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Brainstem node for loss of consciousness due to GABAA receptor-active anesthetics
Abstract
The molecular agents that induce loss of consciousness during anesthesia are classically believed to act by binding to cognate transmembrane receptors widely distributed in the CNS and critically suppressing local processing and network connectivity. However, previous work has shown that microinjection of anesthetics into a localized region of the brainstem mesopontine tegmentum (MPTA) rapidly and reversibly induces anesthesia in the absence of global spread. This implies that functional extinction is determined by neural pathways rather than vascular distribution of the anesthetic agent. But does clinical (systemic-induced) anesthesia employ MPTA-linked circuitry? Here we show that cell-selective lesioning of the MPTA in rats does not, in itself, induce anesthesia or coma. However, it increases the systemic dose of pentobarbital required to induce anesthesia, in a manner proportional to the extent of the lesion. Such lesions also affect emergence, extending the duration of anesthesia. Off-target and sham lesions were ineffective. Combined with the prior microinjection data, we conclude that drug delivery to the MPTA is sufficient to induce loss-of-consciousness and that neurons in this locus are necessary for anesthetic induction at clinically relevant doses. Together, the results support an architecture for anesthesia with the MPTA serving as a key node in an endogenous network of dedicated pathways that switch between wake and unconsciousness. As such, the MPTA might also play a role in syncope, concussion and sleep.
... 18 (2) Lesions of this area reduce the sensitivity of rats to systemic pentobarbital such that anesthesia can no longer be induced at clinically relevant doses. 19 Because the rest of the CNS continues to be exposed to normal anesthetic concentrations of the pentobarbital, but anesthesia is not induced, this observation challenges the hypothesis of global or patch-wise suppression. The primary aim of the present study was to evaluate the effect of mesopontine tegmental anesthesia area lesions on anesthetic induction using agents other than pentobarbital. ...
... The operations were separated by ~2 weeks (13.7 ± 9.2 days). In the first procedure, carried out under chloral hydrate anesthesia (400 mg/kg intraperitoneal; Sigma-Aldrich, Israel), the animals were implanted with a femoral vein catheter that was exteriorized behind the neck and sealed with a sterilized stainless steel plug (additional details in Minert and Devor 19 ). The catheter was filled with heparin in sterile saline (100 units/ml, Kamada Ltd., Israel). ...
... The anesthetics tested were etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine (table 1). Comparison data for pentobarbital using the same methods are available in a previous publication 19 in which we evaluated 17 lesioned animals including the nine lesion group rats used here. Some lesion group, control group, and off-target group animals were tested both before and after lesioning. ...
What we already know about this topic:
Lesions of the mesopontine tegmental anesthesia area in the brainstem render rats strongly insensitive to pentobarbitalThe effects of mesopontine tegmental anesthesia area lesions on responses to other anesthetics have not been previously reported WHAT THIS ARTICLE TELLS US THAT IS NEW: Targeted microinjection of ibotenic acid into the mesopontine tegmental anesthesia area in adult rats led to an up to twofold loss in anesthetic potency of etomidate and propofolIn contrast, the potency of ketamine, medetomidine, and alfaxolone/alfadolone was unaffectedThese observations suggest that the mesopontine tegmental anesthesia area of the brainstem may serve as a key structure to selectively mediate transition from wakefulness into an anesthetic state in response to γ-aminobutyric acid-mediated anesthetics BACKGROUND:: The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid-mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents.
Methods:
Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose-response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16).
Results:
As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls).
Conclusions:
Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action.
... However, it nearly doubled the amount of pentobarbital required to induce anesthesia by the systemic route, with doses reaching levels that are near-lethal for intact rats. 50 The increase was proportional to the extent of the MPTA destroyed. Off-target lesions, near but outside the MPTA, were ineffective. ...
... Off-target lesions, near but outside the MPTA, were ineffective. This observation means that in the absence of the MPTA there is no other nucleus or combination of nuclei in the sleep/ anesthesia circuitry, 4,9,[11][12][13][14]50 including the entire cortex, that is sufficiently sensitive to barbiturate anesthetics to bring about anesthetic induction at clinically relevant doses. Without the MPTA, much higher drug doses are required. ...
... Without the MPTA, much higher drug doses are required. 50 The MPTA appears to be unique, the "first responder." It is not known whether, at elevated systemic concentrations, anesthesia is induced by network action engaged from a second locus, for example, another brainstem nucleus or as a result of global suppression by circulating anesthetic molecules. ...
We review evidence that the induction of anesthesia with GABAergic agents is mediated by a network of dedicated axonal pathways, which convey a suppressive signal to remote parts of the central nervous system. The putative signal originates in an anesthetic-sensitive locus in the brainstem that we refer to as the mesopontine tegmental anesthesia area (MPTA). This architecture stands in contrast to the classical notion that anesthetic molecules themselves directly mediate anesthetic induction after global distribution by the vascular circulation. The MPTA came to light in a systematic survey of the rat brain as a singular locus at which microinjection of minute quantities of GABAergic anesthetics is able to reversibly induce a state resembling surgical anesthesia. The rapid onset of anesthesia, the observed target specificity, and the fact that effective doses are far too small to survive dilution during vascular redistribution to distant areas in the central nervous system are all incompatible with the classical global suppression model. Lesioning the MPTA selectively reduces the animal's sensitivity to systemically administered anesthetics. Taken together, the microinjection data show that it is sufficient to deliver γ-aminobutyric acid A receptor (GABAA-R) agonists to the MPTA to induce an anesthesia-like state and the lesion data indicate that MPTA neurons are necessary for anesthetic induction by the systemic route at clinically relevant doses. Known connectivity of the MPTA provides a scaffold for defining the specific projection pathways that mediate each of the functional components of anesthesia. Because MPTA lesions do not induce coma, the MPTA is not a key arousal nucleus essential for maintaining the awake state. Rather, it appears be a "gatekeeper" of arousal function, a major element in a flip-flop switching mechanism that executes rapid and reversible transitions between the awake and the anesthetic state.
... There are several neuro-transmitters that affect the state of consciousness [69]. Injection of GABAAR agonists causes unconsciousness [58]. According to these physiological pieces of evidence, this inhibitory neurotransmitter is responsible for the loss of consciousness. ...
... On the other hand, several neurotransmitters can affect the state of consciousness [69]. Injection of GABAAR agonists causes unconsciousness [58]. So, It can be a good idea for the future works. ...
In this work, we propose a simple nonlinear network of consciousness that demonstrates how the trauma to the ascending reticular formation could lead to coma. Studies show that the healthy brain works at the edge of chaos. Coma, as a disorder, is a stable state that the inherently chaotic brain could trap in. There are several brain areas playing a critical role in consciousness. A trauma to each of these areas could lead to disruption of conscious experience. Ascending reticular formation, which plays a key role in consciousness, is the focus area of this work. We study the effect of trauma on the connection between the reticular formation and the rest of consciousness network that could lead to stable behavior of the brain, i.e. coma. The effect of increased inhibitory neurotransmitter on the occurrence of unconsciousness is displayed as well. We also show how a local boost would affect a brain in the coma.
... To investigate different responses to intravenous anesthetics in mice during different developmental periods, we used LORR analysis to examine the hypnotic actions of propofol and ketamine in developmental mice [9,21]. The LORR EC 50 of propofol decreased with the development of mice ( Figure 1A and 1B, EC 50 : 13.66 ± 0.20 mg/kg for P14 mice, 12.35 ± 0.19 mg/kg for P21 mice, 10.80 ± 0.17 mg/kg for P28 mice and 9.73 ± 0.20 mg/kg for P35 mice, n=10, F=167.9, ...
... Hypnosis was established as a loss-of-righting reflex (LORR) and a scale of righting reflex. We defined mice rapid forceful righting within 10 s and when placed on side as a negative LORR while no righting attempts within 10 s after completion of the injection and that persisted for at least10 s thereafter as a positive LORR [9,10,21]. ...
It is widely accepted that the induction dose of anesthetics is higher in infants than in adults, although the relevant molecular mechanism remains elusive. We previously showed neuronal hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to hypnotic actions of propofol and ketamine. Interestingly, the expression of HCN channels in neocortex significantly changes during postnatal periods. Thus, we postulated that changes in HCN channels expression might contribute to sensitivity to intravenous anesthetics. Here we showed the EC50 for propofol- and ketamine-induced loss-of-righting reflex (LORR) was significantly lower for P35 than for P14 mice. Cerebrospinal fluid concentrations of propofol and ketamine were significantly higher in P14 mice than in P35 mice, with similar propofol- and ketamine-induced anesthesia at the LORR EC50. Western blotting indicated that the expression of HCN channels in neocortex changed significantly from P14 to P35 mice. In addition, the amplitude of HCN currents in the neocortical layer 5 pyramidal neurons and the inhibition of propofol and ketamine on HCN currents dramatically increased with development. Logistic regression analysis indicated that the changes of HCN channels were correlated with the age-related differences of propofol- and ketamine-induced anesthesia. These data reveal that the change of HCN channels expression with postnatal development may contribute to sensitivity to the hypnotic actions of propofol and ketamine in mice.
... HERs are averages of EEG epochs locked to heartbeat timings, hypothesized to reflect the central processing of cardiac activity (Park & Blanke, 2019). The evidence connecting HERs with the state of consciousness reveals the relevance of studying the brain-heart connection in consciousness research and complements previous evidence showing autonomic dysfunctions in pathological unconsciousness (Leo et al., 2016;Liuzzi et al., 2023;Pérez et al., 2021;Raimondo et al., 2017;Riganello et al., 2021;Riganello, Larroque, et al., 2018;Tobaldini et al., 2018) and the potential of consciousness recovery by stimulating vagal and spinal pathways (Corazzol et al., 2017;Minert & Devor, 2016;Pepa et al., 2013;Yu et al., 2017). ...
Because consciousness does not necessarily translate into overt behaviour, detecting residual consciousness in noncommunicating patients remains a challenge. Bedside diagnostic methods based on EEG are promising and cost-effective alternatives to detect residual consciousness. Recent evidence showed that the cortical activations triggered by each heartbeat, namely, heartbeat-evoked responses (HERs), can detect through machine learning the presence of minimal consciousness and distinguish between overt and covert minimal consciousness. In this study, we explore different markers to characterize HERs to investigate whether different dimensions of the neural responses to heartbeats provide complementary information that is not typically found under standard event-related potential analyses. We evaluated HERs and EEG average non-locked to heartbeats in six types of participants: healthy state, locked-in syndrome, minimally conscious state, vegetative state/unresponsive wakefulness syndrome, comatose and brain-dead patients. We computed a series of markers from HERs that can generally separate the unconscious from the conscious. Our findings indicate that HER variance and HER frontal segregation tend to be higher in the presence of consciousness. These indices, when combined with heart rate variability, have the potential to enhance the differentiation between different levels of awareness. We propose that a multidimensional evaluation of brain-heart interactions could be included in a battery of tests to characterize disorders of consciousness. Our results may motivate further exploration of markers in brain-heart communication for the detection of consciousness at the bedside. The development of diagnostic methods based on brain-heart interactions may be translated into more feasible methods for clinical practice.
... MPTA lesions do not prevent rats from falling asleep, but they do alter sleep-wake patterns by shortening total NREM and REM and enhancing wakefulness (Lanir-Azaria et al., 2018). We suspect that other instances of LOC such as fainting, concussion, epilepsy and hibernation also engage the endogenous sleep-wake circuitry (Hayes et al., 1984;Minert and Devor, 2016). ...
The canonical view of how general anesthetics induce loss-of-consciousness (LOC) permitting pain-free surgery posits that anesthetic molecules, distributed throughout the CNS, suppress neural activity globally to levels at which the cerebral cortex can no longer sustain conscious experience. We support an alternative view that LOC, in the context of GABAergic anesthesia at least, results from anesthetic exposure of a small number of neurons in a focal brainstem nucleus, the mesopontine tegmental anesthesia area (MPTA). The various sub-components of anesthesia, in turn, are effected in distant locations, driven by dedicated axonal pathways. This proposal is based on the observations that microinjection of infinitesimal amounts of GABAergic agents into the MPTA, and only there, rapidly induces LOC, and that lesioning the MPTA renders animals relatively insensitive to these agents delivered systemically. Recently, using chemogenetics, we identified a subpopulation of MPTA "effector-neurons" which, when excited (not inhibited), induce anesthesia. These neurons contribute to well-defined ascending and descending axonal pathways each of which accesses a target region associated with a key anesthetic endpoint: atonia, anti-nociception, amnesia and LOC (by electroencephalographic criteria). Interestingly, the effector-neurons do not themselves express GABA A-receptors. Rather, the target receptors reside on a separate sub-population of presumed inhibitory interneurons. These are thought to excite the effectors by disinhibition, thus triggering anesthetic LOC.
... Finally, we make a connection between the results presented here and the newly emerging ideas involving quantum effects in the brain (see, for instance, [56]). Given that the delivery of anaesthetics specifically targeting the brainstem has been shown to be sufficient for the induction of loss of consciousness [57], and given the recent proposal that quantum effects may be important for xenon-induced anaesthesia [58], the prominent role enjoyed by the brainstem in our structural analysis may have potential implications for quantum-mechanical explanations of consciousness. ...
The underlying anatomical structure is fundamental to the study of brain networks, but the role of brainstem from a structural perspective is not very well understood. We conduct a computational and graph-theoretical study of the human structural connectome incorporating a variety of subcortical structures including the brainstem. Our computational scheme involves the use of Python DIPY and Nibabel libraries to develop structural connectomes using 100 healthy adult subjects. We then compute degree, eigenvector, and betweenness centralities to identify several highly connected structures and find that the brainstem ranks highest across all examined metrics, a result that holds even when the connectivity matrix is normalized by volume. We also investigated some global topological features in the connectomes, such as the balance of integration and segregation, and found that the domination of the brainstem generally causes networks to become less integrated and segregated. Our results highlight the importance of including the brainstem in structural network analyses.
... Finally, we make a connection between the results presented here and the newly emerging 312 ideas involving quantum effects in the brain (see, for instance, [60]). Given that the delivery of 313 anaesthetics specifically targeting the brainstem has been shown to be sufficient for the 314 induction of loss of consciousness [61], and given the recent proposal that quantum effects may 315 be important for xenon-induced anaesthesia [62], the prominent role enjoyed by the brainstem in 316 our structural analysis may have potential implications for quantum-mechanical explanations of 317 consciousness. ...
The underlying anatomical structure is fundamental to the study of brain networks and is likely to play a key role in the generation of conscious experience. We conduct a computational and graph-theoretical study of the human structural connectome incorporating a variety of subcortical structures including the brainstem, which is typically not considered in similar studies. Our computational scheme involves the use of Python DIPY and Nibabel libraries to develop an averaged structural connectome comprised of 100 healthy adult subjects. We then compute degree, eigenvector, and betweenness centralities to identify several highly connected structures and find that the brainstem ranks highest across all examined metrics. Our results highlight the importance of including the brainstem in structural network analyses. We suggest that structural network-based methods can inform theories of consciousness, such as global workspace theory (GWT), integrated information theory (IIT), and the thalamocortical loop theory.
... Finally, we make a connection between the results presented here and the newly emerging ideas involving quantum effects in the brain (see, for instance, [60]). Given that the delivery of anaesthetics specifically targeting the brainstem has been shown to be sufficient for the induction of loss of consciousness [61], and given the recent proposal that quantum effects may be important for xenon-induced anaesthesia [62], the prominent role enjoyed by the brainstem in our structural analysis may have potential implications for quantum-mechanical explanations of consciousness. ...
The underlying anatomical structure is fundamental to the study of brain networks and is likely to play a key role in the generation of conscious experience. We conduct a computational and graph-theoretical study of the human structural connectome incorporating a variety of subcortical structures including the brainstem, which is typically not considered in similar studies. Our computational scheme involves the use of Python DIPY and Nibabel libraries to develop an averaged structural connectome comprised of 100 healthy adult subjects. We then compute degree, eigenvector, and betweenness centralities to identify several highly connected structures and find that the brainstem ranks highest across all examined metrics. Our results highlight the importance of including the brainstem in structural network analyses. We suggest that structural network-based methods can inform theories of consciousness, such as global workspace theory (GWT), integrated information theory (IIT), and the thalamocortical loop theory.
... It is noteworthy that the bulk of neurophysiological evidence indicates that pain is modulated in this way by the engagement of high cortical functions, but that the actual modulation is implemented by descending pathways that target brain structures at mesopontine levels and below (Section 5.1). This is also where pain modulation by opiates and by general anesthetics are believed to operate [62,65,111]. ...
It is nearly axiomatic that pain, among other examples of conscious experience, is an outcome of still-uncertain forms of neural processing that occur in the cerebral cortex, and specifically within thalamo-cortical networks. This belief rests largely on the dramatic relative expansion of the cortex in the course of primate evolution, in humans in particular, and on the fact that direct activation of sensory representations in the cortex evokes a corresponding conscious percept. Here we assemble evidence, drawn from a number of sources, suggesting that pain experience is unlike the other senses and may not, in fact, be an expression of cortical processing. These include the virtual inability to evoke pain by cortical stimulation, the rarity of painful auras in epileptic patients and outcomes of cortical lesions. And yet, pain perception is clearly a function of a conscious brain. Indeed, it is perhaps the most archetypical example of conscious experience. This draws us to conclude that conscious experience, at least as realized in the pain system, is seated subcortically, perhaps even in the “primitive” brainstem. Our conjecture is that the massive expansion of the cortex over the course of evolution was not driven by the adaptive value of implementing consciousness. Rather, the cortex evolved because of the adaptive value of providing an already existing subcortical generator of consciousness with a feed of critical information that requires the computationally intensive capability of the cerebral cortex.
... It is noteworthy that the bulk of neurophysiological evidence indicates that pain is modulated in this way by the engagement of high cortical functions, but that the actual modulation is implemented by descending pathways that target brain structures at mesopontine levels and below (Section 5.1). This is also where pain modulation by opiates and by general anesthetics are believed to operate [62,65,111]. ...
Doubtless, the conscious brain integrates masses of information. But declaring that consciousness simply "emerges" when enough has accumulated, doesn't really explain how first person experience is implemented by neurons. Moreover, empirical observations challenge integrated information theory's (IIT) reliance on thalamo-cortical interactions as the information integrator. More likely, the cortex streams processed information to a still-enigmatic consciousness generator, one perhaps located in the brainstem.
... These inhibitory effects of classical GABAergic anesthetics may be due to the direct activation of postsynaptic GABA A receptors. Indeed, localized injections of pentobarbital into the MPTA can induce a complete state of anesthesia, which appears to be mediated by a circuit of dedicated axonal projections to the nearby arousal nuclei of the brainstem and distant targets in the forebrain and spinal cord [81,84,85]; meanwhile, lesions in this region lead to insomnia [86]. These results provide direct evidence for the role of subcortical regions in mediating GABAergic anesthetic-induced unconsciousness, and MPTA may serve as the on-off switch of GABAergic anesthetic-induced anesthesia. ...
Although general anesthetics have been used in the clinic for more than 170 years, the ways in which they induce amnesia, unconsciousness, analgesia, and immobility remain elusive. Modulations of various neural nuclei and circuits are involved in the actions of general anesthetics. The expression of the immediate early gene c-fos and its nuclear product, c-fos protein can be induced by neuronal depolarization; therefore, c-fos staining is commonly used to identify the activated neurons during sleep and/or wakefulness, as well as in various physiological conditions in the central nervous system. Identifying c-fos expression is also a direct and convenient method to explore the effects of general anesthetics on the activity of neural nuclei and circuits. Using c-fos staining, general anesthetics have been found to interact with sleep- and wakefulness-promoting systems throughout the brain, which may explain their ability to induce unconsciousness and emergence from general anesthesia. This review summarizes the actions of general anesthetics on neural nuclei and circuits based on c-fos expression.
... A significant step forward was the discovery in rats that selective delivery of minute quantities of GABA A -receptor (GABA A -R) agonists into a small brainstem nucleus, the mesopontine tegmental anesthesia area (MPTA), rapidly and reversibly induces a state of general anesthesia. Conversely, lesioning this area does not cause coma as might be expected ), but rather renders rats relatively insensitive to anesthetic induction by GABAergic agents delivered systemically (Devor and Zalkind 2001;Voss et al. 2005;Namjoshi et al. 2009;Minert and Devor 2016;Sukhotinsky et al. 2016;Minert et al. 2017Minert et al. , 2020. Analysis of the mechanisms whereby activating GABA A -Rs in the MPTA induces anesthesia in rats has proceeded apace. ...
The mesopontine tegmental anesthesia area (MPTA) was identified in rats as a singular brainstem locus at which microinjection of minute quantities of GABAergic agents rapidly and reversibly induces loss-of-consciousness and a state of general anesthesia, while lesioning renders animals insensitive to anesthetics at normal systemic doses. Obtaining similar results in mice has been challenging, however, slowing research progress on how anesthetics trigger brain-state transitions. We have identified roadblocks that impeded translation from rat to mouse and tentatively located the MPTA equivalent in this second species. We describe here a series of modifications to the rat protocol that allowed us to document pro-anesthetic changes in mice following localized stereotactic delivery of minute quantities (20 nL) of the GABAA-receptor agonist muscimol into the brainstem mesopontine tegmentum. The optimal locus identified proved to be homologous to the MPTA in rats, and local neuronal populations in rats and mice were similar in size and shape. This outcome should facilitate application of the many innovative gene-based methodologies available primarily in mice to the study of how activity in brainstem MPTA neurons brings about anesthetic loss-of-consciousness and permits pain-free surgery.
... More speculatively still, with the algorithm for consciousness already running in phylogenetically old subcortical structures, the evolving cortex might have begun to provide it with processed multisensory input much as the spinal cord had long been providing it with nociceptive input. This architecture may account for why dysfunction in V1 causes perceptual blindness without blunting consciousness, while dysfunction at focal subcortical loci can cause loss of consciousness encompassing all sensory modalities (Devor and Zalkind 2001;Posner, Saper et al. 2007;Minert and Devor 2015). ...
... The unleashing of an overpowering neural signal amongst cholinergic, noradrenergic, and serotonergic neurons are causing consciousness to fade. During anesthesia, localized effects on the brainstem can result in loss of consciousness due to gamma-aminobutyric acid, GABA, a receptor-active anesthetic [170]. During dreamless sleep, the brainstem prevents the free energy that is available to the cortical areas through a variety of neural transmitters [171]. ...
It is a century-old view that experiential philosophies are not compatible with materialism. In the contextual inconsistency with the reality, that matter is inertly acquiring only a single physical state, philosophers have gained ground in metaphysical beliefs, including dualism, monism, and idealism. We show that a new foundational self-referential identity theory of the mind is needed to bridge the explanatory gap. Panexperiential materialism is a new materialistic framework originating in the spectral domain of matter-wave energy quanta transcending the barrier of thermoquantal information, isomorphically aligning with consciousness. The holistic nature of its instantiation is panexperiential due to the composite states of non-inert matter, depending crucially on their interrelations without embracing essentialist ontology, further entwined with epistemic teleofunctionalism and informational relationalism, and based on the research agenda, concepts, and shared values of quantum chemistry. Panexperiential materialism is characterized by a spectral matter-wave structure, which is conjugate to the prescriptive structural properties of the spacetime domain. Yet panexperiential materialism is not contrary to ordinary materialism, although the latter may be fundamentally grounded in molecular networks. The phenomenology of consciousness is not merely a mental reification in the first-person perspective. The proper guideline should be the reduction of conscious processes to nonreductive physical correlates in the brain. The wet and hot environment of the brain affords quantum-thermal correlations in a transcending energy processing zone where quantum and classical fluctuations are fused to thermoquantal information. The quantum chemical basis incorporates non-self-adjoint analytic extensions in Liouville space and associated Fourier-Laplace transforms that conjoin energy, time, entropy, and temperature. The transformation across hierarchical thermodynamical domains is caused by the negentropic gain wholly implicated by the entropy production arising in the energy exchange resulting in the transformation of information forming informational holarchies, driven by nonlocal teleological mechanisms. The information transformation from the objective to the subjective is a process that is quantum in nature. The process of non-integrated information, actualizing the information-based action as a teleological process of cognition in the entailment of preconscious experientialities, should not be conflated with the experience itself, but rather as an isomorphic connection between mind and brain via the Fourier-Laplace transformation. Our holistic viewpoint denies the existence of integrated information as an emergentist ontology, instead advocating the canonical transformations B and B† as the syntax or universal grammar for intrinsic information (proto-communication). The irreducible character of an informational holarchy where the whole is affected non-synergistically by the non-integrated information is how intrinsic information encapsulates the energy transformation from fusing thermal and quantum fluctuations that result in long-range correlations (phase wave) that constitutes the fundamental dynamics of physical feelings. In panexperiential materialism, there is no issue dividing holists and reductionists, concerning the issue whether the whole or the discrete parts are primary, but rather their interrelations. This relationalism is pivotal in understanding how non-integrated information holistically concresce. Although we consider matter waves to be fundamental, one might say, avoiding the trap of eliminative materialism, that the brain is conjugate to the mind and vice versa.
... In a series of studies, Devor and colleagues (Sukhotinksy et al., 2016;Devor et al., 2016;Minert and Devor, 2016;Minert et al., 2017) identified a region of the pontomesencephalic RF, termed the mesopontine tegmental anesthesia area (MPTA), which when suppressed produces an anesthetic-like state. Specifically, microinjections of the GABA A agonist, muscimol, or the anesthetics, sodium pentobarbital or propofol, into the MPTA, but not into adjacent RF areas, rapidly induced an anesthetized state in rats Minert et al., 2017). ...
We review evidence challenging the hypothesis that memories are processed or consolidated in sleep. We argue that the brain is in an unconscious state in sleep, akin to general anesthesia, and hence is incapable of meaningful cognitive processing – the sole purview of waking consciousness. At minimum, the encoding of memories in sleep would require that waking events are faithfully transferred to and reproduced in sleep. Remarkably, however, this has never been demonstrated, as waking experiences are never truly replicated in sleep but rather appear in very altered or distorted forms. General anesthetics (GAs) exert their effects through endogenous sleep‐wake control systems and accordingly GAs and sleep share several common features: sensory blockade, immobility, amnesia and lack of awareness (unconsciousness). The loss of consciousness in non‐REM (NREM) sleep or to GAs is characterized by: (1) delta oscillations throughout the cortex; (2) marked reductions in neural activity (from waking) over widespread regions of the cortex, most pronounced in frontal and parietal cortices; and (3) a significant disruption of the functional connectivity of thalamocortical and corticocortical networks, particularly those involved in “higher order” cognitive functions. Several (experimental) reports in animals and humans have shown that disrupting the activity of the cortex, particularly the orbitofrontal cortex, severely impairs higher order cognitive and executive functions. The profound and widespread deactivation of the cortex in the unconscious states of NREM sleep or GA would be expected to produce an equivalent, or undoubtedly a much greater, disruptive effect on mnemonic and cognitive functions. In conclusion, we contend that the unconscious, severely altered state of the brain in NREM sleep would negate any possibility of cognitive processing in NREM sleep.
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... The neural activity in the central nervous system during anesthesia has been already characterized at the molecular and spinal levels. The γ-aminobutyric acid type A (GABA-A) and N-methyl-D-aspartate (NMDA) receptors appear to be the most important targets of anesthesia (Minert and Devor, 2016;Zecharia et al., 2009). Furthermore, the general anesthetics decrease the transmission of noxious information ascending from the spinal cord to the brain (Angel, 1993;Campagna et al., 2003;Collins et al., 1995). ...
Background:
General anesthesia (GA) provides an invaluable experimental tool to understand the essential neural mechanisms underlying consciousness. Previous neuroimaging studies have shown the functional integration and segregation of brain functional networks during anesthetic-induced alteration of consciousness. However, the organization pattern of hubs in functional brain networks remains unclear. Moreover, comparisons with the well-characterized physiological unconsciousness can help us understand the neural mechanisms of anesthetic-induced unconsciousness.
Methods:
Resting-state functional magnetic resonance imaging was performed during wakefulness, mild propofol-induced sedation (m-PIS), and deep PIS (d-PIS) with clinical unconsciousness on 8 healthy volunteers and wakefulness and natural sleep on 9 age- and sex-matched healthy volunteers. Large-scale functional brain networks of each volunteer were constructed based on 160 regions of interest. Then, rich-club organizations in brain functional networks and nodal properties (nodal strength and efficiency) were assessed and analyzed among the different states and groups.
Results:
Rich-clubs in the functional brain networks were reorganized during alteration of consciousness induced by propofol. Firstly, rich-club nodes were switched from the posterior cingulate cortex (PCC), angular gyrus, and anterior and middle insula to the inferior parietal lobule (IPL), inferior parietal sulcus (IPS), and cerebellum. When sedation was deepened to unconsciousness, the rich-club nodes were switched to the occipital and angular gyrus. These results suggest that the rich-club nodes were switched among the high-order cognitive function networks (default mode network [DMN] and fronto-parietal network [FPN]), sensory networks (occipital network [ON]), and cerebellum network (CN) from consciousness (wakefulness) to propofol-induced unconsciousness. At the same time, compared with wakefulness, local connections were switched to rich-club connections during propofol-induced unconsciousness, suggesting a strengthening of the overall information commutation of networks. Nodal efficiency of the anterior and middle insula and ventral frontal cortex was significantly decreased. Additionally, from wakefulness to natural sleep, a similar pattern of rich-club reorganization with propofol-induced unconsciousness was observed: rich-club nodes were switched from the DMN (including precuneus and PCC) to the sensorimotor network (SMN, including part of the frontal and temporal gyrus). Compared with natural sleep, nodal efficiency of the insula, frontal gyrus, PCC, and cerebellum significantly decreased during propofol-induced unconsciousness.
Conclusions:
Our study demonstrated that the rich-club reorganization in functional brain networks is characterized by switching of rich-club nodes between the high-order cognitive and sensory and motor networks during propofol-induced alteration of consciousness and natural sleep. These findings will help understand the common neurological mechanism of pharmacological and physiological unconsciousness.
... Anesthesia is another field of medicine informative for the consciousness study in recent years. Minert and Devor (2016), reported that "the effect of localized lesioning of the brainstem mesopontine tegmentum (MPTA) in Wistar-derived Sabra strain rats is sufficient to induce an anesthetic state virtually identical to systemic anesthesia" but that "destruction of the MPTA, or nonspecific suppression of its component neurons, does not induce coma as aRAS function remains unchanged" (Devor & Zalkind, 2001). ...
Introduction:
One of the hardest challenges of the third century is to develop theories that could joint different results for a global explanation of human consciousness. Some important theories have been proposed, trying to explain the emergence of consciousness as the result of different progressive changes in the elaboration of information during brain processing, giving particular attention to the thalamocortical system.
Methods:
In this article, a summary review of results that highlighted as cerebral cortex could not be so fundamental for consciousness generation is proposed. In detail, three topics were analyzed: (a) studies using experimental approach (manipulating stimuli or brain areas), such as decorticated animals or subliminal presentation of stimuli; (b) studies using anatomo-clinical method (conscious inferenced from observed behaviors); and (c) data from neurostimulation of subcortical areas or of the autonomic nervous system.
Results:
We sketch two speculative hypothesis relative, firstly, to the possible independence from cortical areas of the on/off mechanism for consciousness generation and, secondly, to the possible role of information variability generated by the bottom-up exchange of information among neural systems as a switch for consciousness.
Conclusions:
A broad range of evidence regarding the functional role of the brainstem and autonomic nervous system is reviewed for its bearing on a future hypothesis regarding the generation of consciousness experience.
... inhibitor nipecotic acid (that effectively increases GABA levels) in the pontine reticular formation promote wakefulness and retards induction of propofol or isoflurane anesthesia [60]. However, the most direct evidence for subcortical sites mediating anesthetic-induced loss of consciousness comes from the observation that localized injections of GABAergic anesthetics into the mesopontine tegmentum can induce a complete state of anesthesia [61], while lesions to this region produce insomnia [62]. ...
Significant progress has been made in the 21st century towards a comprehensive understanding of the mechanisms of action of general anesthetics, coincident with progress in structural biology and molecular, cellular, and systems neuroscience. This review summarizes important new findings that include target identification through structural determination of anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical roles of neuronal networks in anesthetic effects on memory and consciousness. These recent developments provide a comprehensive basis for conceptualizing pharmacological control of amnesia, unconsciousness, and immobility.
... Based on such mental interactions among individuals, social psychology studies the influences exercised by some individuals on the thoughts, feelings, and behaviors of others (25). Such interpersonal influences induce specific mental phenomena and experiences like attitude, persuasion, social/ political influences, social cognition, etc. From a physiological perspective, the environment represents an external medium for the biological body; from the perspective of social psychology, the surrounding social medium is an intrinsic part of our mind, in the form of mental (psychosocial) reality (26). ...
Human life occurs within a complex bio-psycho-social milieu, a heterogeneous system that is integrated by multiple bidirectional interrelations existing between the abstract-intangible ideas and physical-chemical support of environment. The mind is thus placed between the abstract ideas/ concepts and neurobiological brain that is further connected to environment. In other words, the mind acts as an interface between the immaterial (abstract/ intangible) data and material (biological) support. The science is unable to conceives and explains an interaction between the immaterial and material domains (to understand nature of the mind), this question generating in literature the mind-body problem.
We have published in the past a succession of articles related to the mind-body problem, in order to demonstrate the fact that this question is actually a false issue. The phenomenon of immaterial-material interaction is impossible to be explained because it never occurs, which means that there is no need to explain the immaterial-material interaction. Our mind implies only a temporal association between the immaterial data and material support, this dynamic interrelation being presented and argued here as a solution to the mind-body problem.
The limited psycho-biologic approach of the mind-body problem is expanded here to a more comprehensive and feasible bio-psycho-social perspective, generating thus three distinct (bio-psychological, bio-social, and psycho-social) equations. These three equations can be solved through a solution represented by a dynamic cerebral system (two distinct and interconnected subunits of the brain) which presumably could have the capability of receiving and processing abstract data through association (with no interaction) between immaterial and material data.
... MPTA lesions do not prevent rats from falling asleep, but they do alter sleep-wake patterns by shortening total NREM and REM and enhancing wakefulness (Lanir-Azaria et al., 2018). We suspect that other instances of LOC such as fainting, concussion, epilepsy and hibernation also engage the endogenous sleep-wake circuitry (Hayes et al., 1984;Minert and Devor, 2016). ...
Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. In contrast to the influential concept of a diffuse “reticular activating system,” the past century of neuroscience research has identified a focal region of the upper brainstem that, when damaged, causes coma. This region contains diverse neuronal populations with different axonal projections, neurotransmitters, and genetic identities. Activating some of these populations promotes wakefulness, but it remains unclear which specific neurons are necessary for sustaining consciousness. In parallel, pharmacological evidence has indicated a role for special neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine. However, genetically targeted experiments have indicated that none of these neurotransmitters or the neurons producing them are individually necessary for maintaining wakefulness. In this review, we emphasize the need to determine the specific subset of brainstem neurons necessary for maintaining arousal. Accomplishing this will enable more precise mapping of wakefulness circuitry, which will be useful in developing therapies for patients with coma and other disorders of arousal.
Although general anesthesia is normally induced by systemic dosing, an anesthetic state can be induced in rodents by microinjecting minute quantities of GABAergic agents into the brainstem mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesions to the MPTA render rats relatively insensitive to standard anesthetic doses delivered systemically. Using a chemogenetic approach we have identified and characterized a small subpopulation of neurons restricted to the MPTA which, when excited, render the animal anesthetic by sensorimotor (immobility) and electroencephalographic (EEG) criteria. These “effector-neurons” do not express GABAAδ-Rs, the likely target of GABAergic anesthetics. Rather, we report a distinct sub-population of nearby MPTA neurons which do. During anesthetic induction these likely excite the effector-neurons by disinhibition. Within the effector population ~ 70% appear to be glutamatergic, ~30% GABAergic and ~ 40% glycinergic. Most are projection neurons that send ascending or descending axons to distant targets associated with the individual functional components of general anesthesia: atonia, analgesia, amnesia, and loss-of-consciousness.
We all experience pain at one time or another. Pain is an essential “alarm bell” that tells us that something is wrong, and a “teacher” that reminds us not to do that same thing again. Usually, pain is felt when a stimulus, such as a pinch or an injury, causes electrical pulses to run along one of the cables of nerve fibers in our body and into the brain where they generate an unpleasant sensory and emotional experience. Sometimes pain occurs without any actual stimulus, such as when nerve fibers have been damaged. An example is the phantom pain that amputees sometimes feel in their missing limb. Certain drugs can stop pain by blocking the electrical pulses before they reach the brain. Other drugs stop pain in a different way, by preventing the brain from reading the pain message carried by the electrical pulses. This article explains what happens in the body when we are hurt, how the brain causes this to be felt as pain and how certain drugs can stop pain.
The brain undergoes rapid, dramatic, and reversible transitioning between states of wakefulness and unconsciousness during natural sleep and in pathological conditions such as hypoxia, hypotension, and concussion. Transitioning can also be induced pharmacologically using general anesthetic agents. The effect is selective. Mobility, sensory perception, memory formation, and awareness are lost while numerous housekeeping functions persist. How is selective transitioning accomplished? Classically a handful of brainstem and diencephalic “arousal nuclei” have been implicated in driving brain-state transitions on the grounds that their net activity systematically varies with brain state. Here we used transgenic targeted recombination in active populations mice
General anesthetic agents are thought to induce loss-of-consciousness (LOC) and enable pain-free surgery by acting on the endogenous brain circuitry responsible for sleep-wake cycling. In clinical use, the entire CNS is exposed to anesthetic molecules with LOC usually attributed to synaptic suppression in the cerebral cortex and immobility and analgesia to agent action in the spinal cord and brainstem. This model of patch-wise suppression has been challenged, however, by the observation that all functional components of anesthesia can be induced by focal delivery of minute quantities of GABAergic agonists to the brainstem mesopontine tegmental anesthesia area (MPTA). We compared spectral features of the cortical electroencephalogram (EEG) in rats during systemic anesthesia and anesthesia induced by MPTA microinjection. Systemic administration of (GABAergic) pentobarbital yielded the sustained, δ-band dominant EEG signature familiar in clinical anesthesia. In contrast, anesthesia induced by MPTA microinjection (pentobarbital or muscimol) featured epochs of δ-band EEG alternating with the wake-like EEG, the pattern typical of natural non-rapid-eye-movement (NREM) and REM sleep. The rats were not sleeping, however, as they remained immobile, atonic and unresponsive to noxious pinch. Recalling the paradoxical wake-like quality the EEG during REM sleep, we refer to this state as “paradoxical anesthesia”. GABAergic anesthetics appear to co-opt both cortical and spinal components of the sleep network via dedicated axonal pathways driven by MPTA neurons. Direct drug exposure of cortical and spinal neurons is not necessary, and is probably responsible for off-target side-effects of systemic administration including monotonous δ-band EEG, hypothermia and respiratory depression.
Significance statement
The concept that GABAergic general anesthetic agents induce loss-of-consciousness by substituting for an endogenous neurotransmitter, thereby co-opting neural circuitry responsible for sleep-wake transitions, has gained considerable traction. However, the electroencephalographic (EEG) signatures of sleep and anesthesia differ fundamentally. We show that when the anesthetic state is generated by focal delivery of GABAergics into the mesopontine tegmental anesthesia area (MPTA) the resulting EEG repeatedly transitions between delta-wave-dominant and wake-like patterns much as in REM-NREM sleep. This suggests that systemic (clinical) anesthetic delivery, which indiscriminately floods the entire cerebrum with powerful inhibitory agents, obscures the sleep-like EEG signature associated with the less adulterated form of anesthesia obtained when the drugs are applied selectively to loci where the effective neurotransmitter substitution actually occurs.
The mesopontine tegmental anesthesia area (MPTA) is a small brainstem nucleus that, when exposed to minute quantities of GABAA receptor agonists, induces a state of general anesthesia. In addition to immobility and analgesia this state is accompanied by widespread suppression of neural activity in the cerebral cortex and high delta-band power in the electroencephalogram. Collectively, MPTA neurons are known to project to a variety of forebrain targets which are known to relay to the cortex in a highly distributed manner. Here we ask whether ascending projections of individual MPTA neurons collateralize to several of these cortical relay nuclei, or access only one. Using rats, contrasting retrograde tracers were microinjected pairwise on one side into three ascending relays: the basal forebrain, the zona incerta-lateral hypothalamus and the intralaminar thalamic nuclear group. In addition, in separate animals, each target was microinjected bilaterally. MPTA neurons were then identified as being single-or double-labeled, indicating projection to one target nucleus or collateralization to both. Results indicated that double-labeling was rare, occurring on average in only 1.3% of the neurons sampled. The overwhelming majority of individual MPTA neurons showed specific connectivity, contributing to only one of the major ascending pathways, either ipsilaterally or contralaterally, but not bilaterally. This architecture would permit particular functional aspects of anesthetic loss-of-consciousness to be driven by specific subpopulations of MPTA neurons.
Experiments have shown that general anaesthetics lose their efficacy at pressures of around 20 MPa, but their efficacy is recovered at pressures of around 40 MPa. Molecular dynamics simulations of the general anaesthetic halothane in DMPC or POPC bilayers show that halothane aggregates inside the membrane at 20 MPa, but not at atmospheric pressure, nor at 40 MPa. The parallelism in effects suggests that aggregation could conceivably be the mechanism for pressure reversal. Further molecular dynamics simulations of another general anaesthetic, isoflurane, in POPC show that isoflurane does not aggregate at 20 MPa. This and other quantitative considerations show that general anaesthetic aggregation inside the membrane could not be the mechanism for pressure reversal.
Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABAA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABAA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABAA receptors, continue to be some of the most effective compounds to treat primary insomnia.
The transition from wakefulness to general anesthesia is widely attributed to suppressive actions of anesthetic molecules distributed by the systemic circulation to the cerebral cortex (for amnesia and loss of consciousness) and to the spinal cord (for atonia and antinocice-ption). An alternative hypothesis proposes that anesthetics act on one or more brainstem or diencephalic nuclei, with suppression of cortex and spinal cord mediated by dedicated axonal pathways. Previously, we documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABAA-receptor agonists into an upper brainstem region named the mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesioning this area rendered animals resistant to systemically delivered anesthetics. Here, using rats of both sexes, we applied a modified microinjection method that permitted localization of the anesthetic-sensitive neurons with much improved spatial resolution. Microinjected at the MPTA hotspot identified, exposure of 1900 or fewer neurons to muscimol was sufficient to sustain whole-body general anesthesia; microinjection as little as 0.5 mm off-target did not. The GABAergic anesthetics pentobarbital and propofol were also effective. The GABA-sensitive cell cluster is centered on a tegmental (reticular) field traversed by fibers of the superior cerebellar peduncle. It has no specific nuclear designation and has not previously been implicated in brain-state transitions.
Transient loss of consciousness (TLOC), frequently triggered by perturbation in essential physiological parameters such as pCO2or O2, is considered a passive consequence of generalized degradation in high-level cerebral functioning.However, the fact that it is almost always accompanied by atonia and loss of spinal nocifensive reflexes suggests that it might actually be part of a "syndrome" mediated by neural circuitry, and ultimately be adaptive. Widespread suppression by molecules distributed in the vasculature is also the classical explanation of general anesthesia. Recent data, however, suggest that anesthesia is due, rather, to drug action at a specific brainstem locus, the mesopontine tegmental anesthesia area (MPTA), with the spectrum of anesthetic effects resulting from secondary recruitment of specific axonal pathways. If so, might the MPTA also be involved in TLOC induced by hypercapnia and hypoxia?We exposed rats to gas mixtures that provoke hypercapnia and hypoxia and asked whether cell-selective lesions of the MPTA affect TLOC. Entry into TLOC, monitored as time to loss of the righting reflex (LORR) was unaffected. However, resumption of the righting reflex (RORR), and of response to pinch stimuli (ROPR), was significantly delayed. The extent of both effects correlated with the extent of damage in the MPTA, but was unrelated to damage that extended beyond the borders of the MPTA. The results implicate neurons in a specific common-core region of the MPTA in TLOC induced by both forms of asphyxia. This is the same area responsible for general anesthesia induced by GABAergic anesthetic agents. This implies the involvement of a common set of brain nuclei and dedicated axonal pathways, rather than nonspecific global suppression, in the mechanism mediating all three instances of TLOC.
General anesthetic agents induce loss of consciousness coupled with suppression of movement, analgesia and amnesia. Although these diverse functions are mediated by neural structures located in wide-ranging parts of the neuraxis, anesthesia can be induced rapidly and reversibly by bilateral microinjection of minute quantities of GABAA -R agonists at a small, focal locus in the mesopontine tegmentum (MPTA). State switching under these circumstances is presumably executed by dedicated neural pathways and does not require widespread distribution of the anesthetic agent itself, the classical assumption regarding anesthetic induction. Here we asked whether these pathways serve each hemisphere independently, or whether there is bilateral redundancy such that the MPTA on each side is capable of anesthetizing the entire brain. Either of two GABAA -R ligands were microinjected unilaterally into the MPTA in awake rats, the barbiturate modulator pentobarbital and the direct receptor agonist muscimol. Both agents, microinjected on either side, induced clinical anesthesia including bilateral atonia, bilateral analgesia and bilateral changes in cortical activity. The latter was monitored using c-fos expression and electroencephalography. This action, however, was not simply a consequence of suppressing spike activity in MPTA neurons as unilateral (or bilateral) microinjection of the local anesthetic lidocaine at the same locus failed to induce anesthesia. We propose a model of the state-switching circuitry that accounts for the bilateral action of unilateral microinjection and also for the observation that inactivation with lidocaine is not equivalent to inhibition with GABAA -R agonists. This is a step in defining the overall switching circuitry that underlies anesthesia. This article is protected by copyright. All rights reserved.
A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states.
Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act. The altered states of arousal are sedation-unconsciousness, sedation-analgesia, dissociative anesthesia, pharmacologic non-REM sleep, and neuroleptic anesthesia. Each altered arousal state results from the anesthetic drugs acting at multiple targets in the central nervous system. Our analysis shows that general anesthesia is less mysterious than currently believed.
In the United States, nearly 60,000 patients per day receive general anesthesia for surgery.1 General anesthesia is a drug-induced, reversible condition that includes specific behavioral and physiological traits — unconsciousness, amnesia, analgesia, and akinesia — with concomitant stability of the autonomic, cardiovascular, respiratory, and thermoregulatory systems.2 General anesthesia produces distinct patterns on the electroencephalogram (EEG), the most common of which is a progressive increase in low-frequency, high-amplitude activity as the level of general anesthesia deepens3,4 (Figure 1Figure 1Electroencephalographic (EEG) Patterns during the Awake State, General Anesthesia, and Sleep.). How anesthetic drugs induce and maintain the behavioral states of general anesthesia is an important question in medicine and neuroscience.6 Substantial insights can be gained by considering the relationship of general anesthesia to sleep and to coma. Humans spend approximately one third of their lives asleep. Sleep, a state of decreased arousal that is actively generated by nuclei in the hypothalamus, brain stem, and basal forebrain, is crucial for the maintenance of health.7,8 Normal human sleep cycles between two states — rapid-eye-movement (REM) sleep and non-REM sleep — at approximately 90-minute intervals. REM sleep is characterized by rapid eye movements, dreaming, irregularities of respiration and heart rate, penile and clitoral erection, and airway and skeletal-muscle hypotonia.7 In REM sleep, the EEG shows active high-frequency, low-amplitude rhythms (Figure 1). Non-REM sleep has three distinct EEG stages, with higher-amplitude, lower-frequency rhythms accompanied by waxing and waning muscle tone, decreased body temperature, and decreased heart rate.
Coma is a state of profound unresponsiveness, usually the result of a severe brain injury.9 Comatose patients typically lie with eyes closed and cannot be roused to respond appropriately to vigorous stimulation. A comatose patient may grimace, move limbs, and have stereotypical withdrawal responses to painful stimuli yet make no localizing responses or discrete defensive movements. As the coma deepens, the patient's responsiveness even to painful stimuli may diminish or disappear. Although the patterns of EEG activity observed in comatose patients depend on the extent of the brain injury, they frequently resemble the high–amplitude, low-frequency activity seen in patients under general anesthesia10 (Figure 1). General anesthesia is, in fact, a reversible drug-induced coma. Nevertheless, anesthesiologists refer to it as “sleep” to avoid disquieting patients. Unfortunately, anesthesiologists also use the word “sleep” in technical descriptions to refer to unconsciousness induced by anesthetic drugs.11 (For a glossary of terms commonly used in the field of anesthesiology, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)
This review discusses the clinical and neurophysiological features of general anesthesia and their relationships to sleep and coma, focusing on the neural mechanisms of unconsciousness induced by selected intravenous anesthetic drugs
Microinjection of pentobarbital into a restricted region of rat brainstem, the mesopontine tegmental anesthesia area (MPTA), induces a reversible anesthesia-like state characterized by loss of the righting reflex, atonia, antinociception, and loss of consciousness as assessed by electroencephalogram synchronization. We examined cerebral activity during this state using FOS expression as a marker. Animals were anesthetized for 50 min with a series of intracerebral microinjections of pentobarbital or with systemic pentobarbital and intracerebral microinjections of vehicle. FOS expression was compared with that in awake animals microinjected with vehicle. Neural activity was suppressed throughout the cortex whether anesthesia was induced by systemic or MPTA routes. Changes were less consistent subcortically. In the zona incerta and the nucleus raphe pallidus, expression was strongly suppressed during systemic anesthesia, but only mildly during MPTA-induced anesthesia. Dissociation was seen in the tuberomammillary nucleus where suppression occurred during systemic-induced anesthesia only, and in the lateral habenular nucleus where activity was markedly increased during systemic-induced anesthesia but not following intracerebral microinjection. Several subcortical nuclei previously associated with cerebral arousal were not affected. In the MPTA itself FOS expression was suppressed during systemic anesthesia. Differences in the pattern of brain activity in the two modes of anesthesia are consistent with the possibility that anesthetic endpoints might be achieved by alternative mechanisms: direct drug action for systemic anesthesia or via ascending pathways for MPTA-induced anesthesia. However, it is also possible that systemically administered agents induce anesthesia, at least in part, by a primary action in the MPTA with cortical inhibition occurring secondarily.
The recent discovery of a barbiturate-sensitive "general anesthesia switch" mechanism localized in the rat brain stem mesopontine tegmental anesthesia area (MPTA) has challenged the current view of the nonspecific actions of general anesthetic agents in the CNS. In this study we provide electrophysiological evidence that the antinociception, which accompanies the behavioral state resembling general anesthesia following pentobarbital (PB) microinjections into the MPTA of awake rats, could be accompanied by the attenuation of sensory transmission through the spinothalamic tract (STT). Following bilateral microinjections of PB into the MPTA spontaneous firing rate (SFR), antidromic firing index (FI), and sciatic (Sc) as well as sural (Su) nerve-evoked responses (ER) of identified lumbar STT neurons in the isoflurane-anesthetized rat were quantified using extracellular recording techniques. Microinjections of PB into the MPTA significantly suppressed the SFR (47%), magnitudes of Sc- (26%) and Su-ER (36%), and FI (41%) of STT neurons. Microinjections of PB-free vehicle control did not alter any of the above-cited electrophysiological parameters. The results from this study suggest that antinociception, which occurs during the anesthesia-like state following PB microinjections into the MPTA, may be due, in part, to (in)direct inhibition of STT neurons via switching mechanism(s) located in the MPTA. This study provides a provenance for investigating electrophysiologically the actions on STT neurons of other current agents used clinically to maintain the state of general anesthesia.
The assessment of the depth of anaesthesia in man has received much attention in recent years, following a number of reports of people being aware during surgery. A range of different measures have been suggested for determining the adequacy of anaesthesia in man, but such a critical assessment is rarely applied to laboratory animals. This article describes the methods used to assess anaesthetic depth in both man and animals, and compares the relative states of knowledge about anaesthetic depth in animals and man.
The present study was undertaken to determine the frequency and distribution of GABAergic neurons within the rat pontomesencephalic tegmentum and the relationship of GABAergic cells to cholinergic and other tegmental neurons projecting to the hypothalamus. In sections immunostained for glutamic acid decarboxylase (GAD), large numbers of small GAD-positive neurons (∼50,000 cells) were distributed through the tegmentum and associated with a high density of GAD-positive varicosities surrounding both GAD-positive and GAD-negative cells. Through the reticular formation, ventral tegmentum, raphe nuclei, and dorsal tegineritum, GAD-positive cells were codistributed with larger cells, which included neurons immunostained on adjacent sections for glutamate, tyrosine hydroxylase (TH), serotonin, or choline acetyltransferase (ChAT). In sections dual-immunostained for GAD and ChAT, GABAergic neurons were seen to be intermingled with less numerous cholinergic cells (∼2,600 GAD+ to ∼ 1,400 ChAT+ cells in the laterodorsal tegmental nucleus, LDTg).
Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip-flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip-flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions-for example, in narcolepsy.
Background: Although the effects of propofol on cerebral metabolism have been studied in animals, these effects have yet to be directly examined in humans. Consequently, we used positron emission tomography (PET) to demonstrate in vivo the regional cerebral metabolic changes that occur in humans during propofol anesthesia, Methods: Six volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism, and the other assessed metabolism during anesthesia with a propofol infusion titrated to the point of unresponsiveness (mean rate +/- SD = 7.8 +/- 1.5 mg.kg(-1).h(-1)). Scans were obtained using the (18)fluorodeoxyglucose technique. Results: Awake whole-brain glucose metabolic rates (GMR) averaged 29 +/- 8 mu moles.100g(-1)min(-1) (mean +/- SD). Anesthetized whole-brain GMR averaged 13 +/- 4 mu moles.100g(-1).min(-1) (paired t test, P less than or equal to 0.007), GMR decreased in all measured areas during anesthesia. However, the decrease in GMR was not uniform. Cortical metabolism was depressed 58%, whereas subcortical metabolism was depressed 48% (P less than or equal to 0.001). Marked differences within cortical regions also occurred. In the medial and subcortical regions, the largest percent decreases occurred in the left anterior cingulate and the inferior colliculus. Conclusion: Propofol produced a global metabolic depression on the human central nervous system, The metabolic pattern evident during anesthesia was reproducible and differed from that seen in the awake condition. These findings are consistent with those from previous animal studies and suggest PET may be useful for investigating the mechanisms of anesthesia in humans.
GABAA receptors (GABAARs) and glycine receptors are key elements of the spinal control of nociception and pain. Compromised functioning of these two transmitter systems contributes to chronic pain states. Restoring their proper function through positive allosteric modulators should constitute a rational approach to the treatment of chronic pain syndromes involving diminished inhibitory spinal pain control. Although classical benzodiazepines (i.e., full agonists at the benzodiazepine binding site of GABAARs) potentiate synaptic inhibition in spinal pain controlling circuits, they lack clinically relevant analgesic activity in humans. Recent data obtained from experiments in GABAAR point-mutated mice suggests dose-limiting sedative effects of classical nonspecific benzodiazepines as the underlying cause. Experiments in genetically engineered mice resistant to the sedative effects of classical benzodiazepines and studies with novel less sedating benzodiazepines have indeed shown that profound antihyperalgesia can be obtained at least in preclinical pain models. Present evidence suggests that compounds with high intrinsic activity at α2-GABAAR and minimal agonistic activity at α1-GABAAR should possess relevant antihyperalgesic activity without causing unwanted sedation. On-going preclinical studies in genetically engineered mice and clinical trials with more selective benzodiazepine site agonists should soon provide additional insights into this emerging topic.
© 2015 Elsevier Inc. All rights reserved.
Anesthetics have been used in clinical practice for over a hundred years, yet their mechanisms of action remain poorly understood. One tempting hypothesis to explain their hypnotic properties posits that anesthetics exert a component of their effects by "hijacking" the endogenous arousal circuitry of the brain. Modulation of activity within sleep- and wake-related neuroanatomic systems could thus explain some of the varied effects produced by anesthetics. There has been a recent explosion of research into the neuroanatomic substrates affected by various anesthetics. In this review, we will highlight the relevant sleep architecture and systems and focus on studies over the past few years that implicate these sleep-related structures as targets of anesthetics. These studies highlight a promising area of investigation regarding the mechanisms of action of anesthetics and provide an important model for future study.
1.1. By the use of microelectrode and evoked potential techniques, effects of pentothal (thiopental sodium) on neural activity in the somatosensory cortex and the brain stem were studied.2.2. A clear-cut relation between the evoked slow potential and unit response is not proved either in the somatosensory cortex or in the mesencephalic reticular formation.3.3. The spontaneous firing of a neuron is the most sensitive component to pentothal anaesthesia. It is first to be affected with a small dose of this drug while the unit response to peripheral stimulation still persists. This is equally true for cortical and brain stem neurons.4.4. When the spike train of unit response is examined under the action of pentothal, the spikes which are suppressed are those occurring in the later phases of the train, while the early occurring spikes may persist unchanged.5.5. The sensitivity to pentothal of the unit response elicited by peripheral stimulation is a function of the latency of the very first spike of the response. The shorter the latency, the more resistant the unit response is to pentothal. This is true in the mesencephalic reticular formation as well as in the lemniscal system.
Tonic immobility (TI) is also known as "immobility response", "immobility reflex", "animal hypnosis", etc. It is an innate antipredatory behavior characterized by an absence of movement, varying degrees of muscular activity, and a relative unresponsiveness to external stimuli. Experimentally, TI is commonly produced by manually forcing an animal into an inverted position and restraining it in that position until the animal becomes immobile. Part of the neural mechanism(s) of TI involves the medullo-pontine reticular formation, with influence from other components of the brain, notably the limbic system. It has been observed that TI is more prolonged in stressed animals, and systemic injection of corticosterone (CORT) also potentiates this behavior. At present, the anatomical brain regions involved in the CORT modulation of TI are unknown. Thus, our study was made to determine if some pontine areas could be targets for the modulation of TI by CORT. A unilateral nucleus pontis oralis (PnO) microinjection of 1 μL of CORT (0.05 μg/1 μL) in rats resulted in clear behavioral responses. The animals had an increased duration of TI caused by clamping the neck (in this induction, besides of body inversion and restraint, there is also clamping the neck), with an enhancement in open-field motor activity, which were prevented by pretreatment injection into PnO with 1 μL of the mineralocorticoid-receptor antagonist spironolactone (0.5 μg/1 μL) or 1 μL of the glucocorticoid-receptor antagonist mifepristone (0.5 μg/1 μL). In contrast, these behavioral changes were not seen when CORT (0.05 μg/1 μL) was microinjected into medial lemniscus area or paramedian raphe. Our data support the idea that, in stressful situations, glucocorticoids released from adrenals of the prey reach the PnO to produce a hyper arousal state, which in turn can prolong the duration of TI.
Anesthesia, slow-wave sleep, syncope, concussion and reversible coma are behavioral states characterized by loss of consciousness, slow-wave cortical electroencephalogram, and motor and sensory suppression. We identified a focal area in the rat brainstem, the mesopontine tegmental anesthesia area (MPTA), at which microinjection of pentobarbital and other GABA(A) receptor (GABA(A)-R) agonists reversibly induced an anesthesia-like state. This effect was attenuated by local pre-treatment with the GABA(A)-R antagonist bicuculline. Using neuroanatomical tracing we identified four pathways ascending from the MPTA that are positioned to mediate electroencephalographic synchronization and loss of consciousness: (i) projections to the intralaminar thalamic nuclei that, in turn, project to the cortex; (ii) projections to several pontomesencephalic, diencephalic and basal forebrain nuclei that project cortically and are considered parts of an ascending "arousal system"; (iii) a projection to other parts of the subcortical forebrain, including the septal area, hypothalamus, zona incerta and striato-pallidal system, that may indirectly affect cortical arousal and hippocampal theta rhythm; and (iv) modest projections directly to the frontal cortex. Several of these areas have prominent reciprocal projections back to the MPTA, notably the zona incerta, lateral hypothalamus and frontal cortex. We hypothesize that barbiturate anesthetics and related agents microinjected into the MPTA enhance the inhibitory response of local GABA(A)-R-bearing neurons to endogenous GABA released at baseline during wakefulness. This modulates activity in one or more of the identified ascending neural pathways, ultimately leading to loss of consciousness.
The "ascending reticular activating system" theory proposed that neurons in the upper brainstem reticular formation projected to forebrain targets that promoted wakefulness. More recent formulations have emphasized that most neurons at the pontomesencephalic junction that participate in these pathways are actually in monoaminergic and cholinergic cell groups. However, cell-specific lesions of these cell groups have never been able to reproduce the deep coma seen after acute paramedian midbrain lesions that transect ascending axons at the caudal midbrain level. To determine whether the cortical afferents from the thalamus or the basal forebrain were more important in maintaining arousal, we first placed large cell-body-specific lesions in these targets. Surprisingly, extensive thalamic lesions had little effect on electroencephalographic (EEG) or behavioral measures of wakefulness or on c-Fos expression by cortical neurons during wakefulness. In contrast, animals with large basal forebrain lesions were behaviorally unresponsive and had a monotonous sub-1-Hz EEG, and little cortical c-Fos expression during continuous gentle handling. We then retrogradely labeled inputs to the basal forebrain from the upper brainstem, and found a substantial input from glutamatergic neurons in the parabrachial nucleus and adjacent precoeruleus area. Cell-specific lesions of the parabrachial-precoeruleus complex produced behavioral unresponsiveness, a monotonous sub-1-Hz cortical EEG, and loss of cortical c-Fos expression during gentle handling. These experiments indicate that in rats the reticulo-thalamo-cortical pathway may play a very limited role in behavioral or electrocortical arousal, whereas the projection from the parabrachial nucleus and precoeruleus region, relayed by the basal forebrain to the cerebral cortex, may be critical for this process.
Procedures are described for lesioning two components of the hippocampal formation (hippocampus, subiculum) using multiple injections of small amounts of ibotenic acid (IBO). The resulting loss of cells is more selective and limited than can be obtained with conventional techniques. Thus, problems associated with damage to adjacent areas, fibers-of-passage, and damage to the vasculature are minimized. The results of behavioral experiments indicate that the effects of IBO lesions of the hippocampus are more subtle than those found with conventional lesion techniques. The general approach of using multiple injections of small amounts of neurotoxins can be used to selectively lesion other components of the hippocampal formation.
Low levels of cerebral concussion in the cat produce reversible behavioral suppression presumably associated with unconsciousness. This injury is also associated with increased rates of glucose utilization in regions within the dorsomedial pontine tegmentum. Microinjection of carbachol into these regions produced behavioral suppression resembling that following concussion. These data, together with previously published observations on cholinergic responses to brain injury, suggest that concussive unconsciousness may be attributable in part to activation of cholinergic pontine sites.
General anaesthetics are much more selective than is usually appreciated and may act by binding to only a small number of targets in the central nervous system. At surgical concentrations their principal effects are on ligand-gated (rather than voltage-gated) ion channels, with potentiation of postsynaptic inhibitory channel activity best fitting the pharmacological profile observed in general anaesthesia. Although the role of second messengers remains uncertain, it is now clear that anaesthetics act directly on proteins rather than on lipids.
Although the effects of propofol on cerebral metabolism have been studied in animals, these effects have yet to be directly examined in humans. Consequently, we used positron emission tomography (PET) to demonstrate in vivo the regional cerebral metabolic changes that occur in humans during propofol anesthesia.
Six volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism, and the other assessed metabolism during anesthesia with a propofol infusion titrated to the point of unresponsiveness (mean rate +/- SD = 7.8 +/- 1.5 mg.kg-1.h-1). Scans were obtained using the 18fluorodeoxyglucose technique.
Awake whole-brain glucose metabolic rates (GMR) averaged 29 +/- 8 mumoles.100 g-1.min-1 (mean +/- SD). Anesthetized whole-brain GMR averaged 13 +/- 4 mumoles.100 g-1.min-1 (paired t test, P < or = 0.007). GMR decreased in all measured areas during anesthesia. However, the decrease in GMR was not uniform. Cortical metabolism was depressed 58%, whereas subcortical metabolism was depressed 48% (P < or = 0.001). Marked differences within cortical regions also occurred. In the medial and subcortical regions, the largest percent decreases occurred in the left anterior cingulate and the inferior colliculus.
Propofol produced a global metabolic depression on the human central nervous system. The metabolic pattern evident during anesthesia was reproducible and differed from that seen in the awake condition. These findings are consistent with those from previous animal studies and suggest PET may be useful for investigating the mechanisms of anesthesia in humans.
Clinical observations have established that certain parts of the brain are essential for consciousness whereas other parts are not. For example, different areas of the cerebral cortex contribute different modalities and submodalities of consciousness, whereas the cerebellum does not, despite having even more neurons. It is also well established that consciousness depends on the way the brain functions. For example, consciousness is much reduced during slow wave sleep and generalized seizures, even though the levels of neural activity are comparable or higher than in wakefulness. To understand why this is so, empirical observations on the neural correlates of consciousness need to be complemented by a principled theoretical approach. Otherwise, it is unlikely that we could ever establish to what extent consciousness is present in neurological conditions such as akinetic mutism, psychomotor seizures, or sleepwalking, and to what extent it is present in newborn babies and animals. A principled approach is provided by the information integration theory of consciousness. This theory claims that consciousness corresponds to a system's capacity to integrate information, and proposes a way to measure such capacity. The information integration theory can account for several neurobiological observations concerning consciousness, including: (i) the association of consciousness with certain neural systems rather than with others; (ii) the fact that neural processes underlying consciousness can influence or be influenced by neural processes that remain unconscious; (iii) the reduction of consciousness during dreamless sleep and generalized seizures; and (iv) the time requirements on neural interactions that support consciousness.
The actions of neurotransmitters involved in the sleep-wakefulness cycle on neurons located in the ventral part of the oral pontine tegmentum were studied in a rat brain-slice preparation. Results show that glutamate and histamine evoke depolarizations and spike firing while serotonin and gamma-aminobutyric acid evoke hyperpolarizations. The excitatory and inhibitory actions of these neurotransmitters increase pontine neuron activity during the conditions occurring during paradoxical sleep.
1. General anesthesia is achieved by anesthetic action in the central nervous system (CNS). 2. Whereas amnesia and unconsciousness are due to anesthetic action in the brain, recent evidence suggests that immobility in response to a noxious stimulus is achieved by anesthetic effects in the spinal cord. The putative spinal cord site(s) include dorsal horn cells and motor neurons. 3. The extent to which anesthetic action in the brain influences the spinal cord probably varies among anesthetics. Furthermore, anesthetics can indirectly influence the brain by their actions within the spinal cord, i.e. by modulating ascending transmission of sensory information.
GABA(A) receptors are ligand-operated chloride channels assembled from five subunits in a heteropentameric manner. Using immunocytochemistry, we investigated the distribution of GABA(A) receptor subunits deriving from 13 different genes (alpha1-alpha6, beta1-beta3, gamma1-gamma3 and delta) in the adult rat brain. Subunit alpha1-, beta1-, beta2-, beta3- and gamma2-immunoreactivities were found throughout the brain, although differences in their distribution were observed. Subunit alpha2-, alpha3-, alpha4-, alpha5-, alpha6-, gamma1- and delta-immunoreactivities were more confined to certain brain areas. Thus, alpha2-subunit-immunoreactivity was preferentially located in forebrain areas and the cerebellum. Subunit alpha6-immunoreactivity was only present in granule cells of the cerebellum and the cochlear nucleus, and subunit gamma1-immunoreactivity was preferentially located in the central and medial amygdaloid nuclei, in pallidal areas, the substantia nigra pars reticulata and the inferior olive. The alpha5-subunit-immunoreactivity was strongest in Ammon's horn, the olfactory bulb and hypothalamus. In contrast, alpha4-subunit-immunoreactivity was detected in the thalamus, dentate gyrus, olfactory tubercle and basal ganglia. Subunit alpha3-immunoreactivity was observed in the glomerular and external plexiform layers of the olfactory bulb, in the inner layers of the cerebral cortex, the reticular thalamic nucleus, the zonal and superficial layers of the superior colliculus, the amygdala and cranial nerve nuclei. Only faint subunit gamma3-immunoreactivity was detected in most areas; it was darkest in midbrain and pontine nuclei. Subunit delta-immunoreactivity was frequently co-distributed with alpha4 subunit-immunoreactivity, e.g. in the thalamus, striatum, outer layers of the cortex and dentate molecular layer. Striking examples of complementary distribution of certain subunit-immunoreactivities were observed. Thus, subunit alpha2-, alpha4-, beta1-, beta3- and delta-immunoreactivities were considerably more concentrated in the neostriatum than in the pallidum and entopeduncular nucleus. In contrast, labeling for the alpha1-, beta2-, gamma1- and gamma2-subunits prevailed in the pallidum compared to the striatum. With the exception of the reticular thalamic nucleus, which was prominently stained for subunits alpha3, beta1, beta3 and gamma2, most thalamic nuclei were rich in alpha1-, alpha4-, beta2- and delta-immunoreactivities. Whereas the dorsal lateral geniculate nucleus was strongly immunoreactive for subunits alpha4, beta2 and delta, the ventral lateral geniculate nucleus was predominantly labeled for subunits alpha2, alpha3, beta1, beta3 and gamma2; subunit alpha1- and alpha5-immunoreactivities were about equally distributed in both areas. In most hypothalamic areas, immunoreactivities for subunits alpha1, alpha2, beta1, beta2 and beta3 were observed. In the supraoptic nucleus, staining of conspicuous dendritic networks with subunit alpha1, alpha2, beta2, and gamma2 antibodies was contrasted by perykarya labeled for alpha5-, beta1- and delta-immunoreactivities. Among all brain regions, the median emminence was most heavily labeled for subunit beta2-immunoreactivity. In most pontine and cranial nerve nuclei and in the medulla, only subunit alpha1-, beta2- and gamma2-immunoreactivities were strong, whereas the inferior olive was significantly labeled only for subunits beta1, gamma1 and gamma2. In this study, a highly heterogeneous distribution of 13 different GABA(A) receptor subunit-immunoreactivities was observed. This distribution and the apparently typical patterns of co-distribution of these GABA(A) receptor subunits support the assumption of multiple, differently assembled GABA(A) receptor subtypes and their heterogeneous distribution within the adult rat brain.
Concussion, asphyxia, and systemically administered general anesthetics all induce reversible depression of the organism's response to noxious stimuli as one of the elements of loss of consciousness. This is so even for barbiturate anesthetics, which have only modest analgesic efficacy at subanesthetic doses. Little is known about the neural circuits involved in this form of antinociception, although for anesthetic agents, at least, it is usually presumed that the drugs act in widely distributed regions of the nervous system. We now report the discovery of a focal zone in the brainstem mesopontine tegmentum in rats at which microinjection of minute quantities of pentobarbital induces a transient, reversible anesthetic-like state with non-responsiveness to noxious stimuli, flaccid atonia, and absence of the righting reflex. The behavioral suppression is accompanied by slow-wave EEG and, presumably, loss of consciousness. This zone, which we refer to as the mesopontine tegmental anesthesia locus (MPTA), apparently contains a barbiturate-sensitive 'switch' for both cortical and spinal activity. The very existence of the MPTA locus has implications for an understanding of the neural circuits that control motor functions and pain sensation, and for the cerebral representation of consciousness.
Br J Anaesth 2002; 89: 91–101
Identifying the central nervous system sites of action of anaesthetics is important for understanding the link between their molecular actions and clinical effects. The aim of the present pilot study was to compare the anaesthetic effect of bilateral microinjections of propofol and thiopentone (both 200 microg/microl, in Intralipid and 0.9% saline respectively) into a recently discovered anaesthetic-sensitive region in the rat brainstem, the "mesopontine tegmental anaesthetic area" (MPTA). Microinjections (1 microl per side) were made into the MPTA of fifteen male Sprague-Dawley rats. The effect of each agent on spontaneous behaviour, postural control and nociceptive responsiveness was subjectively assessed according to established criteria. The main finding was that thiopentone induced an "anaesthesia-like" state, including complete atonia and loss of righting ability, in 20% of the subjects. Overall, thiopentone significantly reduced postural control and had a moderate antinociceptive effect compared to saline microinjections (P < 0.01 and 0.05, respectively, Wilcoxon test). In contrast, propofol did not induce "anaesthesia" in any animal tested, although a similar antinociceptive effect to that of thiopentone was observed (P < 0.05, Wilcoxon test). In summary, propofol and thiopentone have different effects when microinjected into the MPTA. While both agents reduced reflex withdrawal to a nociceptive stimulus, only thiopentone induced an "anaesthesia-like" state.
Microinjection of pentobarbital and GABA(A)-receptor agonists into a brainstem region we have called the mesopontine tegmental anesthesia area (MPTA; Devor and Zalkind [2001] Pain 94:101-112) induces a general anesthesia-like state. As in systemic general anesthesia, rats show loss of the righting reflex, atonia, nonresponsiveness to noxious stimuli, and apparent loss of consciousness. GABA(A) agonist anesthetics acting on the MPTA might suppress movement by engaging endogenous motor regulatory systems previously identified in research on decerebrate rigidity and REM sleep atonia. Anterograde and retrograde tracing revealed that the MPTA has multiple descending projections to pontine and medullary areas known to be associated with motor control and atonia. Prominent among these are the dorsal pontine reticular formation and components of the rostral ventromedial medulla (RVM). The MPTA also has direct projections to the intermediate gray matter and ventral horn of the spinal cord via the lateral and anterior funiculi. These projections show a rostrocaudal topography: neurons in the rostral MPTA project to the RVM, but only minimally to the spinal cord, while those in the caudal MPTA project to both targets. Finally, the MPTA has ascending projections to motor control areas including the substantia nigra, subthalamic nucleus, and the caudate-putamen. Projections are bilateral with an ipsilateral predominance. We propose that GABA(A) agonist anesthetics induce immobility at least in part by acting on these endogenous motor control pathways via the MPTA. Analysis of MPTA connectivity has the potential for furthering our understanding of the neural circuitry responsible for the various functional components of general anesthesia.
The neural correlates of consciousness must be identified, but how? Anesthetics can be used as tools to dissect the nervous system. Anesthetics not only allow for the experimental investigation into the conscious-unconscious state transition, but they can also be titrated to subanesthetic doses in order to affect selected components of consciousness such as memory, attention, pain processing, or emotion. A number of basic neuroimaging examinations of various anesthetic agents have now been completed. A common pattern of regional activity suppression is emerging for which the thalamus is identified as a key target of anesthetic effects on consciousness. It has been proposed that a neuronal hyperpolarization block at the level of the thalamus, or thalamocortical and corticocortical reverberant loops, could contribute to anesthetic-induced unconsciousness. However, all anesthetics do not suppress global cerebral metabolism and cause a regionally specific effect on thalamic activity. Ketamine, a so-called dissociative anesthetic agent, increases global cerebral metabolism in humans at doses associated with a loss of consciousness. Nevertheless, it is proposed that those few anesthetics not associated with a global metabolic suppression effect might still have their effects on consciousness mediated at the level of thalamocortical interactions, if such agents scramble the signals associated with normal neuronal network reverberant activity. Functional and effective connectivity are analysis techniques that can be used with neuroimaging to investigate the signal scrambling effects of various anesthetics on network interactions. Whereas network interactions have yet to be investigated with ketamine, a thalamocortical and corticocortical disconnection effect during unconsciousness has been found for both suppressive anesthetic agents and for patients who are in the persistent vegetative state. Furthermore, recovery from a vegetative state is associated with a reconnection of functional connectivity. Taken together these intriguing observations offer strong empirical support that the thalamus and thalamocortical reverberant network loop interactions are at the heart of the neurobiology of consciousness.
Clinical observations have established that certain parts of the brain are essential for consciousness whereas other parts are not. For example, different areas of the cerebral cortex contribute different modalities and submodalities of consciousness, whereas the cerebellum does not, despite having even more neurons. It is also well established that consciousness depends on the way the brain functions. For example, consciousness is much reduced during slow wave sleep and generalized seizures, even though the levels of neural activity are comparable or higher than in wakefulness. To understand why this is so, empirical observations on the neural correlates of consciousness need to be complemented by a principled theoretical approach. Otherwise, it is unlikely that we could ever establish to what extent consciousness is present in neurological conditions such as akinetic mutism, psychomotor seizures, or sleepwalking, and to what extent it is present in newborn babies and animals. A principled approach is provided by the information integration theory of consciousness. This theory claims that consciousness corresponds to a system's capacity to integrate information, and proposes a way to measure such capacity. The information integration theory can account for several neurobiological observations concerning consciousness, including: (i) the association of consciousness with certain neural systems rather than with others; (ii) the fact that neural processes underlying consciousness can influence or be influenced by neural processes that remain unconscious; (iii) the reduction of consciousness during dreamless sleep and generalized seizures; and (iv) the time requirements on neural interactions that support consciousness.
Amnesia, hypnosis and immobility are essential components of general anaesthesia. This review highlights recent advances in our understanding of how these components are achieved at a molecular level.
Commonly used volatile anaesthetic agents such as isoflurane or sevoflurane cause immobility by modulating multiple molecular targets predominantly in the spinal cord, including gamma-aminobutyric acidA receptors, glycine receptors, glutamate receptors and TREK-1 potassium channels. In contrast, intravenously applied drugs such as propofol or etomidate depress spinal motor reflexes almost exclusively via enhancing gamma-aminobutyric acidA receptor function. Studies on knock-in animals showed that etomidate and propofol act via gamma-aminobutyric acidA receptors containing beta3 subunits, whereas gamma-aminobutyric acidA receptors including alpha2 and gamma subunits mediate the myorelaxant properties of diazepam. These findings suggest that a large fraction of gamma-aminobutyric acidA receptors in the spinal cord assemble from alpha2, beta3 and most probably gamma2 subunits. The hypnotic actions of etomidate are mediated by beta3-containing gamma-aminobutyric acidA receptors expressed in the brain. In contrast, gamma-aminobutyric acidA receptors harbouring beta2 subunits produce sedation, but not hypnosis. Furthermore, there is growing evidence that extrasynaptic gamma-aminobutyric acidA receptors in the hippocampus containing alpha5 subunits contribute to amnesia.
Clinical anaesthesia is based on drug actions at multiple anatomical sites in the brain. The finding that amnesia, hypnosis and immobility involve distinct molecular targets opens new avenues for developing improved therapeutic strategies in anaesthesia.
Classical anesthetics of the gamma-aminobutyric acid type A receptor (GABA(A))-enhancing class (e.g., pentobarbital, chloral hydrate, muscimol, and ethanol) produce analgesia and unconsciousness (sedation). Dissociative anesthetics that antagonize the N-methyl-D-aspartate (NMDA) receptor (e.g., ketamine, MK-801, dextromethorphan, and phencyclidine) produce analgesia but do not induce complete loss of consciousness. To understand the mechanisms underlying loss of consciousness and analgesia induced by general anesthetics, we examined the patterns of expression of c-Fos protein in the brain and correlated these with physiological effects of systemically administering GABAergic agents and ketamine at dosages used clinically for anesthesia in rats. We found that GABAergic agents produced predominantly delta activity in the electroencephalogram (EEG) and sedation. In contrast, anesthetic doses of ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects, ketamine induced Fos expression in cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep-promoting ventrolateral preoptic nucleus (VLPO). In contrast, GABAergic agents suppressed Fos in the same arousal-promoting systems but increased the number of Fos-immunoreactive neurons in the VLPO compared with waking control animals. All anesthetics tested induced Fos in the spinally projecting noradrenergic A5-7 groups. 6-hydroxydopamine lesions of the A5-7 groups or ibotenic acid lesions of the ventrolateral periaqueductal gray matter (vlPAG) attenuated antinociceptive responses to noxious thermal stimulation (tail-flick test) by both types of anesthetics. We hypothesize that neural substrates of sleep-wake behavior are engaged by low-dose sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the analgesic effects of both NMDA receptor antagonists and GABA(A) receptor-enhancing anesthetics.
1. Stimulation of the reticular formation of the brain stem evokes changes in the EEG, consisting of abolition of synchronized discharge and introduction of low voltage fast activity in its place, which are not mediated by any of the known ascending or descending paths that traverse the brain stem. The alteration is a generalized one but is most pronounced in the ipsilateral hemisphere and, sometimes, in its anterior part. 2. This response can elicited by stimulating the medical bulbar reticular formation, pontile and midbrain tegmentum, and dorsal hypothalamus and subthalamus. The bulbar effect is due to ascending impulses relayed through these more cephalic structures. The excitable substrate possesses a low threshold and responds best to high frequencies of stimulation. 3. Some background synchrony of electrocortical activity is requisite for manifestation of the response. In the "encephale isolé", reticular stimulation has no additional effect upon the fully activated EEG. With synchrony, in spontaneous drowsiness or light chloralosane anesthesia, the effect of reticular stimulation is strikingly like Berger's alpha wave blockade, or any arousal reaction. In full chloralosane anesthesia, high voltage slow waves are blocked but no increase in lower amplitude, fast activity occurs. With barbiturate anesthesia, the reticular response is difficult to elicit or is abolished. 4. In the chloralosane preparation, the secondary cortical response evoked by a sensory volley is generally unaffected by reticular stimulation. Consequent sensory after-discharge is abolished, however, as is pyramidal tract discharge and jerky movements referable to it. Outside the sensory receiving area, secondary responses themselves may be reduced or prevented. 5. The convulsive spikes produced by local strychnine and those of a fit following supramaximal cortical excitation, are not decreased by stimulating the reticular formation. 6. The cortical recruiting response induced by low frequency stimulation of the diffuse thalamic projection system is reduced or abolished by reticular stimulation. 7. There is some indication that the cortical effect of reticular stimulation may be mediated by this diffuse thalamic projection system, for synchronized activity within it is similarly prevented by reticular excitation, and direct high frequency stimulation of this system, within the thalamus, reproduces the reticular response. It is possible, however, that other mechanisms may be involved in its mediation. 8. The reticular response and the arousal reaction to natural stimuli have been compared in the "encéphale isolé", in which EEG synchrony was present during spontaneous relaxation or was produced by recruiting mechanisms, and the two appear identical. 9. The possibility that the cortical arousal reaction to natural stimuli is mediated by collaterals of afferent pathways to the brain stem reticular formation, and thence through the ascending reticular activating system, rather than by intra-cortical spread following the arrival of afferent impulses at the sensory receiving areas of the cortex, is under investigation. 10. The possibility is considered that a background of maintained activity within this ascending brain stem activating system may account for wakefulness, while reduction of its activity either naturally, by barbiturates, or by experimental injury and disease, may respectively precipitate normal sleep, contribute to anesthesia or produce pathological somnolence.
The mechanisms through which general anaesthetics, an extremely diverse group of drugs, cause reversible loss of consciousness have been a long-standing mystery. Gradually, a relatively small number of important molecular targets have emerged, and how these drugs act at the molecular level is becoming clearer. Finding the link between these molecular studies and anaesthetic-induced loss of consciousness presents an enormous challenge, but comparisons with the features of natural sleep are helping us to understand how these drugs work and the neuronal pathways that they affect. Recent work suggests that the thalamus and the neuronal networks that regulate its activity are the key to understanding how anaesthetics cause loss of consciousness.
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