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. 2024 Jun 11;141(1):162–171. doi: 10.1213/ANE.0000000000007114

Distinct Neural Mechanisms Between Anesthesia Induction and Emergence: A Narrative Review

Donghang Zhang *,†,✉, Yiyong Wei ‡
PMCID: PMC12140560  PMID: 38861419

Abstract

Anesthesia induction and emergence are critical periods for perioperative safety in the clinic. Traditionally, the emergence from general anesthesia has been recognized as a simple inverse process of induction resulting from the elimination of general anesthetics from the central nervous system. However, accumulated evidence has indicated that anesthesia induction and emergence are not mirror-image processes because of the occurrence of hysteresis/neural inertia in both animals and humans. An increasing number of studies have highlighted the critical role of orexinergic neurons and their involved circuits in the selective regulation of emergence but not the induction of general anesthesia. Moreover, additional brain regions have also been implicated in distinct neural mechanisms for anesthesia induction and emergence, which extends the concept that anesthetic induction and emergence are not antiparallel processes. Here, we reviewed the current literature and summarized the evidence regarding the differential mechanism of neural modulation in anesthesia induction and emergence, which will facilitate the understanding of the underlying neural mechanism for emergence from general anesthesia.

The emergence of general anesthesia has once been thought to be a simple inverse process of induction resulting from the elimination of general anesthetics. However, the existence of hysteresis/neural inertia, an intrinsic tendency of the central nervous system to resist transitions between unconscious and conscious states, provides evidence that anesthesia induction and emergence are not mirror-image processes.1 Notably, hysteresis/neural inertia cannot be solely explained by pharmacokinetics but can be affected by genetic and pharmacologic manipulation in flies and mice.1,2 This phenomenon is also observed in humans when comparing dose responses of slow-wave activity or functional magnetic resonance imaging (fMRI) signals between anesthesia induction and emergence,3,4 indicating that asymmetric neural dynamics exist between induction and emergence and cannot solely result from pharmacokinetic effects. These findings provide important evidence that the induction and emergence of general anesthesia are not simple antiparallel processes, but the underlying neural mechanism is not well understood.

General anesthesia shares the common feature of reversible loss of consciousness with natural sleep.5–7 Current evidence has shown that many brain nuclei and circuits that regulate sleep-wake behaviors are also associated with the actions of general anesthetics,6–9 suggesting that a shared neural mechanism exists between sleep-wake cycles and general anesthesia. Orexinergic neurons play a critical role in maintaining wakefulness,10 and earlier data showed that exogenous administration of orexin facilitated the emergence of general anesthesia in rats.11,12 Kelz et al13 reported that orexinergic neurons selectively regulate emergence but not the induction of volatile anesthesia, which provided the earliest evidence that anesthesia induction and emergence are not mirror-image processes. Since then, many orexinergic neuron-involving circuits have been found to selectively modulate emergence from general anesthesia. On the other hand, several brain regions were reported to be solely associated with anesthetic induction. For example, the gamma-aminobutyric acid (GABA) levels in the pontine reticular formation (PnO) were related to propofol induction but not to the emergence period. 13 In recent years, an increasing number of studies have revealed that more brain nuclei and circuits, as well as neuron types, play different roles in anesthesia induction and emergence, which supports the concept that distinct neurobiology underlies anesthesia induction and emergence. Interestingly, there is divergence in the selective modulation of emergence among diverse groups of general anesthetics, even among subclasses of the same type. In this review, we summarize the evidence of the distinct neural mechanisms involved in anesthesia induction and emergence (Table and Figure), which may provide new insights into the emergence of anesthesia from general anesthesia.

Table.

Study Characteristics

Study Animals Sex Anesthetics Brain region Behavioral indicators Effects on induction period Effects on emergence period
Kelz et al14 Mice Both Isoflurane and sevoflurane PeFLHOrx Induction time; emergence time; EC50 No change Inhibition of PeFLHOrx delays emergence
Zhao et al15 Rats Male Isoflurane PeFLHOrx-PVT Induction time; emergence time; EC50 No change Activation of PeFLHOrx-PVT accelerates emergence
Yang et al16 Rats Male Isoflurane DRNSer Induction time; emergence time No change Activation of DRNSer accelerates emergence
Li et al17 Rats and mice Male Isoflurane DRNSer Induction time; emergence time No change Activation of DRNSer accelerates emergence
Ma et al18 Mice Male Sevoflurane DRNSer Induction time; emergence time No change Activation of DRNSer accelerates emergence
Li et al19 Rats Male Isoflurane PeFLHOrx-VTADA Induction time; emergence time No change Activation of PeFLHOrx-VTADA accelerates emergence
Zhang et al20 Rats Male Isoflurane BFOrx Induction time; emergence time No change Activation of BFOrx accelerates emergence
Dong et al21 Rats Male Sevoflurane BFOrx Induction time; emergence time No change Activation of BFOrx accelerates emergence
Wang et al22 Rats Male Isoflurane PeFLHOrx-BF, PeFLHOrx-LC Induction time; emergence time No change Activation of PeFLHOrx-BFOrx or PeFLHOrx-LC accelerates emergence
Cai et al23 Mice Male Isoflurane BFPV Induction time; emergence time Activation of BFPV delays induction No change
Ao et al24 Mice Male Isoflurane LCTH-PVT Induction time; emergence time No change Activation of LCTH-PVT accelerates emergence
Bu et al25 Mice Male Isoflurane PVTGlu Induction time; emergence time No change Activation of PVTGlu accelerates emergence
Zhou et al26 Mice Male Sevoflurane LHOrx-LHbGABA Induction time; emergence time No change Activation of LHOrx-LHbGABA accelerates emergence
Shirasaka et al27 Rats Male Propofol PFCOrx Induction time; emergence time No change Activation of PFCOrx accelerates emergence
Liu et al28 Mice Male Propofol TRNGABA Induction time; emergence time No change Activation of TRNGABA accelerates emergence
Lu et al29 Mice Male Isoflurane PBN-LH, PBN-BF Induction time; emergence time No change Activation of PBN-LH or PBN-BF accelerates emergence
Luo et al30 Rats Male Propofol and isoflurane PBN Induction time; emergence time No change Activation of PBN accelerates emergence
Fu et al31 Rats Male Propofol CMTGABA Induction time; emergence time; ED50 No change Activation of CMTGABA accelerates emergence
Yang et al32 Mice Male Isoflurane OTDA Induction time; emergence time No change Activation of OTDA accelerates emergence
Zhang et al33 Mice Male Sevoflurane NAcD1R-VP Induction time; emergence time No change Activation of NAcD1R-VP accelerates emergence
Niu et al34 Mice Male Sevoflurane NAcD2R-VP Induction time; emergence time Activation of NAcD2R-VP accelerates induction No change
Liu et al35 Mice Male Sevoflurane SCN Induction time; emergence time No change Activation of SCN accelerates emergence
Vanini et al13 Rats Male Propofol or isoflurane PnOGABA Induction time; emergence time Activation of PnOGABA delays induction No change
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Abbreviations: BFOrx, orexinergic terminals in basal forebrain; CMTGABA, GABAergic neurons of central medial thalamic nucleus; DRNSer, serotonergic neurons of dorsal raphe nucleus; EC50, the concentration or dose at which 50% of the animals lost or recoverd their righting reflex; LCOrx, orexinergic terminals in locus coeruleus; LHOrx, orexinergic neurons of lateral hypothalamus; LHbGABA, GABAergic neurons of lateral habenula; NAcD1R, dopamine D1-receptor neurons of nucleus accumbens; NAcD2R, dopamine D2-receptor neurons of nucleus accumbens; OTDA, dopaminergic terminals of olfactory tubercle; PBN, parabrachial nucleus; PeFLHOrx, orexinergic neurons of perifornical lateral hypothalamic area; PFCOrx, orexinergic terminals in prefrontal cortex; PnO, pontine reticular formation; PV, parvalbumin neurons; PVTGlu, glutamatergic neurons of paraventricular thalamic nucleus; SCN, suprachiasmatic nucleus; TH, tyrosine hydroxylase; TRNGABA, GABAergic neurons of thalamic reticular nucleus; VP, ventral pallidum; VTADA, dopaminergic neurons of ventral tegmental area.

Figure.

Figure.

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Sagittal section of the rodent brain showing the nuclei and circuits with selective modulation during anesthesia induction and emergence from general anesthesia. BF, basal forebrain; CMTGABA, GABAergic neurons of the central medial thalamic nucleus; DRNSer, serotonergic neurons of the dorsal raphe nucleus; Iso, isoflurane; LC, locus coeruleus; LHOrx, orexinergic neurons of the lateral hypothalamus; LHbGABA, GABAergic neurons of the lateral habenula; OTDA, dopaminergic terminals of the olfactory tubercle; PBN, parabrachial nucleus; PeFLHOrx, orexinergic neurons of the perifornical lateral hypothalamic area; PFC, prefrontal cortex; PnO, pontine reticular formation; Pro, propofol; PVTGlu, glutamatergic neurons of the paraventricular thalamic nucleus; SCN, suprachiasmatic nucleus; Sevo, sevoflurane; TRNGABA, GABAergic neurons of the thalamic reticular nucleus; VP, ventral pallidum; VTADA, dopaminergic neurons of the ventral tegmental area.

The original studies that reported differential effects of general anesthetics on the EC50 (the concentration or dose at which 50% of the animals lost or recovered their righting reflex) between loss of righting reflex (LORR) and recovery of righting reflex (RORR) were included. Considering that only a limited number of studies14,15,31 have reported the EC50 of LORR or RORR, we also included studies with outcomes of induction and emergence time.

ROLE OF OREXINERGIC NEURONS IN THE LATERAL HYPOTHALAMUS (LH) UNDER GENERAL ANESTHESIA

Orexinergic neurons, located exclusively in the lateral hypothalamus (LH), mainly help to maintain wakefulness, while the loss of orexinergic neurons causes narcolepsy.10,36 In 2008, Kelz and colleagues first provided evidence that orexinergic neurons in the perifornical hypothalamus selectively regulate emergence from volatile anesthesia.14 Isoflurane and sevoflurane inhibited the activity of orexinergic neurons in the perifornical hypothalamus.14 Notably, genetic ablation of orexinergic neurons or systemic administration of a selective orexin-1 receptor antagonist delayed emergence time without affecting the induction time or EC50 of the LORR.14 This study proposed the notion that the neural circuits governing anesthetic induction and emergence might be distinct. Zhao et al15 also reported the differential modulatory role of orexinergic neurons in the perifornical lateral hypothalamic area (PeFLH) in isoflurane induction and emergence in rats. The activation of PeFLH orexinergic neurons decreased the recovery time from isoflurane and increased the EC50 of the RORR, whereas the inhibition of PeFLH orexinergic neurons prolonged emergence without affecting the induction time or EC50 of the LORR.15 Taken together, the current evidence indicates that orexinergic neurons play an important role in the selective modulation of emergence from volatile anesthesia. However, the activity of orexinergic neurons remains unchanged during halothane anesthesia, and the induction and emergence from halothane anesthesia do not change in orexin-deficient mice,37 suggesting that other wake-promoting regions or circuits but not the orexin system regulate the emergence from halothane anesthesia.

ROLE OF PROJECTIONS INVOLVING OREXINERGIC NEURONS UNDER GENERAL ANESTHESIA

Many regions, including the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), basal forebrain (BF), locus coeruleus (LC), paraventricular thalamic nucleus (PVT), lateral habenula (LHb), and prefrontal cortex (PFC), have been found to mediate the selective modulation of orexinergic neurons during emergence from general anesthesia.

The DRN, located in the brainstem, mainly sends serotonergic inputs to the forebrain and regulates diverse functions or diseases, such as stress, anxiety, sociability, temperature, sensory and motor functions, and sleep-wakefulness.38–40 Yang et al16 reported that serotonergic neurons in the DRN mediate the emergence-promoting effects of orexinergic neurons. Injecting orexin-A into the DRN promoted emergence from isoflurane anesthesia in rats, whereas injection of an orexin receptor type 1 antagonist prolonged emergence. However, neither orexin-A nor an orexin receptor type 1 antagonist influenced isoflurane induction.16 Additionally, they showed that isoflurane inhibited the activities of serotonergic neurons in the DRN, which could be partially reversed by orexin-A injection.16 However, this study did not directly manipulate the activities of serotonergic neurons in the DRN to observe the responses to isoflurane anesthesia. Moreover, the activity of serotonergic neurons was detected via c-Fos staining but not via real-time imaging. Two studies17,18 also revealed the differential role of DRN serotonergic neurons in the induction and emergence of volatile anesthesia. Li et al17 used both c-Fos staining and fiber photometry to show that the activity of DRN serotonergic neurons gradually decreased under isoflurane exposure but recovered before emergence occurred, suggesting a close relationship between the activity of DRN serotonergic neurons and consciousness levels under isoflurane anesthesia. Activation of DRN serotonergic neurons facilitates emergence from isoflurane anesthesia, whereas inhibition prolongs emergence without affecting induction time.17 Similar findings were observed under sevoflurane anesthesia.18 These 3 studies16–18 suggested that DRN serotonergic neurons selectively regulate emergence from volatile anesthesia, which is at least partially modulated by serotonergic inputs. However, whether this phenomenon occurs for other types of general anesthetics, such as propofol, needs to be determined in future studies.

The VTA, a midbrain region that contains a large proportion of dopaminergic neurons, is well known for modulating reward,41 addictions,42 negative emotions,41 and sleep-wakefulness cycles.43 Similar to previous findings in the DRN,16 injecting orexin-A into the VTA19 also promoted emergence from isoflurane anesthesia in rats, whereas injection of an antagonist of the orexin-1 receptor delayed emergence. However, neither orexin-A nor antagonists of the orexin-1 receptor altered the induction time of isoflurane anesthesia. The authors also showed that orexin-A enhanced the firing frequency of dopaminergic neurons in the VTA,19 suggesting that dopaminergic neurons in the VTA partially mediate the emergence-promoting effects of the orexin system.19

The BF mainly sends cholinergic projections and is implicated in sleep-wakefulness, cognition, learning, sensory signaling, and Alzheimer’s and Parkinson’s diseases.44–48 Previous studies have shown that injecting orexin-A into the BF selectively accelerated emergence from isoflurane20 and sevoflurane anesthesia.21 Consistently, activation of orexinergic terminals in the BF promoted the emergence of isoflurane anesthesia without affecting induction.22 In addition to orexin-A, the administration of histamine to the nucleus basalis magnocellularis of the BF facilitated the emergence of isoflurane anesthesia in rats,49 suggesting the contribution of the histaminergic pathway in the BF to the emergence from isoflurane anesthesia. However, they did not assess whether the induction process was changed.49 Unlike orexinergic signaling, activation of GABAergic neurons in the BF influences both isoflurane induction and emergence processes, as evidenced by increased induction time and decreased emergence time in mice.50 The role of 2 common subtypes of GABAergic neurons in the BF, namely, somatostatin (SOM)- and parvalbumin (PV)-expressing neurons, in general anesthesia was further studied.23 Activation of SOM neurons shortened the induction time and prolonged the emergence time of isoflurane anesthesia. However, the activation of PV neurons prolonged the induction time but did not affect the emergence time of mice under isoflurane anesthesia, suggesting the selective modulation of isoflurane emergence by BF PV neurons. Nevertheless, the effects of PV neurons on the EC50 of RORR should be determined to confirm this conclusion.

The LC, which mainly contains norepinephrine (NE) neurons, projects noradrenergic outputs throughout the central nervous system and primarily regulates arousal.51 As in the BF, activation of orexinergic terminals in the LC facilitated emergence from isoflurane anesthesia without affecting induction.22 Interestingly, plasma concentrations of orexin-A were elevated during emergence from isoflurane anesthesia.20 In the clinic, evidence has shown that plasma orexin-A levels increase in surgical patients during the emergence of sevoflurane52,53 or propofol53 anesthesia but do not change during induction. Therefore, plasma orexin-A levels might be a novel indicator of consciousness during the emergence period of general anesthesia. However, manipulation of the noradrenergic system of the LC affected both the induction and emergence of isoflurane anesthesia.54 The activation of LC-NE neurons induced cortical activation on electroencephalography (EEG), delayed isoflurane induction, and facilitated emergence, which was prevented by treatment with α1 or β noradrenergic antagonists.54 There is also a significant proportion of tyrosine hydroxylase (TH) neurons in the LC. Ao et al24 investigated the role of TH neurons in the LC under isoflurane anesthesia. They showed that the activity of LC TH neurons increased during emergence from isoflurane anesthesia. Activation of LC TH neurons or their projections to the PVT facilitated emergence and induced cortical activation, whereas inhibition produced the opposite effects. However, the induction time was not affected by manipulating the LC TH-PVT projection.24

The PVT, a glutamatergic node, regulates many important behaviors, such as motivation and reward,55 fear,56 drug addiction,57 and sleep-wakefulness.58 Activation of PVT neurons induces wakefulness from sleep, whereas inhibition of PVT neurons suppresses wakefulness.58 The PVT is also an effective downstream signal that mediates the selective emergence-promoting effects of PeFLH orexinergic neurons under isoflurane anesthesia.15 However, the PeFLH-PVT circuit regulates both the induction and emergence of desflurane anesthesia.15 Bu et al25 also reported that activation of PVT glutamatergic neurons accelerated the emergence of isoflurane anesthesia in mice without affecting the induction process. Using fiber photometry, they showed that the Ca2+ signals gradually decreased after isoflurane inhalation and began to increase before RORR occurred but merely recovered to the approximate level of that at LORR after emergence. These results provide direct evidence for the theory of anesthetic hysteresis/neural inertia. However, a longer recording time is necessary to determine whether the activity will return to the baseline level before anesthesia, which could exclude the possibility of signal decay. Similarly, Ren et al58 demonstrated that activation of PVT glutamatergic neurons shortens the emergence time from isoflurane anesthesia in mice, but they did not test whether the induction process is affected. Notably, previous studies have indicated that PVT activity is associated with both the induction and emergence of sevoflurane59,60 and propofol anesthesia,61 indicating that the neuronal effectors of action of other types of general anesthetics are distinct from those of isoflurane.

The LHb, located at the posterior-dorsal-medial end of the thalamus, serves as a key region in the pathophysiology of several psychiatric disorders, especially major depression.62 The LHb receives LH orexinergic inputs, and activation of the projection from LH orexinergic neurons to LHb glutamate decarboxylase (GAD2)-expressing neurons shortens the emergence time of sevoflurane anesthesia, whereas inhibition of this pathway prolongs emergence time without affecting induction time.26

The PFC is considered to serve as the highest center for neural integration and is related to numerous important functions or disorders, such as emotions, reward, decision-making, cognition, motor functions, psychopathology, sleep, and wakefulness.63–65 In addition to volatile anesthetics, the orexin system also regulates the general anesthesia induced by propofol. Shirasaka et al27 reported that the injection of orexin-A in the PFC promoted the emergence of propofol, whereas the administration of an orexin-1 receptor antagonist prolonged the emergence time without affecting the induction time. Therefore, orexinergic neurons serve as common targets of both volatile and intravenous anesthetics to regulate emergence. They further showed that the orexin system may facilitate the emergence of propofol by inducing the release of NE and dopamine (DA) to enhance the noradrenergic and dopaminergic activity of the PFC.27

OTHER BRAIN REGIONS THAT DIFFERENTIALLY REGULATE ANESTHESIA INDUCTION AND EMERGENCE

Many brain regions have been found to differentially regulate anesthesia induction and emergence, although whether these differences are mediated by orexinergic inputs remains unclear. These regions included the thalamic reticular nucleus (TRN), parabrachial nucleus (PBN), central medial thalamic nucleus (CMT), olfactory tubercle (OT), ventral pallidum (VP), suprachiasmatic nucleus (SCN), and PnO.

The TRN is primarily composed of GABAergic neurons and is associated with the regulation of sensory processing,66 emotions,67 attention,68 learning and memory,68 neurodevelopmental disorders,69 and sleep-wakefulness behaviors.70,71 Liu et al28 explored the role of the anterior TRN in propofol anesthesia in mice. They found that the activities of GABAergic neurons in the anterior TRN were inhibited after propofol infusion but gradually increased before RORR occurred. However, it remains unclear whether the activity at the RORR exhibited a full return to its preanesthetic baseline. Activation of GABAergic neurons in the anterior TRN promoted emergence from propofol anesthesia, whereas inhibition of these neurons delayed emergence. However, manipulation of TRN GABAergic neurons did not affect induction time. Interestingly, 1 study50 showed that activation of GABAergic terminals in the TRN prolonged isoflurane induction and accelerated emergence in mice. However, activation of noradrenergic terminals in the TRN delays the emergence of propofol anesthesia and promotes the induction process.72 Therefore, the distinct modulatory effects on induction and emergence in the TRN might depend on the type of neuronal population and the diverse groups of general anesthetics used. Notably, the circuits involved in TRN GABAergic neurons under propofol anesthesia have not been elucidated. Moreover, the role of other subregions of the TRN73 in general anesthesia also needs to be addressed in future studies.

The PBN, located in the pons, plays a role in regulating many behaviors, such as sensory transmission,74,75 defensive behaviors,76 feeding,77 and emotions.78 The PBN is also a well-known wake-promoting brain region.79 However, evidence regarding the differential effects of PBN on anesthesia induction and emergence is mixed. Lu et al29 investigated the role of PBN-related projections under isoflurane anesthesia in mice. Optogenetic activation of the PBN-LH or PBN-BF pathway shortened the emergence time from isoflurane anesthesia without affecting the induction time. An increase in the number of PBN projections might be associated with the distinct modulatory effects of isoflurane anesthesia on induction and emergence. Similarly, Luo et al30 reported that activation of the PBN promoted the emergence of both propofol and isoflurane anesthesia without affecting the induction time. Muindi et al80 also reported that electrical stimulation of the PBN could induce reanimation from isoflurane anesthesia in mice. However, the neuronal populations in the PBN that regulate emergence should be determined because a previous study showed that activation of PBN glutamatergic neurons accelerated the emergence of sevoflurane and prolonged the induction time.81

The CMT, a member of the limbic thalamus, participates in processing nociceptive signals as well as their related negative emotions.82 Consistent with the results in the PFC,27 Fu et al31 reported that microinjection of NE into the CMT facilitated the emergence of propofol anesthesia but did not affect the induction time or EC50 of the LORR. Propofol enhances GABAergic transmission in CMT slices, which is partially reversed by the application of NE.31 Hence, the noradrenergic system was suggested to play a role in the selective regulation of propofol emergence.

In addition to olfaction, the OT also regulates learning, motivated behaviors, and drug seeking.83 The OT receives dense inputs from dopaminergic neurons via several nuclei, such as the VTA.84 Yang et al32 reported that local injection of D1 receptor (D1R) and D2R agonists into the OT accelerated the emergence from isoflurane anesthesia, while injection of antagonists of D1R and D2R prolonged the recovery time. Optogenetic activation of dopaminergic terminals in the OT also promoted the emergence of isoflurane anesthesia. However, D1R/D2R agonists, D1R/D2R antagonists, or optogenetic stimulation of dopaminergic terminals in the OT did not affect anesthesia induction. This study did not identify the source of dopaminergic inputs. Additionally, whether other neuronal types, such as dopamine D3 receptor-expressing granule cells in the OT,33 selectively regulate the emergence from isoflurane anesthesia needs to be determined.

DA receptor-expressing neurons are the predominant type of neurons in the nucleus accumbens (NAc), which is well known for controlling reward and drug addictions.85,86 Recent studies have demonstrated a role for the NAc in the regulation of general anesthesia. Zhang et al87 showed that the activity of NAcD1R neurons began to decrease after sevoflurane exposure and gradually recovered before RORR occurred. The Ca2+ signals at the LORR and RORR were comparable. Moreover, after RORR, the Ca2+ signals rapidly increased to an approximate level at preanesthesia, which was different from the slow recovery observed in the PVT.25 Therefore, the recovery rate of neural activity after RORR might differ among nuclei, and it will be interesting to investigate the underlying molecular basis. Optical activation of NAcD1R neurons prolonged induction time and shortened arousal time. These findings were consistent with those of another study.88 They further showed that the activity of the NAcD1R- VP pathway was inhibited under sevoflurane anesthesia.87 Activation of the NAcD1R-VP pathway reduces emergence time, whereas inhibition of the NAcD1R-VP pathway prolongs emergence from sevoflurane anesthesia but does not change induction time.87 Consistently, activation of the NAcD1R-VP induced reanimation from sevoflurane anesthesia.89 Conversely, activation of the NAcD2R-VP shortened the induction time of sevoflurane anesthesia in mice without affecting emergence time.34 These findings suggest that different types of dopamine receptor-expressing neurons in the NAc-VP might differentially regulate the induction and emergence of sevoflurane anesthesia.

The SCN, located in the anterior-ventral hypothalamus, contributes to regulating circadian rhythms,90,91 such as sleep-wakefulness circuits.92,93 A recent study reported that the activity of the SCN was associated with emergence from general anesthesia.35 Liu et al35 reported that monochromatic blue light (MBL) exposure enhanced the neuronal activity of the SCN under sevoflurane anesthesia in mice. MBL shortened the emergence time from sevoflurane anesthesia without influencing the induction time. These responses to MBL were abolished by SCN lesions. However, whether manipulation of the activity of the SCN directly influences the emergence of sevoflurane anesthesia should be determined.

The PnO is a region of the ascending reticular activating system and is implicated in sleep-wakefulness and general anesthesia.94 Vanini et al13 reported that PnO selectively regulates the induction process of general anesthesia. Decreasing GABA levels in the PnO shortened the induction of propofol or isoflurane in rats, whereas increasing GABA levels in the PnO prolonged the induction. However, the occurrence rate of emergence from propofol or isoflurane was not altered.13 More regions that selectively regulate the induction of general anesthesia might be identified in future studies.

Using fMRI, Huang et al4 provided human evidence regarding distinct neural mechanisms between anesthesia induction and emergence in large-scale brain networks. During the period from propofol delivery to unconsciousness, temporal autocorrelation of fMRI signals (an index of neural processing timescales) across the whole brain gradually increased, but functional connectivity gradually decreased. After consciousness recovery, rapid recovery of cortical but not subcortical neural processing and an abrupt increase in subcorticocortical functional connectivity were observed. These findings indicate asymmetric neural dynamics between propofol induction and emergence, which cannot be solely explained by pharmacokinetic effects.

DISCUSSION

Current evidence consistently indicates that orexinergic neurons are critical for the selective regulation of emergence from general anesthesia induced by both volatile and intravenous anesthetics. Many brain regions have been found to mediate the emergence-promoting effects of orexinergic neurons. Moreover, plasma orexin-A levels might be a novel biomarker for the emergence of general anesthesia. Interestingly, the orexin system appears to not be associated with halothane anesthesia.37 In recent years, emerging brain nuclei and circuits as well as neural types have been indicated to be associated with the distinct modulation between anesthesia induction and emergence, although their relationships with orexinergic neurons and the underlying molecular mechanism remain elusive. Notably, the distinct mechanisms underlying the differences between induction and emergence were not consistent among the different types of general anesthetics. For example, manipulation of PVT activity can selectively modulate the emergence of isoflurane anesthesia15,25 but affects both the induction and emergence of sevoflurane,59 desflurane,15 and propofol61 anesthesia. There is also divergence in the role of individual brain regions in the selective modulation of anesthesia induction and emergence. For example, activation of the NAcD1R-VP circuit selectively accelerates the emergence of sevoflurane anesthesia,87 whereas activation of the NAcD2R-VP circuit selectively accelerates the induction of sevoflurane anesthesia.34 Most recent studies reporting that induction is not a simple inverse process of emergence have focused on isoflurane anesthesia, and additional brain nuclei or circuits might differentially regulate the different periods of general anesthesia induced by other general anesthetics.

In addition to induction time, more reliable indicators, such as the EC50, should be used to assess the exact effects on anesthesia induction because it might be difficult to observe significant differences in induction time during the rapid induction period. For example, one study reported that the activation of PBN astrocytes did not affect the induction time of isoflurane anesthesia in mice but did significantly affect the EC50 of the LORR.95 Importantly, poor study methods or designs might influence the results in the following cases: (1) extremely high doses of the anesthetic will cause a rapid LORR that cannot detect a difference in the induction time even if the nucleus in question does modulate induction; (2) assessment of the LORR that is too infrequent to detect a difference between groups; (3) lack of temperature maintenance or measurement in experimental mice to exclude the influence of hypothermia; and (4) use of pharmacologic antagonists or knockouts that enable the investigators to determine what happens in the naturalistic processes of induction or emergence that avoid the potential confounds of exogenous excitation/inhibition of neurons in ways that may never occur during the normal induction or emergence process. In this review, although all included studies reported changes in induction and emergence times, only 3 studies14,15,31 reported EC50 values. Future studies are suggested to calculate the EC50 to determine the effects on anesthetic induction and emergence processes.

It should be determined whether sex differences exist in the distinct modulatory mechanism between anesthesia induction and emergence, as most of the current evidence on this topic was obtained from male rodents. Generally, females are more resistant to volatile anesthetics, which might be modulated by testosterone, and the underlying neuronal circuits are thought to be related to ventral hypothalamic sleep-promoting regions.96 This might explain why women showed a greater incidence of awareness during general anesthesia. In addition to neuronal populations in the central nervous system, glial cells might also be associated with selective regulation under general anesthesia. One study97 reported that mice lacking the mitochondrial complex I gene (Ndufs4) in astrocytes exhibited delayed emergence from isoflurane or halothane anesthesia, but the induction process did not change, suggesting that the normal mitochondrial function of astrocytes is selectively associated with emergence from volatile anesthesia.

In summary, this study comprehensively summarized the current evidence regarding the distinct neural mechanisms involved in the induction and emergence of general anesthesia, which will improve the understanding of the mechanisms underlying the emergence of general anesthesia.

DISCLOSURES

This manuscript was handled by: Peter A. Goldstein, MD.

Footnotes

Reprints will not be available from the authors.

Funding: This work was supported by the National Natural Science Foundation of China (grant 82301403 to D.Z.) and Health Commission of Sichuan Province (grant 21PJ014 to D.Z.).

The authors declare no conflicts of interest.

D. Zhang and Y. Wei contributed equally to this work.

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