br._j._anaesth.-2003-antognini-233-8-2.pdf |
BRAIN CONNECTIVITY Volume 2, Number 6, 2012
a Mary Ann Liebert, Inc.
DOI: 10.1089/brain.2012.0107
REVIEW ARTICLE
General Anesthesia and Human Brain Connectivity
Anthony G. Hudetz
Abstract
General anesthesia consists of amnesia, hypnosis, analgesia, and areflexia. Of these, the mechanism of hypnosis, or loss of consciousness, has been the most elusive, yet a fascinating problem. How anesthetic agents suppress human consciousness has been investigated with neuroimaging for two decades. Anesthetics substantially reduce the global cerebral metabolic rate and blood flow with a degree of regional heterogeneity characteristic to the an- esthetic agent. The thalamus appears to be a common site of modulation by several anesthetics, but this may be secondary to cortical effects. Stimulus-dependent brain activation is preserved in primary sensory areas, suggest- ing that unconsciousness cannot be explained by cortical deafferentation or a diminution of cortical sensory re- activity. The effect of general anesthetics in functional and effective connectivity is varied depending on the agent, dose, and network studied. At an anesthetic depth characterized by the subjects’ unresponsiveness, a par- tial, but not complete, reduction in connectivity is generally observed. Functional connectivity of the frontopar- ietal association cortex is often reduced, but a causal role of this change for the loss of consciousness remains uncertain. Functional connectivity of the nonspecific (intralaminar) thalamic nuclei is preferentially reduced by propofol. Higher-order thalamocortical connectivity is also reduced with certain anesthetics. The changes in func- tional connectivity during anesthesia induction and emergence do not mirror each other; the recovery from an- esthesia may involve increases in functional connectivity above the normal wakeful baseline. Anesthetic loss of consciousness is not a block of corticofugal information transfer, but a disruption of higher-order cortical infor- mation integration. The prime candidates for functional networks of the forebrain that play a critical role in main- taining the state of consciousness are those based on the posterior parietal-cingulate-precuneus region and the nonspecific thalamus.
Key words: anesthesiology; consciousness; default-mode network; functional connectivity; resting state
Introduction
How anesthetics suppress human consciousness has been a mystery for 166 years since the first demonstra- tion of ether anesthesia. Anesthetic agents comprise a wide variety of molecules acting on numerous receptors, channels, and other protein targets in the body (Alkire et al., 2008; Franks, 2006; Hemmings et al., 2005; Rudolph and Antko- wiak, 2004). Their effect on consciousness would not be so mysterious if they simply suspended all brain functions by a widespread, nonspecific suppression of neuronal activity throughout the brain, sometimes called the wet-blanket the- ory (Sukhotinsky et al., 2007). However, as we now under- stand, a host of subconscious and autonomic functions are still operational when conscious perception and volition are suppressed.
At a small dose, anesthetics first suppress thinking, fo- cused attention, and working memory. As the dose is in-
creased, consciousness and voluntary responsiveness begin to fade. When subjects no longer respond to verbal stimula- tion, we presume that their consciousness is gone. This is a conjecture supported by the loss of episodic memory of the stimuli, but does not define the residual mental contents of the subject at the time of stimulation. Upon further increases in anesthetic dose, nociceptive and autonomic reflexes are suppressed. The latter are mediated at the brainstem and spi- nal level and are thought to occur after the loss of conscious- ness. At even higher dose, brain electrical activity is turned into intermittent, and ultimately, complete suppression. For the time being, loss of consciousness will be operationally de- fined as a loss of voluntary responsiveness, excluding limit- ing factors such as the use of muscle relaxants, the presence of motor impairment, or akinetism.
Functional neuroimaging by now has become a principal tool to study the neural correlates of consciousness. In the field of anesthesia research, neuroimaging investigations
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
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have focused on the mechanisms of memory, pain perception, and consciousness. Basically, three aspects of brain activity during anesthesia have been studied with neuroimaging: (1) the degree of baseline activity, as reflected by regional cere- bral metabolic rate (CMR) and regional cerebral blood flow (CBF), (2) the responsiveness of neuronal networks to sensory input or task, and (3) the functional connectivity of large-scale networks of the brain. Currently, functional connectivity is in the forefront of interest. This review focuses on neuroimaging studies of anesthetic modulation of brain connectivity. Before discussing functional connectivity, we will briefly review the effect of anesthetics on CBF and metabolism, because they provide an essential context for the connectivity studies.
Anesthetics Suppress Baseline Metabolic Activity
Early imaging studies convincingly demonstrated that general anesthetics produced substantial, global reductions in cerebral metabolic rate and CBF. The first study to link re- gional brain effects of anesthesia to the loss of consciousness was conducted by Alkire and his colleagues in 1995 (Alkire et al., 1995) using positron-emission tomography (PET) to in- vestigate effect of propofol anesthesia on CMR in volunteers. They found that when the infusion rate of propofol was titrated to the point when subjects no longer responded to verbal commands, CMR decreased in every region of the brain, by 30%–70%. In subsequent studies, this strong global metabolic suppression was found to be a common effect of several other anesthetic agents (Alkire et al., 1997; Bonhomme et al., 2001; Fiset et al., 1999; Veselis et al., 1997).
In addition to the large overall reduction, a certain degree of regional heterogeneity in CMR or CBF was observed that was dose dependent and characteristic to the anesthetic agent. For example, the effect of propofol on CMR was more heterogeneous than those of halothane and isoflurane (Alkire, 2008). Midazolam at a sedative-amnesic dose re- duced CBF in select regions involved in arousal, attention, and memory (Reinsel et al., 2000; Veselis et al., 2004). When both agents were titrated to similar sedative-hypnotic end- points, propofol (1.2 and 2.7 lg/mL) decreased rCBF in the anterior brain regions, whereas thiopental (4.8 and 10.6 lg/ mL) decreased rCBF primarily in the cerebellar and posterior brain regions (Veselis et al., 1997, 2004). In study by Fiset with propofol (0.5 to 2.67lg/mL plasma), the largest dose- dependent reductions in CBF were seen in the medial thala- mus, certain medial posterior parietal, occipitotemporal, and orbitofrontal regions (Fiset et al., 1999, 2005).
Currently, it is unclear if the preferential reductions in CMR/CBF are responsible for the loss of consciousness or they simply reflect a consequence of altered network interac- tions. Shulman and colleagues (2009) have argued that the effect of anesthesia on the global metabolic baseline was im- portant for loss of consciousness. Nevertheless, in certain neu- rologic patients, consciousness was found present with substantially decreased global cerebral metabolism (Laureys et al., 1999). In fact, individual subjects can have substantially different baseline CMR (Alkire et al., 1995), suggesting that a correlation between absolute CMR and consciousness may be variable. Also, an exception to the global cerebral suppression by anesthetics is ketamine, which actually increases CMR in most brain regions (Langsjo et al., 2005). Ketamine differs from most other agents in that it is an antagonist of the
NMDA subtype of glutamate receptors (similar to nitrous oxide and Xenon). However, it is possible that ketamine—a hallucinogenic drug—does not completely suppress con- sciousness, and that its CMR effects are consistent with pre- served subjective experience. Sanders and colleagues (2012) distinguish among consciousness, connectedness, and re- sponsiveness as three possible targets of general anesthesia. Ketamine anesthesia may be best described as a state of dis- connection (from the environment), while anesthesia with other agents may produce complete unconsciousness, that is, an absence of all subjective experience.
The Thalamus Is a Common Target of Anesthetics
When the effects of halothane and isoflurane were first compared, a common site of regional suppression turned out to be the thalamus (Alkire et al., 2000). This observation led to the theory of a thalamic switch of consciousness (Alkire et al., 2000), suggesting that a hyperpolarization block of tha- lamocortical neurons would disrupt the functioning of thala- mocortical circuits necessary for consciousness. The thalamus as a common site of anesthetic modulation has been subse- quently confirmed for several other anesthetic agents, as well as other states of unconsciousness such as non-REM (dreamless) sleep and persistent vegetative state (Alkire and Miller, 2005). Whether the thalamus itself is the primary tar- get of anesthetic modulation or its changes reflect indirect ef- fects on other parts of the brain is currently unclear. Some investigations suggest that the thalamus is more of a read- out of cortical information, integrating the results of cortical computations (Mumford, 1991; Ward, 2011). Thalamic sup- pression by anesthetics may in fact follow in time the anes- thetic suppression of cortical activity, suggesting an indirect role (Velly et al., 2007). Thus, the thalamic effects of anesthesia are more likely to be consequential, secondary to the cortical effect of anesthetics (Alkire et al., 2008). Yet, the thalamus may be too intimately interacting with the cortex to separate their roles from each other entirely. Moreover, limited behav- ioral functions survive thalamic ablation in cats and rats (but not in humans), which makes it ambiguous if any true con- sciousness; that is, subjective experience or awareness of any kind remains present without a thalamus (Villablanca and Marcus, 1972). Finally, the thalamus is a heterogeneous structure of many nuclei with differing functions and cellular composition, and as we will explain below, a differentiation in the anesthetic effects on its component regions may be nec- essary to understand its involvement in modulating the state of consciousness.
Frontoparietal Cortex Is a Major Target of Anesthetics
A second major group of regions strongly suppressed by various anesthetic agents have been identified in the fronto- parietal association cortex. As already mentioned, the largest reductions in CBF by propofol were seen in the region involv- ing the cuneus, precuneus, and posterior cingulate and retro- splenial cortex (Fiset et al., 1999) and in the in the frontal cortex (Veselis et al., 2004). Frontal CBF was also reduced with sevoflurane, but only at high concentrations, 1.0 to 2.0 MAC (Kaisti et al., 2002, 2003). The dorsolateral prefrontal and superior/posterior parietal association cortex have been implicated for their involvement in various cognitive func- tions, including attention, perception, working memory, and
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consciousness itself (Naghavi and Nyberg, 2005; Rees et al., 2002). These cortical areas were also depressed in other states of unconsciousness, such as sleep, coma, anesthesia, and sei- zures (Baars et al., 2003). For example, in unconscious pa- tients in vegetative state, regional cerebral metabolism for glucose was found impaired in the prefrontal, premotor, and parietotemporal association areas, the posterior cingulate cortex and precuneus (Laureys et al., 1999). In the patients who subsequently recovered, the return of awareness was ac- companied by the restoration of function in the frontoparietal regions.
Observations from epilepsy, stroke, vegetative state, and anesthesia converge, suggesting that a common cortical area, the region of posterior cingulate, retrosplenial, and pre- cuneus, has a critical role in consciousness (Vogt and Laureys, 2005). Alkire and colleagues (2008) described a presumptive consciousness circuit that consists of the medial parietal cor- tex, precuneus, and posterior cingulate cortex (PCC), as well as lateral frontoparietal association areas and the thala- mus. The cortical aspects of this network shows a certain de- gree of homology with the so-called default-mode network (DMN) that is characterized by relatively high resting-state metabolic rate and, presumably, high neuronal activity dur- ing stimulation or task-free condition (Raichle et al., 2001). Alkire further differentiates between the functional roles in the ventral and dorsal PCC, emphasizing their involvement in the perception and orientation of the body in space and the subjective first-person aspect of self-awareness, respec- tively. In the model, the effects of anesthesia suppressing sen- sory awareness, self-awareness, and motor output are linked with the disruption of both frontoparietal and mediolateral networks. As will be discussed in more detail below, a break- down of connectivity in the frontoparietal cortical network was found in propofol-induced unconsciousness (Boveroux et al., 2010). Figure 1 illustrates the consciousness network in a simplified form (without the dorsal–ventral division of the PCC), together with linked functionalities targeted by general anesthesia. Also involved in the circuit is the intrala- minar thalamus and related subcortical structures as will be explained in a subsequent section.
Sensory Cortical Responsiveness Is Attenuated in Anesthesia
In addition to baseline changes in CMR and CBF, several investigations were conducted to determine how anesthetic agents altered the brain’s functional activation patterns evoked by sensory stimuli. As it turned out, most cortical- evoked responses were reduced, but not fully blocked under anesthesia at sedative hypnotic depths. This confirmed that the cause of unconsciousness could not be a block of tha- lamocortical information transfer. The first studies were per- formed with tactile stimulation, which was suppressed by isoflurane at 0.7% or 1.3% (Antognini et al., 1997) and by pro- pofol at comparable sedative hypnotic doses (0.5, 1.5, and 3.5 lg/mL target) (Bonhomme et al., 2001). Subsequently, Ker- ssens and colleagues (2005) used auditory word stimulation during 1% and 2% sevoflurane anesthesia and found a dose- dependent suppression of auditory blood oxygen level dependent (BOLD) activation, suggesting limited processing and memory of the presented auditory material. Thalamic ac- tivation was preserved at 1% sevoflurane. In the latter two
Schematic of the hypothesized consciousness net- work. The network involves major cortical components of the default-mode network as well as other regions. The PCC serves as the central hub of neuronal information flow that generates both directly and via additional cortical centers the various expressions of human consciousness. The circuit is functionally modulated by the ascending arousal system from the BS, BF and HT regions (simplified for clarity) that converge on the nonspecific ILN, whose connectivity with the cortex plays a major role in regulating the state of con- sciousness. PCC, posterior cingulate cortex; BS, brainstem; BF, basal forebrain; HT, hypothalamic; ILN, intralaminar tha- lamic nuclei; LPC, lateral parietal cortex; ACC, anterior cingu- late cortex; mPFC, medial prefrontal cortex. Based on (Alkire 2008; Hudetz 2006, 2012; Liu et al. 2012a).
studies, Bonhomme and colleagues (2001) evaluated the level of consciousness by the subjects’ response to a verbal com- mand; Kerssens and colleagues (2005) assessed memory by au- ditory recognition after emergence (not reflecting the state of consciousness), but they noted the general absence of motor re- sponsiveness to scanner noise at 1% sevoflurane. Dueck and colleagues (2005) also found dose-dependent impairment of BOLD response to acoustic stimulation by propofol (0.5 to 2.0lg/mL target). However, even at the deepest sedative level, propofol did not totally eliminate primary cortical responses to acoustic stimulation, suggesting that auditory information was still processed at some level. Plourde and coworkers (2006) also investigated the dose-dependent effect of propofol anesthesia on auditory processing with stimuli of increasing complexity. They found that propofol anesthesia at 4.6 lg/mL plasma concentration reduced BOLD activations by 40%–50%, although voice-specific and word-specific activa- tions were abolished. Paradoxically, in some brain regions, scrambled words elicited greater activation than regular words during anesthesia, perhaps reflecting a greater effort to analyze word meaning. Both primary and association audi- tory cortices remained responsive to auditory stimuli, but the responses became nonspecific, suggesting a loss of higher- level analysis. In the study by Ramani and coworkers (Ramani et al., 2007), light sedation with 0.25 MAC sevoflurane attenuated CBF responses predominantly in the visual and other higher-order association cortices. In addition, Boveroux and coworkers (2010) found that cross-modal interactions be- tween visual and auditory cortices disappeared during deep
FIG. 1.
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propofol sedation (3.2lg/mL plasma). Finally, Liu and co- workers (2012b) obtained additional evidence that in deep se- dation with propofol (2lg/mL target), memory task-related responses to auditory word presentation persisted in the pri- mary auditory cortex (PAC), but they vanished in higher areas associated with mnemonic processes such as the inferior frontal gyrus (IFG).
Taken together, with the exception of somatosensory re- sponses (Antognini et al., 1997; Bonhomme et al., 2001), func- tional imaging studies have shown that general anesthetics at a hypnotic dose preferentially reduced brain activation in higher-order information-processing regions, but not in the primary sensory areas. We speculate that the stronger sup- pressive effect of anesthetics on tactile or nociceptive activa- tion may be due to peripheral and spinal suppression of the ascending stimuli—an effect that is absent in other sensory modalities. It then follows that the loss of consciousness is not due to a simple block of corticofugal information transfer, but presumably to a lack of higher-order integration in the cortex. It should be noted that the latter may or may not be due to a selective anesthetic sensitivity of the higher-order cortex. Anesthetic drugs may target brain regions fairly evenly as the wet-blanket theory suggests. However, the at- tenuation of neuronal activations may result in a cumulative effect upward in the cortical hierarchy, in the direction of pri- mary information flow, thus making the higher-order regions fail first. The anesthetic cascade may appear as a top-down failure, but really driven by bottom-up effects.
Functional Connectivity Is Altered in Anesthesia
What makes consciousness specifically sensitive to anes- thetics? One suggestion is that the complexity of neuronal op- erations required to support conscious functions (Tononi, 2004; Tononi and Edelman, 1998) plays a role. The more ex- tensive and complex the neuronal system is, the more sensi- tive it may be to the accumulation of locally disruptive effects. Polysynaptic pathways have been known to be vul- nerable 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 dy- namic interaction of large-scale networks of the brain that function to integrate information (Tononi, 2004, 2005, 2008). These functional networks may bind information from en- dogenous and exogenous sources and make the computa- tional 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 sub- ject, 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 re- gional CMR across subjects. It took another 10 years after Biswal’s discovery (Biswal et al., 1995, 1997) to first examine the effect of anesthetics resting-state functional connectivity using the temporal correlation of low-frequency BOLD sig-
nals. Peltier and colleagues (2005) studied the concentration- dependent effect of sevoflurane on functional connectivity on motor cortices. They used the original seed voxel-based ap- proach 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 midazo- lam 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 somatomo- tor, 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 crit- ical 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 undif- ferentiated, 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 con- nectivity in the sensory-motor network was increased. They suggested that the reduction in PCC connectivity was a corre- lated with reduced consciousness.
However, the results were substantially different with sevoflurane (Deshpande et al. 2010). 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) sevo- flurane, functional connectivity was reduced across the entire DMN. It remained unclear whether changes in prefrontal con- nectivity occurred at the time consciousness was lost, presum- ably 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. Preclin- ical studies (Imas et al., 2005, 2006) 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,
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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) sevo- flurane anesthesia using seed-based connectivity analysis. They showed that during sevoflurane administration, func- tional 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 sup- ported by data (Stamatakis et al., 2010) obtained during light-to-moderate sedation with propofol (0.27 and 0.67 lg/ mL plasma), demonstrating increased connectivity of the PCC as a seed region with the anterior cingulate cortex, so- matosensory, and motor cortex and parts of the reticular acti- vating 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 ad- ditional 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 con- sciousness 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 vol- unteers anesthetized by halothane or isoflurane to loss of re- sponsiveness (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) connectiv- ity. 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 res- onance 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 respon- siveness. 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 thala- mus may be indirect, driven by actions on the cortex or sub- cortical areas that project to the thalamus (Alkire et al., 2000, 2008; Vahle-Hinz et al. 2007).
Detailed analyses of both corticocortical and thalamocorti- cal RSNs during wakefulness and two levels of propofol se- dation (1.75 and 3.20lg/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 partic- ular the default (correlated with the PCC) and executive- control (correlated with the middle frontal gyrus) networks. The authors showed that propofol suppressed the frontopar- ietal medial DMN and lateral executive-control networks. Propofol also suppressed thalamic connectivity with the frontal–parietal association regions, and disrupted the anti- correlation between the default and executive-control systems normally observed during wakefulness. Consistent with previ- ous findings, corticocortical and thalamocortical connectivi- ties 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 lg/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 van- ished in higher areas associated with mnemonic processes such as the IFG. At the same time, propofol disrupted connec- tions of the PAC with the frontal regions and the thalamus. Surprisingly, connectivity of the IFG with a set of widely dis- tributed 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 endoge- nous information in an autonomous manner.
The discordant results regarding the anesthetic modulation of thalamocortical functional connectivity may not be surpris- ing given the anatomical and functional complexity of the thalamus. One could assume that the connectivity of the var- ious thalamic nuclei may not change in a homogeneous man- ner 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, b), and it is thought to enable consciousness. Recently, we investigated the effect of propofol on thalamo- cortical functional connectivity with BOLD fMRI (Hudetz et al., 2012; Liu et al., 2012a) and found that during deep se- dation (2 lg/mL target) thalamocortical connectivity of the nonspecific (intralaminar) thalamic nuclei was preferentially reduced (Fig. 2). 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,
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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. The brain was partitioned into 300 regions, and the regions containing < 10 voxels were removed. Nonspe- cific connectivity is based on intralaminar nuclei as a seed; specific connectivity is based on the reminder of thalamus as seed. Deep sedation was defined as absent responsiveness to verbal commands. Data are from seven volunteers (Liu et al., 2012b). Note the substantial and reversible reduction of nonspecific thalamocortical connectivity during deep sedation (Figure by the courtesy of Dr. Xiaolin Liu).
cortical activation to auditory stimuli persisted, confirming that anesthetic unconsciousness cannot be explained by corti- cal deafferentation or a diminution of cortical sensory reactiv- ity. Thus, these findings support the theory that the cause of anesthetic unconsciousness is a failure of information inte- gration (Alkire et al., 2008; Hudetz, 2006) that appears to correlate with a dysfunction of the nonspecific thalamocort- ical system. Figure 1 emphasizes the critical role of the intra- laminar thalamus in modulating the cortical circuits for consciousness.
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 se- dation with propofol on functional interactions for six known RSNs, such as the DMN, dorsal and ventral attention, sa- lience, visual, and motor systems. As opposed to the earlier seed-based technique, a complex series of novel analysis tools, including independent-component analysis, hierarchi- cal clustering, region-of-interest covariance, and partial corre- lation 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 inte- gration 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 tech- niques (Lee et al., 2009a, b, 2011), these findings reaffirm the significance of cortical networks with the parietal cortex as a hub for consciousness and its modulation by general an- esthesia (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 lg/ mL) was titrated by target-controlled infusion to Ramsay se- dation scale of 5–6; the depth of sedation was also assessed by aperiodic EEG analysis. Propofol conferred significant reduc- tions in corticocortical (involving occipital, temporal, and pa- rietal lobes) and subcorticocortical connectivity (mainly with thalamus and putamen) while sparing the connectivity of pri- mary sensory regions as seen other studies before. The strength of long-range connectivity between multimodal as- sociation regions and the subcortical and primary sensory re- gions 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.
Table 1 summarizes the anesthesia studies on brain func- tional 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 pa- tient responsiveness was assessed using an objective scale, for example, Observer Assessment of Alertness and Sedation (OAAS) or Ramsay score, or not.
Regaining Consciousness Has Unique Neural Correlates
As already mentioned, recent investigations suggest that the neural processes of losing and regaining consciousness
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Table 1. Effect of Anesthetics on Functional Connectivity Assessed by Neuroimaging
Authors Method
White and Alkire, 2003 PET Peltier et al., 2005 fMRI Kiviniemi et al., 2005 fMRI Vincent et al., 2007 fMRI Grecius et al., 2008 fMRI Deshpande et al., 2010 fMRI Martuzzi et al., 2010 fMRI
Stamatakis et al., 2010 fMRI Mhuirchertaigh et al., 2010 fMRI Boveroux et al., 2010 fMRI
Schrouff et al., 2011 fMRI
Liu et al., 2012b fMRI
Langsjo et al., 2012 PET
Schroter et al., 2012 fMRI
Agent
Isoflurane, Halothane Sevoflurane Midazolam Isoflurane Midazolam Sevoflurane Sevoflurane
Propofol Propofol Propofol
Propofol
Propofol
Dexmedetomidine, Propofol
State
Unconsciousness Unconsciousness Sedation Unconsciousness Sedation Unconsciousness Unconsciousness
Light sedation Sedation
Deep sedation
Deep sedation Deep sedation Unconsciousness Unconsciousness Deep sedation
Seed or network
Motor cortex, thalamus Motor cortex
Auditory visual Default-mode network Posterior cingulate Prefrontal cortex Default, sensory cortex,
hippocampus/insula Posterior cingulate Posterior cingulate Frontoparietal,
thalamocortical Frontoparietal,
frontotemporal cortex Auditory cortex,
inferior frontal gyrus Anterioposterior cortex
Association cortex, thalamocortical
Thalamocortical
Observation
Reduced Reduced Increased Preserved Reduced Reduced Preserved,
reduced Increased Increased Reduced
Reduced, preserved
Reduced Reduced Reduced Reduced
Liu et al., 2012a fMRI
PET, positron-emission tomography; functional magnetic resonance imaging (fMRI).
Propofol Propofol
do not mirror each other. For example, a substantial asymme- try in regional thalamocortical functional connectivity was observed during wakefulness before and after propofol seda- tion (Hudetz et al., 2012). The functional connectivity of sev- eral thalamocortical networks was increased well above the preanesthetic baseline after the participants regained con- sciousness. This was interpreted as a probable recruitment of additional neural resources as required for the restoration of conscious functionalities of the brain. An apparent imped- iment to reversing the state of unconsciousness has been termed neural inertia (Friedman et al., 2010).
A recent investigation by Langsjo and colleagues (2012) specifically examined the neural correlates of awakening from light dexmedetomidine (2.8 to 3.2ng/mL plasma) or propofol (1.8lg/mL) anesthesia. A novel feature of this study with dexmedetomidine was that it allowed a dissocia- tion of the state-related changes in consciousness from the ef- fects of the anesthetic drug by choosing an anesthetic depth at which participants could be aroused to consciousness by gen- tle tactile or verbal stimulation without changing the anes- thetic dose. Clearly, dexmedetomidine is not a complete anesthetic nor is the hypnosis it produces comparable to that of other anesthetic agents. Its main target regions are pre- sumed to be subcortical and mediated via a2 adrenergic re- ceptor agonism (Nelson et al., 2003). Nevertheless, the use of dexmedetomidine allowed the comparison of neural con- nectivity patterns between the conscious and unconscious states at the same drug level. The authors then found that awakening from unconsciousness, defined by the presence of motor response to spoken command, was associated with the activation of a network of subcortical and limbic re- gions functionally coupled with parts of frontal and inferior parietal cortices. The anterior cingulate and its connectivity with the inferior parietal region predicted the conscious state particularly well. We note that this study was performed with PET; therefore, as explained before, functional connec-
tivity was based on a different type of analysis (partial least- square covariation with the state) from that obtained by fMRI (temporal correlation of BOLD signals). Nevertheless, the results supported the role of anterioposterior integration in regaining volitional consciousness by linking motor inten- tions (posterior regions) with motor control (anterior regions). In another study, restoration of consciousness during propofol anesthesia achieved by cholinergic activation of the cerebral cortex was associated with rCBF increases in the thalamus and precunus (Xie et al., 2011). Similarly, the recovery of pa- tients from a vegetative or minimally conscious state typically an increase in cerebral metabolism in the precuneus and PCC (Laureys and Schiff, 2012), suggesting that the medial posterior complex, roughly defined as the PCC, precuneus, and perhaps the retrosplenial cortex, plays a critical and common role in the process of recovery of consciousness. An analysis of the change in connectivity of latter region during restoration of conscious- ness should be a revealing next step of investigation.
Can Neuroimaging Reveal the Neural Basis of Anesthetic Unconsciousness?
The answer to the stated question depends on whether the neuroimaging techniques measure the neural activities rele- vant to those that are minimally necessary to support con- sciousness. Clearly, complimentary approaches such EEG, magnetoencephalography (MEG), and intracortical electro- physiology could in principle provide more specific informa- tion on neuronal connectivity, but with lower spatial resolution or with limited spatial coverage. The pattern of neuronal connectivity essential for consciousness is neverthe- less unclear. Equally important, the answer depends on our definition of unconsciousness as a state. To date, the clinical assessment of the state of consciousness has been entirely be- havioral. This approach is quite reliable when a rational, pur- poseful response from the subject is obtained; however, it
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fails to provide suitable evidence in noncommunicating or immobilized patients. Studies with the isolated forearm tech- nique (Russell and Wang, 1996) reveal that anesthetized pa- tients are likely to understand verbal commands and respond purposefully. In this experiment, a tourniquet is ap- plied to the upper forearm to prevent immobilization of the forearm muscles, thus allowing the patient to signal with her fist. Could we assess the presence of semantic analysis and volition directly from the brain activity? In a few in- stances, fMRI has been used as a surrogate measure to deter- mine the presence of a covert voluntary response in brain- injured patients who showed no sign of meaningful behav- ioral communication (Bardin et al., 2011; Owen et al., 2006). For example, patients were asked to imagine playing tennis, moving around the home, or swimming while regional brain activation specifically associated with the imagined ac- tivity was measured with fMRI. In some cases, patients showed voluntary response when they were behaviorally un- responsive. However, others failed to perform the imagery task, in spite of that they were responsive outside the MRI scanner, suggesting that command-based assessment is not always reliable, as it depends on the ability or the will of the patient to cooperate. Simply speaking, the absence of vo- lition does not imply the absence of conscious perception.
Without asking the subject to respond, Davis and col- leagues (2007) tested speech comprehension in awake, lightly sedated, and deeply sedated volunteers with fMRI. Subjects listened to sentences with or without ambiguous words con- tained. Specific frontotemporal activation indicated the pres- ence of semantic comprehension that was lost during light sedation, while perceptual processing of speech was lost in deep sedation, suggesting a graded degradation of cognitive function with deeper sedation. However, due to the lack of an independent reference, it remains unclear to what extent con- sciousness was present when semantic analysis was sup- pressed, or if perceptual processing was a prerequisite for consciousness at all.
While stimulus-free and task-free (resting-state) assess- ment of brain activity patterns or RSNs is always possible, a caveat is that during rest, we cannot assess the level of con- sciousness. Which of the RSNs, if any, is necessary and suffi- cient for consciousness? Recently, He and Raichle (2009) suggested that slow cortical potential (SCP, < 1 Hz) may be a neural correlate of consciousness and its modulation by an- esthesia. The SCP is thought to be generated in the superficial layers of the cortex by synchronous excitatory input to the apical dendrites of pyramidal cells presumed to play a pri- mary role in the integration of information encoded in neuro- nal signals derived from specific and nonspecific thalamic and long-range corticocortical pathways. Support to this pro- posal was taken from a human study of cortical auditory- evoked cortical DC potentials that were specifically abolished under anesthesia (Fitzgerald et al., 2001). However, this study employed very deep anesthesia with a high dose of propofol (5.5 lg/mL) or methohexital (2.8 lg/mL), which does not allow the identification of critical events that may occur at the point of loss and return of consciousness. Moreover, Koch (2009) argued against the causal involvement of the SCP in consciousness or conscious content, because it cannot account for the specificity and informational richness of con- scious experience. As pointed out before (Alkire et al., 2008), large-scale stereotypic coherence of potentials as seen in deep
anesthesia, coma, and similar unconscious states lack specific- ity and information content as would be required for con- sciousness. Moreover, it is likely that the fast dynamics (microstates) of diverse neuronal configurations at the ms- to-100 ms time scale (Koenig et al., 2002) is an essential prop- erty that gives rise to the ongoing stream of consciousness. Recent attempts to link neuronal microstates with fMRI sig- nals (Lehmann, 2010; Musso et al., 2010) may be the next fron- tier to further explore the neural correlates of consciousness and anesthetic unconsciousness.
We also have a difficulty in pinpointing when exactly the consciousness is lost under anesthesia. While it is plausible that at a high-enough anesthetic dose consciousness is in fact absent, the challenge remains to determine when this transition actually occurs. Does it occur abruptly or gradual- ly? To find the neural correlate of anesthetic-induced uncon- sciousness, we either have to know the neural correlate of consciousness itself, or we need to have an assessment of the state of consciousness independent of the observed neural events. To date, we have neither. An approach to alleviate this difficulty is to consider consciousness as a graded phe- nomenon (Tononi, 2008), one that fades gradually under the effect of anesthesia. This assumption unlocks the neural events from a specific transition in the consciousness state; however, it also makes it difficult to separate the graded neu- ral changes specifically associated with conscious processing from those that are not.
Moreover, a higher degree of functional correlation may not necessarily indicate more effective communication or in- formation transfer. In fact, high correlation or hypersyn- chrony may exactly imply the opposite effect (Alkire et al., 2008; Schrouff et al., 2011; Stamatakis et al., 2010). Reduced functional connectivity may indicate the uncoupling of cer- tain regions from the network, thus an impairment of infor- mation integration. Increased connectivity, on the other hand, may be interpreted as a reduction in the discriminable brain states, implying an increasing prevalence of stereotypic activity patterns. Consequently, either a disruption in connec- tivity or its nonspecific, stereotypic increase may reduce the level of consciousness. In fact, convincing evidence in support of a reduced, stereotypic pattern of neuronal connectivity during suppressed consciousness has been obtained during both anesthesia and nonrapid-eye-movement sleep (Ferrarelli et al., 2010; Massimini et al., 2005). In both cases, the investi- gators applied transcranial magnetic of stimulation (TMS) of the cortex to elicit a sequence of propagating electrocortical waves, indicating cortical neuronal communication in wake- fulness. In the unconscious state, the propagating waves were extinguished and reduced to a local stereotypical response, suggesting a breakdown of cortical effective connectivity. Future extension of TMS experiments to fMRI may bring further insight into the spatiotemporal dynamics of stimulus- related neuronal connectivity of networks, including subcorti- cal structures. In this regard, the use of directional connectivity assessment such as Granger causality or the use of effective connectivity model-based approaches such as dynamic causal modeling holds much promise (Boly et al., 2012a; Boly et al., 2012b; Deshpande and Hu, 2012; Heine et al., 2012).
Finally, determining the causal role of neural events in modulating consciousness remains a difficult problem (Crick and Koch, 2003). As anesthetic agents influence several of molecular targets in a multitude of brain structures
GENERAL ANESTHESIA AND HUMAN BRAIN CONNECTIVITY 299
simultaneously, functional brain maps and networks inform little about the primary functional targets of anesthesia and about their causal relationship to a change in conscious functions. The observed changes in functional and effective connectivity may be either causal or consequential to the failure of conscious processing. Simultaneous multimodal imaging and electrophysiological investigations (Boly et al., 2012b) together with noninvasive perturbational ap- proaches (Ferrarelli et al., 2010) may eventually provide the desired insight.
At the spatiotemporal scale of neuroimaging, the currently considered a prime candidate for anesthetic unconsciousness is a disruption of the connectivity of posterior parietal cortex and of the nonspecific thalamus. The latter involve mainly the intralaminar nuclei or, more generally, the matrix cells in var- ious thalamic nuclei. The significance of the latter region for consciousness is consistent with the observation that a small, but specific, lesion of the medial thalamus produces unconsciousness (Schiff, 2008). On the other hand, several principal structures, including the basal ganglia, tectum, basal forebrain, hippocampus, and cerebellum, which play important roles in cognitive functions, are nevertheless un- necessary for consciousness due to their fundamentally paral- lel architecture (Tononi and Koch, 2008). Nevertheless, it remains to be determined if any of the anesthetic effects ob- served so far can represent the final common neural event causally involved in unconsciousness. To date, relatively few anesthetic agents have been studied with functional im- aging and compared under the same conditions, mostly pro- pofol, and to a lesser extent, sevoflurane, midazolam, and ketamine. The patterns of change seen with these agents are different, and it is anticipated that more agent-dependent pe- culiarities will surface before the unitary basis of uncon- sciousness is found.
Conclusions
The modulation of functional connectivity by general anes- thetic agents is an active area of investigation. To date, no consensus has emerged with respect to the common neural mechanism by which anesthetics modulate the state of con- sciousness. The significance of functional brain connectivity changes during general anesthesia for the loss and return of consciousness remain to be confirmed. Anesthetics do not completely block thalamocortical connectivity. Although they may scramble the information transmitted, neuroimag- ing is currently unable to test this possibility. Higher-order thalamocortical connectivity appears to be reduced by propo- fol; this has yet to be confirmed with other agents. The effect of anesthetics on corticocortical connectivity is varied; it de- pends on the anesthetic agent and the specific network exam- ined. In most cases, the suppressive effects of anesthetics on connectivity are partial, and it remains to be determined if such effects are sufficient to explain loss of consciousness or they are consequential to a change in function. In particular, frontoparietal connectivity is often reduced in anesthesia, but its causal role in the loss of consciousness remains uncer- tain. Networks based on the posterior parietal-cingulate-pre- cuneus region as a hub and on the nonspecific thalamus are putative candidates for the neural correlate of the state of con- sciousness. The observed changes in functional connectivity during anesthesia induction and emergence do not mirror
each other; the recovery from anesthesia may involve in- creases in functional connectivity above the normal wakeful baseline. This leaves the existence of an unitary correlate of consciousness in question, as it should be a change fully re- versible with loss and return of consciousness. In searching for the neural basis of consciousness, an obvious limitation is the lack of an approach for the assessment of mental con- tents that can be reliably applied under sedated conditions. Surrogate methods based on event-related responses to cog- nitive tasks may in part help overcome this obstacle. Future efforts should also focus on the determination of anesthetic- induced changes in directional or effective connectivity in local and large-scale networks as a means to better under- stand their necessary and sufficient role for modulating the state of consciousness. Multimodal measures of connectivity based on high-resolution fMRI/EEG/MEG, as well as animal models in which specific neuronal pathways may be experi- mentally manipulated, should aid the understanding of the basis of anesthetic modulation of consciousness.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Anthony G. Hudetz Department of Anesthesiology Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226
E-mail: [email protected]
br._j._anaesth.-2003-antognini-233-8-2.pdf |
British Journal of Anaesthesia 91 (2): 233±8 (2003) DOI: 10.1093/bja/aeg168
Spinal anaesthesia indirectly depresses cortical activity associated with electrical stimulation of the reticular formation
J. F. Antognini1,2*, S. L. Jinks1, R. Atherley1, C. Clayton1 and E. Carstens2
1Department of Anesthesiology and Pain Medicine and 2Section of Neurobiology, Physiology and Behavior, University of California, Davis, CA 95616 USA
*Corresponding author. E-mail: [email protected]
Background. Neuraxial blockade reduces the requirements for sedation and general anaes- thesia. We investigated whether lidocaine spinal anaesthesia affected cortical activity as deter- mined by EEG desynchronization that occurs following electrical stimulation of the midbrain reticular formation (MRF).
Methods. Six goats were anaesthetized with iso ̄urane, and cervical laminectomy performed to permit spinal application of lidocaine. The EEG was recorded before, during and after focal electrical stimulation (0.1, 0.2, 0.3 and 0.4 mA) in the MRF while keeping the iso ̄urane concen- tration constant.
Results. During lidocaine spinal anaesthesia, the spectral edge frequency (SEF) after MRF elec- trical stimulation (13.6 (SD 1.0) Hz, averaged across all stimulus currents) was less than the SEF during control and recovery periods (18.6 (3.6) Hz and 17.2 (2.2) Hz, respectively; P<0.05). Bispectral index values were similarly affected: 69 (10) at control compared with 55 (6) during the spinal block (P<0.05).
Conclusions. These results suggest that lidocaine spinal anaesthesia blocks ascending somato- sensory transmission to mildly depress the excitability of reticulo±thalamo±cortical arousal mechanisms.
Br J Anaesth 2003; 91: 233±8
Keywords: anaesthetic techniques, regional, subarachnoid; anaesthetics local, lidocaine; anaesthetics volatile, iso ̄urane; brain, reticular formation; theories of anaesthetic action, mechanisms
Accepted for publication: April 1, 2003
Neuraxial blockade is commonly used to abolish sensations elicited by noxious stimuli, particularly those occurring during a surgical procedure. Patients often receive sedation during these procedures, and occasionally the neuraxial block is combined with a general anaesthetic. Recent human and animal studies have documented that neuraxial block- ade reduces sedative requirements and the concentration of sevo ̄urane needed to achieve a bispectral (BIS) value of 50.1±4 The presumed underlying physiological mechanism is that the spinal anaesthetic blocks ascending somatosen- sory drive onto reticulo±thalamo±cortical projection path- ways, thereby reducing their excitability and hence decreasing the arousal level of the brain. This change in cortical arousability might reduce anaesthetic requirements for blockade of memory and consciousness. One measure of cortical activity is the EEG. The EEG changes in a
predictable way as anaesthetic concentration is increased, and includes a reduction in evoked responses to somato- sensory input. Stimulation of the midbrain reticular forma- tion (MRF) can `desynchronize' the EEG, such that it changes from a high-amplitude, low-frequency to a low- amplitude, high-frequency pattern, approaching that observed in the state of consciousness.5 We have recently used a differential anaesthetic delivery method in goats to investigate the indirect effects of iso ̄urane action in the torso (and hence spinal cord) on the ef®cacy of electrical MRF stimulation to alter the EEG.6 We found that MRF stimulation was more likely to desynchronize the EEG when the torso iso ̄urane concentration was low as compared with when it was high.6 In the present study we hypothesized that spinal lidocaine, by blocking ascending somatosensory transmission, would similarly reduce the ef®cacy (i.e. raise
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003
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the current threshold) of MRF stimulation to desynchronize the EEG.
Methods
This study was approved by the University of California, Davis Animal Care and Use committee. Goats were chosen as the experimental species to enable comparison with our earlier study.6 Six female goats weighing 51 (SD 8) kg were anaesthetized with iso ̄urane via mask, intubated and mechanically ventilated. An i.v. catheter was inserted into a forelimb vein for infusion of lactated Ringer's solution. Rectal temperature was measured and maintained at 37.8 (0.8) °C. A craniotomy was performed to permit insertion of stimulating electrodes. A cervical laminectomy was per- formed and the dura incised, exposing the upper cervical spinal cord. Following surgery, pancuronium 0.15±0.2 mg kg±1 was administered i.v. and repeated every 2±3 h. End- tidal carbon dioxide was maintained at 34 (5) mm Hg and PAO2 was periodically measured to ensure values greater than 200 mm Hg.
The methods for recording EEG and stimulating the MRF have been described previously6 and are reiterated in brief here. The head was secured in a stereotaxic frame and a bipolar stimulating electrode (Frederick Haer, Inc., Bowdoinham, ME, USA) was stereotaxically positioned in the MRF (0±3 mm rostral to interaural line, 5±7 mm lateral to midline, 30±32 mm below surface of the cortex). The bifrontal EEG was monitored using platinum needle elec- trodes inserted into the periosteum overlying the frontal bones. The EEG was ampli®ed (Model 8±10E, Grass Instruments, Quincy, MA, USA), ®ltered (0.3±35 Hz) and digitized using a commercial program (PolyViewPro, Astro-Med, West Warwick, RI, USA). In addition, we monitored the bifrontal EEG using an Aspect-1000 BIS monitor (Aspect Medical Systems, Newton, MA, USA). Processed EEG data (BIS, spectral edge frequency (SEF) 95% (SEF95)) were downloaded to a personal computer. These data represented averages of 5-s epochs. The BIS and SEF correlate with anaesthetic depth in the goat.7
The MRF stimulation paradigm consisted of a 2-s train of 0.1-ms pulses delivered at 300 Hz, at intervals of 2±4 min. The current intensities were 0.1, 0.2, 0.3 and 0.4 mA. The iso ̄urane concentration was adjusted to permit EEG desynchronization and this varied from animal to animal (mean 1.7%, range 1.5±2%), but once we established that EEG desynchronization could be produced in an animal the iso ̄urane concentration was held constant.
The EEG data were collected for the 1-min periods before and after the onset of electrical stimulation. The BIS monitor used a rolling average with a 15-s delay. We analysed the EEG data for the 30-s periods immediately preceding and following onset of the electrical stimulus. We averaged the six 5-s epochs to determine the average value for each period. We waited 2±4 min between stimuli to permit the EEG to return to baseline. After collection of
control data, lidocaine 4% was microinjected into the upper cervical cord (approximate C2 level). In brief, several passes were made into each quadrant with a 30g needle attached to a microsyringe (Hamilton) and a total of 25 ml was injected (approximately 6 ml in each quadrant).8 We then placed lidocaine 4%, 2 ml over the cord, followed by iced saline, which was replaced periodically. These three techniques were used to ensure an adequate spinal block. This was manifested by an expected decrease in mean arterial pressure (MAP), which was treated by administra- tion of warm crystalloid and occasional phenylephrine. The MAP was 99 (27) mm Hg before the block and 66 (14) mm Hg when MRF stimulation was performed during the block. A cloth tie placed around the dura surrounding the spinal cord prevented lidocaine and saline from travelling rostrally to the brainstem and brain. In some animals the ef®cacy of the lidocaine/cold spinal block was veri®ed by an absence of EEG desynchronization in response to noxious stimulation of a fore or hind foot that had elicited EEG desynchroniza- tion before the lidocaine block. The MRF stimulation paradigm was repeated 10±15 min after instillation of the lidocaine and iced saline, after which the iced saline and lidocaine were removed to permit recovery. The MRF stimulation was repeated 1±2 h after the spinal block to document recovery. In one animal we repeated the MRF stimulation paradigm before and after administration of nitroprusside (titrated to MAP 45±55 mm Hg) to determine if hypotension might affect the EEG response, while in another goat we microinjected cerebrospinal ̄uid (CSF) intraspinally to determine if the microinjection technique itself affected the response. In two animals the spinal cord was anaesthetized again with lidocaine and iced saline, the cord frozen with dry ice, followed by complete transection with scissors. The MRF stimulation was then repeated. This ensured complete deafferentation below the spinal cord transection.
Following data collection, a lesion was made at the MRF stimulation site by passing direct current through the stimulating electrode, and the animal was killed using additional iso ̄urane and i.v. potassium chloride. The brain was removed, ®xed in formalin, and cut into 50-mm frozen sections to microscopically verify the MRF lesion site. Technical problems prevented us from recovering sites in all animals; however, the coordinates used have, in previous studies, consistently placed electrodes in the MRF.6 9
Data are expressed as mean (SD). An `area under the curve' analysis was used to evaluate SEF95 and BIS values (before and after stimulation) at each anaesthetic condition (control, spinal block, recovery).6 10 11 For example, for each experimental condition (i.e. control pre-spinal lido- caine; during spinal block, and recovery), the SEF values after MRF stimulation at each current intensity were summed and compared with the summed SEF values in the absence of MRF stimulation. These values were compared across experimental conditions using ANOVA followed by a Student±Newman±Keuls post-hoc test.
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Spinal lidocaine and cortical activity
Fig 1 These individual examples of the EEG at different stimulating currents (0.1±0.3 mA) and during different anaesthetic conditions demonstrate that lidocaine spinal anaesthesia affected the propensity for EEG desynchronization. Before application of spinal lidocaine (control), the EEG was easily desynchronized by electrical stimulation of the MRF (2-s duration, dotted line) while during a spinal block EEG desynchronization was more dif®cult to achieve. The recovery EEG again showed signi®cant desynchronization at the lowest electrical current. The inset shows the stimulating site. RF, reticular formation; PAG, periaqueductal gray.
P<0.05 was considered signi®cant. We chose to sum data points across stimulation currents primarily because we were interested in changes in overall sensitivity rather than changes at a speci®c stimulation current. We also analysed whether MAP correlated with the evoked BIS and SEF values for control, spinal block and recovery periods combined. In brief, evoked BIS values at each stimulus current were summed and correlated with the MAP at which the values were obtained. A similar analysis was performed for SEF.
Results
Before spinal anaesthetic block, electrical stimulation of the MRF resulted in EEG desynchronization which was mani- fest as increases in BIS and SEF (Figs 1 and 2). A measurable desynchronization often occurred at the lowest stimulating current (0.1 mA) and became more pronounced as the stimulating current was increased. During spinal anaesthetic block, MRF stimulation was less ef®cacious in eliciting EEG desynchronization. Signi®cant increases in the BIS and SEF were not observed until the MRF stimulation current was at 0.3±0.4 mA, and the magnitude of change was lower. Recovery occurred 1±2 h after the spinal block was initiated.
Under control conditions before spinal block, SEF95 after MRF electrical stimulation was greater than after MRF stimulation in the presence of spinal block (18.6 (3.6) Hz vs 13.6 (1.0) Hz, summed and averaged across all stimulus currents; P<0.05). Similarly, BIS was signi®cantly greater before spinal block than during spinal block (69 (10) vs 55 (6), P<0.05). The mean post-stimulation SEF95 and BIS
values (summed across all current intensities) were lower during spinal block than control (pre-block) and recovery (post-block) conditions (Fig. 2). Moreover, the current threshold to elicit increased SEF95 or BIS (Fig. 2) tended to be lower (»0.1 mA) during the pre-block condition compared with the period during spinal blockade (0.3±0.4 mA). The spinal block appeared to be effective, as demonstrated by the lack of EEG response to noxious stimulation (Fig. 3). In another animal in which CSF instead of lidocaine was injected intraspinally, EEG responses to MRF stimulation were unaffected (Fig. 3). Complete transection of the spinal cord yielded results similar to lidocaine block (Fig. 3). Nitroprusside-induced hypotension (MAP »50 mm Hg) only slightly reduced the evoked BIS response (averaged over the 0.2, 0.3 and 0.4 mA currents), from 68 to 64. The latter value was well above the average evoked BIS value (53) for the same current intensities during spinal block. The summed evoked BIS and SEF values did not correlate with MAP (r2=0.06 for the BIS±MAP, r2=0.08 for the SEF±MAP; P>0.05).
Discussion
We found that spinal cord anaesthesia using lidocaine indirectly affected the EEG desynchronization response to electrical stimulation of the MRF. This suggests that the arousal state of the brain is altered during spinal anaesthesia and that sedative and anaesthetic requirements (to depress brain arousal) will be lower during a spinal anaesthetic.
The present ®ndings are consistent with our recent report using differential delivery of iso ̄urane to the cranial and torso (and hence spinal) circulation in goats.6 In this latter
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Antognini et al.
Fig 2 Spectral edge frequency (SEF95) and bispectral index (BIS) values before and after electrical stimulation plotted at each electrical current applied to the midbrain reticular formation during control, lidocaine spinal block and recovery conditions. The iso ̄urane concentration was 1.7 (0.2)%. The electrical current during the control and recovery periods was associated with EEG desychronization, as seen in the greater BIS and SEF values (*P<0.05 compared with pre-stimulus curve; **P<0.05 compared with curve during spinal block). Data are mean (SD).
study,6 electrical MRF stimulation elicited EEG desynchro- nization (assessed by increased SEF and BIS values) at signi®cantly lower current intensities when the iso ̄urane concentration delivered to the torso was low (~0.3%) compared with when it was high (~1.2%). Thus, two different means of inducing spinal anaesthesia result in a reduced ef®cacy to elicit cortical activation by MRF stimulation. This indirect, spinally mediated reduction in the excitability of reticulo±thalamo±cortical `arousal' mechanisms may partly account for our ®nding that increased torso concentrations of volatile or injected anaesthetic agents blunt cortical EEG desynchronization in response to peripheral noxious stimuli.9 12 13
Previous studies have shown that neuraxial blockade using local anaesthetics has indirect effects on sedative requirements. Ben-David and colleagues1 found that mid- azolam requirements were decreased in patients receiving spinal anaesthesia. In rats recieving spinal bupivicaine, less thiopental was required for sedation and for blocking responses to noxious stimuli applied above the level of the block.2 Spinal anaesthesia appears to have sedative effects.3 In humans, epidural lidocaine anaesthesia decreased the concentration of sevo ̄urane required to achieve a BIS value of 50.4 Thus, blocking ascending somatosensory transmis- sion appears to reduce reticulo±thalamo±cortical arousa- bility, consistent with reduced anaesthetic requirements to achieve unconsciousness.
We propose the following mechanism by which spinal anaesthesia affects the excitability of reticulo±thalamo± cortical arousal systems. First, local anaesthetics such as
lidocaine block the sodium channel and thereby prevent propagation of action potentials along the axon. The spinal anaesthetic would therefore be expected to reduce ascend- ing transmission of impulses from spinal cord neurones to the brainstem reticular formation and other supraspinal centres. This would presumably lead to reduced synaptic release of excitatory neurotransmitters such as glutamate. Previous studies from our laboratory14 15 and others16 have shown that a variety of anaesthetic agents reduce both spontaneous and evoked responses of nociceptive and non- nociceptive dorsal horn neurones. Importantly, systemic administration of thiopental was recently shown to signi®- cantly depress the spontaneous ®ring of spinoreticular and dorsal spinocerebellar tract neurones identi®ed by anti- dromic stimulation.17 Furthermore, such a reduction in ascending spinoreticular activity presumably reduces the excitability of target neurones in the brainstem reticular formation. Consistent with this, using differential iso ̄urane delivery in goats we have shown that excitatory responses of neurones in the MRF9 or medial thalamus12 to noxious stimuli were signi®cantly greater when the torso iso ̄urane concentration was 0.3% than when it was 1.2%. Moreover, differential delivery of propofol to the torso signi®cantly depressed nociceptive responses of MRF neurones.13 These ®ndings suggest that a reduction in ascending somatosen- sory traf®c by spinal anaesthetics decreases the excitability of MRF and medial thalamic neurones, while increased ascending traf®c increases their excitability. We speculate that excitatory afferent input onto MRF neurones maintains them in a relatively depolarized and hence more excitable
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Fig 3 (A) Microinjection of cerebrospinal ̄uid (CSF) into the spinal cord did not affect the EEG response to midbrain reticular formation electrical stimulation (0.1 mA at dotted line). Transecting the spinal cord, however, did decrease the response to MRF stimulation. (B) A clamp applied to the forelimb before spinal block evoked EEG desynchronization while no such response occurred during spinal block. The large wide swings in the EEG just before and during clamp application are artefacts.
state, raising the probability that they will ®re action potentials when subjected to intracranial electrical stimula- tion. Reduced afferent input via spinal anaesthesia would reduce the excitability of MRF cells, lowering their probability of ®ring. A further requirement of our proposed mechanism is that at least some of the MRF and medial thalamic neurones that receive input from spinal neurones participate in neural systems involved in regulating activity in cortical and subcortical neurones (the `ascending reticular activating system').18 These cortical and subcortical neurones would thereby be more sensitive to anaesthetics such as iso ̄urane. The exact mechanism by which general anaesthetics produce their effects is unknown. However, effects at the gamma-aminobutyric acid receptor are thought to be important, at least as regards amnesia and loss of consciousness, although effects at other receptors (e.g. glutamate receptors) might be involved.19 The present
report, combined with other animal studies2 and studies in humans,1 3 4 strongly suggest that neuraxial blockade reduces sedative and anaesthetic requirements by `deaf- ferentation' (i.e. decreased ascending sensory input into the brain). This has important clinical implications, as anaes- thetists should expect to reduce anaesthetic and sedative drug doses during neuraxial blockade, unless the blockade involves lower dermatomes alone. In this latter setting the neuraxial blockade might have less effect on sedative requirements, as sensory information from higher derma- tomes would be expected to reach the brain and increase arousal.
We performed intraspinal microinjections in addition to topical application of lidocaine because deeper ®bre tracts that transmit ascending somatosensory information might have been otherwise variably affected by topical application alone.20 We cannot exclude the possibility that some ascending somatosensory information reached the brain, although responses to noxious stimulation appeared to be abolished (Fig. 3B). Furthermore, the hypotension that followed spinal block might have contributed to the effect on evoked responses, but the minimal effect of nitroprus- side-induced hypotension suggests that hypotension could not account for all of the effects on the EEG response to MRF stimulation. Finally, MAP did not correlate with evoked BIS or SEF, indicating that changes in MAP were not a major factor in our results.
We do not believe that local effects of lidocaine or iced saline on blood vessels are likely to be important factors. The goat has a unique cerebral circulation in that the vertebral arteries do not contribute to cerebral circulation. In fact, blood normally ̄ows from the brain and brainstem to the spinal cord via the basilar artery.21 In addition, any lidocaine entering the venous system would be transported to the systemic circulation where it would be greatly diluted. It seems unlikely that any lidocaine would be transported to the brainstem via the local venous system.
In summary, we found that spinal lidocaine anaesthesia decreased cortical activity, as measured by EEG changes induced by electrical stimulation of the reticular formation. This effect is consistent with other studies suggesting that spinal anaesthesia decreases sedative and anaesthetic requirements.
Acknowledgements
Supported in part by NIH GM57970 and GM61283 to JFA and NRSA NS43935±01 to SLJ.
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