showed reduced functional connectivity with the thalamus, as well as with several other brain regions. Of note is that whole-brain connectivity of the thalamus and putamen was assessed during auditory and somatosensory stimulation, so the results may not parallel those obtained during resting conditions. Moreover, the effect of anesthetics on the thalamus may be indirect, driven by actions on the cortex or subcortical areas that project to the thalamus (Alkire et al., 2000
; Vahle-Hinz et al.
Detailed analyses of both corticocortical and thalamocortical RSNs during wakefulness and two levels of propofol sedation (1.75 and 3.20
μg/mL plasma) were performed by Boveroux and coworkers (2010
). The level of consciousness was evaluated at each sedation level using the Ramsay scale (Ramsay et al., 1974
). Instead of the traditional seed-based approach, principal components analysis was used to extract resting-state networks in individual subjects, in particular the default (correlated with the PCC) and executive-control (correlated with the middle frontal gyrus) networks. The authors showed that propofol suppressed the frontoparietal medial DMN and lateral executive-control networks. Propofol also suppressed thalamic connectivity with the frontal–parietal association regions, and disrupted the anticorrelation between the default and executive-control systems normally observed during wakefulness. Consistent with previous findings, corticocortical and thalamocortical connectivities of the primary sensory regions (auditory and visual) were relatively preserved during deep sedation. However, functional connectivity representing the auditory–visual cross-modal interactions was conspicuously absent, again suggesting the loss of higher-order integration.
More recently, Liu and coworkers (2012b
) investigated the effect of propofol deep sedation (2
μg/mL target) on BOLD fMRI functional connectivity using the PAC or IFG as seeds. This study was different from the usual resting-state approach in that it derived connectivity during a memory task of verbally presented material. As in previous studies, task-related responses persisted in the PAC, but they vanished in higher areas associated with mnemonic processes such as the IFG. At the same time, propofol disrupted connections of the PAC with the frontal regions and the thalamus. Surprisingly, connectivity of the IFG with a set of widely distributed brain regions in the temporal, frontal, and parietal lobes (with exception of the PAC) was preserved. The latter regions have been implicated in verbal comprehension and memory. It appeared that propofol blocked the projection of sensory information to high-order processing networks, which nevertheless may have continued to process endogenous information in an autonomous manner.
The discordant results regarding the anesthetic modulation of thalamocortical functional connectivity may not be surprising given the anatomical and functional complexity of the thalamus. One could assume that the connectivity of the various thalamic nuclei may not change in a homogeneous manner under anesthesia. An important distinction between the roles of first-order and second-order relay nuclei (Guillery and Sherman, 2002
), the reticular nucleus (Min, 2010
), and the nonspecific intralaminar nuclei (Bogen, 1995
; John, 2002
) has been made with reference to consciousness. For example, the nonspecific thalamic system is involved in the regulation of cortical arousal and the higher integration of information (Jasper, 1998a
), and it is thought to enable consciousness. Recently, we investigated the effect of propofol on thalamocortical functional connectivity with BOLD fMRI (Hudetz et al., 2012
; Liu et al., 2012a
) and found that during deep sedation (2
μg/mL target) thalamocortical connectivity of the nonspecific (intralaminar) thalamic nuclei was preferentially reduced (). Corresponding changes in the specific thalamic system were relatively modest. Upon withdrawal of the anesthetic, both systems recovered in some regions, even above the waking baseline. The latter was interesting from the point of recent findings, suggesting that induction and recovery may be mediated in part by different neuronal mechanisms (Friedman et al., 2010
). As in former studies, cortical activation to auditory stimuli persisted, confirming that anesthetic unconsciousness cannot be explained by cortical deafferentation or a diminution of cortical sensory reactivity. Thus, these findings support the theory that the cause of anesthetic unconsciousness is a failure of information integration (Alkire et al., 2008
; Hudetz, 2006
) that appears to correlate with a dysfunction of the nonspecific thalamocortical system. emphasizes the critical role of the intralaminar thalamus in modulating the cortical circuits for consciousness.
FIG. 2. Specific (A) and nonspecific (B) thalamocortical functional connectivity in baseline wakefulness, deep sedation, and recovery. Functional connectivity was obtained from seed-based analysis of the temporal correlation of fMRI blood oxygen-dependent signals. (more ...)
So far, only one investigation has used an information theory-based approach to quantify the effect of anesthesia on functional integration in the brain based on fMRI data. Schrouff and colleagues (2011
) analyzed the effect of deep sedation with propofol on functional interactions for six known RSNs, such as the DMN, dorsal and ventral attention, salience, visual, and motor systems. As opposed to the earlier seed-based technique, a complex series of novel analysis tools, including independent-component analysis, hierarchical clustering, region-of-interest covariance, and partial correlation were used. The authors then used mutual information as a measure of information integration within and between the RSNs and found that with one exception, all system integration variables were significantly reduced under propofol sedation. In addition, they found that the integration between the parietal and frontal regions and between the parietal and temporal regions was substantially reduced. Complemented by similar results obtained with electrophysiological techniques (Lee et al., 2009a
), these findings reaffirm the significance of cortical networks with the parietal cortex as a hub for consciousness and its modulation by general anesthesia (Alkire et al., 2008
Finally, in a recent study of functional connectivity and global integration (Schroter et al., 2012
) was analyzed by wavelet decomposition and graph–theoretical analysis of fMRI time series in wakefulness and propofol-induced loss of consciousness. Propofol plasma concentration (>1.2
μg/mL) was titrated by target-controlled infusion to Ramsay sedation scale of 5–6; the depth of sedation was also assessed by aperiodic EEG analysis. Propofol conferred significant reductions in corticocortical (involving occipital, temporal, and parietal lobes) and subcorticocortical connectivity (mainly with thalamus and putamen) while sparing the connectivity of primary sensory regions as seen other studies before. The strength of long-range connectivity between multimodal association regions and the subcortical and primary sensory regions declined more than that of short-range connectivity, and there was a general decrease in whole brain integration as estimated from the eigenvalues of principal components analysis.
summarizes the anesthesia studies on brain functional connectivity performed todate. Some of the variability in results between the studies may be due to a difference in the anesthetic endpoint; for example, mild or deep sedation or unconsciousness. Also, there were differences whether patient responsiveness was assessed using an objective scale, for example, Observer Assessment of Alertness and Sedation (OAAS) or Ramsay score, or not.
Effect of Anesthetics on Functional Connectivity Assessed by Neuroimaging