Consciousness, Memory, and Anesthesia

Key Points

▪
Mechanisms of consciousness and memory, and their interruption by general anesthetics, are important scientific problems that have clinical relevance for the practice of anesthesiology.
▪
Consciousness is characterized by both wakefulness (i.e., the brain being aroused) and awareness (i.e., subjective experience).
▪
Anesthetics act at structures in the brainstem, hypothalamus, and basal forebrain that regulate sleep-wake states, which may account for loss of wakefulness.
▪
Anesthetics disrupt connectivity and communication across cortical and thalamocortical networks, which may account for loss of awareness.
▪
Memory can be subdivided into explicit (conscious) and implicit (unconscious) recall; an example of explicit episodic recall is remembering a surgical event.
▪
Suppression of explicit episodic recall is one of the most potent effects of most general anesthetics.
▪
Effects on the hippocampus, amygdala, and prefrontal cortex—as well as the connectivity of these structures—may account for anesthetic-induced amnesia, even before loss of consciousness.

Introduction

Scientific and Clinical Importance

Consciousness and memory are among the most fascinating and complex subjects in all of science. The richness of human consciousness and memory—and the ability to express this richness in language—is a defining characteristic of homo sapiens . Consciousness and memory also have clinical relevance for the anesthesiologist; together, the experience and explicit episodic recall of surgical events is known as the problem of “intraoperative awareness.” When formally assessed, this complication occurs in approximately 1 to 2 cases per 1000 and is associated with a high incidence of posttraumatic stress disorder (PTSD). The incidence of intraoperative consciousness without recall is substantially higher. To advance the field of perioperative brain monitoring, a detailed understanding of the neurobiology of consciousness, memory, and anesthesia is required.

Consciousness

Definitions

The field of consciousness studies has been plagued by the indiscriminate use of the term “consciousness.” When we refer to consciousness, we mean subjective experience . In simple terms, it is what we lose when we have dreamless sleep and what we regain again in the morning upon awakening. There are, however, several important definitions and distinctions that should be considered.

1.
Awareness : Cognitive neuroscientists and philosophers use the term “awareness” to mean only subjective experience. In clinical anesthesiology, we (inaccurately) use the term “awareness” to include both consciousness and explicit episodic memory (the taxonomy of memory will be discussed in the next major section of the chapter).
2.
Connected versus disconnected consciousness : Connected consciousness is the experience of environmental stimuli (such as surgery), whereas disconnected consciousness is an endogenous experience (such as a dream state).
3.
Consciousness versus responsiveness : An individual may fully experience a stimulus (such as the command “Open your eyes!”) but not be able to respond (as when a patient is paralyzed but conscious during surgery).

There have been a number of theories proposed to explain the mechanisms of consciousness and general anesthesia. Advances in neuroscience, however, have enabled us to move beyond speculative frameworks and focus on a systems-based approach to both subjects. The remainder of this section on consciousness adopts such an approach by discussing (1) brainstem and hypothalamic nuclei regulating the sleep-wake cycle (and therefore arousal states) ( Figs. 9.1 and 9.2 ); (2) the role of the thalamus in consciousness and anesthesia; (3) cortical-subcortical connectivity, with a focus on the thalamocortical system, which is thought to mediate the experiential component of consciousness; and (4) corticocortical communication.

Fig. 9.1, Neurobiology of wakefulness. Multiple neurochemical systems in subcortical regions (shown here in rodent brain) promote arousal and activation of the cortex. Monoaminergic neurons (light green) in the rostral brainstem and caudal hypothalamus innervate the cortex as well as many subcortical regions including the hypothalamus and thalamus. These monoaminergic regions include noradrenergic neurons (locus coeruleus), serotonergic neurons (dorsal and median raphe nuclei), dopaminergic neurons (ventral tegmental area), and histaminergic neurons (tuberomammillary nucleus). Wake-promoting signals also arise from cholinergic regions (dark green with hatching) , including the pedunculopontine and laterodorsal tegmental nuclei and basal forebrain. General anesthetics have been demonstrated to suppress many of these regions.

Fig. 9.2, Neurobiology of slow-wave sleep. GABA-ergic neurons in the ventrolateral preoptic area and median preoptic nucleus in the hypothalamus (shown here in rodent brain) promote sleep by inhibiting wake-promoting neurons in the caudal hypothalamus and brainstem. These hypothalamic nuclei are activated by general anesthetics.

Subcortical Nuclei Regulating Arousal

It was hypothesized in the mid-1990s that anesthetics suppress consciousness by actions at the subcortical nuclei that evolved to control sleep-wake cycles. The past decades have supported the hypothesis that anesthetics interact with a number of these sleep-wake centers, although precise interactions and contributions to the state of general anesthesia have yet to be elucidated. The following is a description of select subcortical nuclei in the brainstem and hypothalamus that mediate sleep-wake cycles and, potentially, some traits of anesthesia.

Brainstem

Locus ceruleus

Norepinephrine is synthesized in the locus ceruleus (LC), which is located in the pons and projects widely throughout the cortex. Like other monoaminergic neuronal populations, LC activity is highest during waking consciousness, decreased during nonrapid eye movement (NREM) sleep, and at its nadir during rapid eye movement (REM) sleep. Thus LC is associated with cortical arousal only during wakefulness and not with the cortical activation during REM sleep. LC neurons are hyperpolarized by halothane. The role of norepinephrine (generated by LC) in anesthesia is further supported by studies demonstrating that barbiturate anesthesia time is increased by antagonizing norepinephrine and reduced by agonizing it. Norepinephrine transmission in the basal forebrain may be of particular relevance to anesthetic depth. It has been found that LC noradrenergic neurons modulate the state of isoflurane anesthesia as well as emergence therefrom. Of note, administration of ketamine is associated with an increase of activity in the LC and appears to contribute to its anesthetic effects.

LC and the role of norepinephrine in hypnosis are of particular interest due to the role of the α-2 agonist dexmedetomidine in clinical care. Microinjection of dexmedetomidine in the LC results in reduced levels of consciousness that can be prevented by coadministration of the α-2 antagonist atipamezole. After exposure to dexmedetomidine, brain changes somewhat mimic NREM sleep in that the LC and tuberomammillary nucleus (TMN) are deactivated, whereas the ventrolateral preoptic nucleus (VLPO) is activated. Data in dopamine-β-hydroxylase knockout mice (which lack the ability to synthesize norepinephrine) demonstrate a hypersensitivity to dexmedetomidine, suggesting alternative mechanisms of action. However, selective knockdown of α-2A adrenergic receptors from LC prevent dexmedetomidine-induced loss of righting reflex, a marker of general anesthesia in rodents.

Laterodorsal/pedunculopontine tegmentum

Along with the basal forebrain, the laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT) in the pons are the brain’s source of acetylcholine. There are direct projections to the thalamus from LDT/PPT with a known role in the generation of slow oscillations and sleep spindles, which together represent a neurophysiologic sign that information transfer to the cortex is likely blocked. As with the noradrenergic LC, activity of the LDT/PPT is high during waking consciousness and decreases during NREM sleep. However, in contrast to the LC and other monoaminergic neurons, the cholinergic LDT/PPT is also active during REM sleep, during which the cortex is aroused. Furthermore, activation of cholinergic neurons in LDT or PPT induces REM sleep. Thus, both states of cortical activation across the sleep-wake cycle are associated with high cholinergic tone. General anesthetics modulate cholinergic projections from the LDT/PPT. Sleep spindles occur during halothane anesthesia and are associated with decreased cholinergic transmission to the medial pontine reticular formation (PRF). There is evidence that synaptic and extrasynaptic γ-aminobutyric acid (GABA) receptors play a role in modulating LDT neurons, which could provide a direct link to molecular mechanisms of numerous general anesthetics. However, there has been relatively little study of the role of LDT/PPT in anesthetic mechanisms, with a greater focus on cholinergic neurons in the basal forebrain.

Pontine reticular formation

The PRF is part of the reticular activating system, which plays an important role in cortical arousal. Although GABA is the primary inhibitory neurotransmitter in the brain, the actions of GABA in the PRF are associated with cortical arousal. For example, there is increased time spent in the waking state when the GABA _A receptor agonist muscimol is microinjected in the PRF. When the GABA _A antagonist bicuculline is microinjected, wakefulness is suppressed, but REM sleep (another state of cortical arousal) is triggered. Vanini and colleagues found that decreased levels of GABA in the PRF correlated with isoflurane-induced unconsciousness, muscular hypotonia, and decreased respiratory rate. Since the effects of anesthetics are normally associated with a potentiation of GABA activity, these findings highlight that a specific neuroanatomic and neurochemical milieu can play a unique and unexpected role in the mechanisms of consciousness and anesthesia. In addition, Vanini and colleagues found that GABA-ergic transmission in the rat PRF modulates the loss of consciousness induced by isoflurane but does not appear to affect emergence, providing evidence for asymmetry between the two processes.

The mesopontine tegmental anesthesia area is located in the PRF. When pentobarbital is microinjected in this area, a reversible state with anesthetic traits is induced. More recently, this phenomenon has been defined with greater spatial resolution, with the identification of around 1900 neurons in this area that can induce general anesthesia.

Ventral tegmental area

Dopaminergic neurons of the ventral tegmental area (VTA) in the midbrain have not classically been considered key mediators of the sleep-wake cycle because of relatively less evidence of state-dependent changes compared with neurons in other brainstem nuclei. This view has been challenged in sleep neurobiology. A dopaminergic pathway regulating sleep-wake states has been identified in Drosophila and dopaminergic neurons of the VTA have more recently been found to play a role in mammalian sleep. There has been renewed interest in the ability of dopaminergic activity to reverse or accelerate recovery from general anesthesia. Studies of the dopamine agonist methylphenidate have revealed an ability to reverse the sedative effects of both isoflurane and propofol. VTA appears to be the source of the dopaminergic transmission mediating arousal during exposure to anesthesia, as evidenced by the fact that electrical stimulation of the VTA or selective stimulation of VTA dopaminergic neurons can reverse anesthetic-induced unconsciousness.

Hypothalamus

Ventrolateral preoptic nucleus

The anterior hypothalamus has long been hypothesized to play a role in sleep-wake regulation. VLPO is a structure in this region that transmits GABA and galanin. Neurons in VLPO are maximally active during NREM and REM sleep; the median preoptic nucleus (MnPO) is also active during sleep. Of note, the activity profile of GABA-ergic neurons in VLPO correlates with sleep amount, whereas the activity of GABA-ergic neurons in MnPO correlates with homeostatic sleep pressure or propensity. Importantly, activity of the VLPO during sleep is correlated with inhibition of other arousal centers in the brainstem and hypothalamus. Given its potentially central role as a mediator of sleep, VLPO became an attractive candidate as a mediator of anesthetic-induced unconsciousness. Nelson and colleagues demonstrated activation of VLPO after systemic administration of propofol or pentothal ; recent studies have examined the mechanistic significance of these findings. Eikermann and colleagues conducted studies of rats with chronic lesions of VLPO, finding that ablation of VLPO resulted in sleep deprivation (as expected) but conferred increased sensitivity to the effects of isoflurane. This finding would argue against a critical role of VLPO in the mechanism of anesthesia. However, Moore and colleagues demonstrated that acute lesions of VLPO conferred resistance to the effects of isoflurane, an effect that appeared to be mediated specifically through the sleep-active neurons in VLPO. These neurons are actually depolarized (i.e., activated) by isoflurane. Taken together, these data suggest that VLPO plays a role in anesthetic-induced unconsciousness (as evidenced by acute lesion data), but that the effects of sleep deprivation associated with chronic VLPO lesions could overwhelm this role. Curiously, direct administration of dexmedetomidine, an α-2-adrenergic agonist, to the VLPO can destabilize the state of isoflurane anesthesia.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here