Current and Developing Approaches for Facilitating Emergence from General Anesthesia

Anesthesiology · 2025-09-09 · 5 citations

Despite the widespread use of clinical anesthesia, the process of emergence from general anesthesia remains primarily driven by anesthetic elimination. Although emergence from general anesthesia is typically safe, prolonged delays strain resource-intensive settings and contribute to increased healthcare costs. In addition to improving access to care, providing clinicians with more precise control over emergence could offer diagnostic potential and improve patient outcomes. For decades, this unmet need has motivated research into the mechanisms underlying anesthetic emergence. Now, the first agents for facilitating emergence are entering the market, with more in development. This narrative review critically evaluates advancements in the development of emergence-promoting therapies, examining insights from preclinical research to clinical trials. This study categorizes prospective emergence agents/strategies into one of three primary approaches: (1) strategies that primarily manipulate anesthetic pharmacokinetics, (2) agents designed to directly target anesthetic receptor-binding sites, and (3) strategies that leverage arousal-promoting neural pathways. The parallel development of these approaches, each with their distinct strengths and limitations, holds promise for paving the way for a tailored approach to facilitate emergence.

Convergent Control of NREM Sleep and Anesthesia by Prefrontal Layer 5 Extratelencephalic Neurons

Research Square · 2025-11-19

Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness

Communications Biology · 2025-08-20 · 2 citations

Understanding the neurophysiological changes underlying conscious-unconscious transitions is a key goal in neuroscience. Using magnetic resonance neuroimaging, we investigate the network connectivity and neurovascular changes occurring as the human brain transitions from wakefulness to dexmedetomidine-induced hypnosis, and recovery. Hypnosis led to widespread decreases in functional connectivity strength and increased structure-function coupling, indicating functional patterns more constrained by the underlying anatomical connectivity. As individuals began to regain consciousness, both connectivity markers returned towards awake levels, with particularly prominent coupling changes across the cerebellum. Neurovascular dynamics were disrupted during hypnosis as well: cerebral blood flow decreased globally-most notably in the brainstem, thalamus, and cerebellum-and continued decreasing even as recovery commenced, except within the cerebellum. Notably, regions with higher functional connectivity strength during wakefulness exhibited greater blood flow reductions during hypnosis. Hypnosis also heightened the amplitude of low-frequency fluctuations in the hemodynamic signal, especially in visual and somatomotor regions. Critically, individuals who regained consciousness faster displayed higher baseline levels of both neurovascular, but not connectivity, markers. Together, these results reveal that the induction of, and emergence from, dexmedetomidine-induced unconsciousness involve widespread, coordinated changes in brain connectivity and neurovascular function; across our findings, we also highlight the recurrent role of cerebellum in conscious-unconscious transitions.

The Administration of Ketamine Is Associated with Dose-Dependent Stabilization of Cortical Dynamics in Humans

Journal of Neuroscience · 2025-04-09 · 5 citations

During wakefulness, external stimuli elicit conscious experiences. In contrast, dreams and drug-induced dissociated states are characterized by vivid internally generated conscious experiences and reduced ability to perceive external stimuli. Understanding the physiological distinctions between normal wakefulness and dissociated states may therefore disambiguate signatures of responsiveness to external stimuli from those that underlie conscious experience. The hypothesis that conscious experiences are associated with brain criticality has received considerable theoretical and experimental support. Consistent with this hypothesis, statistical signatures of criticality are similar in normal wakefulness and dissociative states but are abolished in dreamless sleep and under anesthesia. Thus, while statistical measures of criticality are associated with the ability to have conscious experience, they do not readily distinguish between perception of the external world from internally generated percepts. Here, we investigate distinct, dynamical, signatures of criticality during escalating ketamine doses in high-density EEG in human male volunteers. We show that during normal wakefulness, EEG is found at a critical point between damped and exploding oscillations. With increasing doses of ketamine, as dissociative symptoms intensify, activity is progressively stabilized-most prominently at higher frequencies. We also show that stabilization is a more reliable marker of the effects of ketamine than conventional measures such as power spectra. These findings suggest that stabilization of cortical dynamics correlates with decreased ability to respond to and perceive external stimuli rather than the ability to have conscious experiences per se. Altogether, these results suggest that combining statistical and dynamical criticality measures may distinguish wakefulness, dissociation, and unconsciousness.

Convergent Control of NREM Sleep and Anesthesia by Prefrontal Layer 5 Extratelencephalic Neurons

bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-11

The cortical mechanisms that actively suppress consciousness remain poorly understood. Here, we identify a specific subset of prefrontal cortical (PFC) neurons preferentially active under anesthesia while most neurons are suppressed. Chemogenetic activation of these excitatory neurons enhances anesthetic potency and deepens NREM sleep, whereas their inhibition blunts anesthetic effects. We identify these NREM and Anesthesia Promoting (NAP) neurons as PFC Layer 5 extratelencephalic (L5 ET) neurons. Remarkably, NAPs have sparse cortical projections and predominately communicate with subcortical nuclei including anterior and reticular thalamic nuclei, hypothalamus, and claustrum. We identify a transgenic mouse line that labels L5 ET neurons and verify that PFC L5 ET neurons are uniquely activated under anesthesia. Furthermore, we show that activation of PFC L5 ET neurons promotes deep NREM sleep. These findings identify a unique excitatory PFC circuit that promotes both naturally-occurring and drug-induced unconsciousness, with implications for both sleep regulation and anesthetic action.

Alluring Potential to Accelerate Emergence and Ameliorate Opioid-induced Respiratory Depression without Antagonizing Analgesia: Danavorexton Enters the Anesthetic Landscape

Anesthesiology · 2025-03-11

Parafacial GABAergic neurone ablation induces behavioural resistance to volatile anaesthetic-induced hypnosis without reducing sleep

British Journal of Anaesthesia · 2025-04-15 · 3 citations

<h2>Abstract</h2><h3>Background</h3> It is hypothesised that general anaesthetics co-opt the neural circuits regulating endogenous sleep and wakefulness to produce hypnosis. To further probe this association, we focused on the GABAergic neurones of the parafacial zone (PZ^GABA), a brainstem site capable of promoting non-rapid eye movement sleep. <h3>Methods</h3> To determine whether PZ neurones are activated by a hypnotic dose of anaesthetics, c-Fos immunohistochemistry was performed. The behavioural and physiological contributions of PZ^GABA neurones to anaesthetic sensitivity were assessed in mice transfected with an adeno-associated virus (AAV)-driving expression of an mCherry fluorescent control or a caspase that irreversibly eliminates PZ^GABA neurones. EEG-defined sleep was measured in PZ^GABA-ablated and mCherry control mice, as was the homeostatic drive to sleep after sleep deprivation. <h3>Results</h3> Consistent with anaesthetic-induced depolarisation, hypnotic doses of isoflurane significantly increased c-Fos expression three-fold in PZ^GABA neurones compared with oxygen-exposed mice. PZ^GABA-ablated mice developed significant and durable behavioural resistance to both isoflurane- and sevoflurane-induced hypnosis, with roughly 50% higher likelihood of intact righting than controls. PZ^GABA-ablated mice emerged from isoflurane significantly faster than mCherry controls with purposeful movements. The degree of anaesthetic resistance was inversely correlated with the number of surviving PZ^GABA neurones. Despite confirming that PZ^GABA ablation reduced the potency of two distinct volatile anaesthetics behaviourally, ablation did not alter the amount of endogenous sleep or wakefulness, nor did it affect the homeostatic sleep drive after sleep deprivation, and it did not produce EEG signatures of anaesthetic resistance during isoflurane exposure. <h3>Conclusions</h3> There was an unexpected dissociation in which destruction of up to 70–80% of PZ^GABA neurones was sufficient to alter anaesthetic susceptibility behaviourally without causing insomnia or altering sleep pressure. These findings suggest that PZ^GABA neurones are more critical to drug-induced hypnosis than to the regulation of natural sleep and arousal.

Effects of the Quinone Analog Ubiquinone-5 on Murine Mitochondria and Hypnosis

Anesthesiology · 2025-05-02 · 3 citations

BACKGROUND: A functional anesthetic target has long been suspected to reside within mitochondria, and disruption of bioenergetic capacity is believed to play a role in the anesthetic response. Unfortunately, the exact mechanism by which changes in mitochondrial target activity result in clinically relevant anesthetic endpoints remains unknown. Here, the authors leveraged knowledge of propofol toxicity to guide drug discovery and uncover a previously unknown pharmacologic target within mitochondria. They hypothesized that, like propofol, quinone analogs would interfere with electron transfer, cause excessive proton leak within mitochondria, and induce hypnosis. The authors tested their hypothesis using the short-chain coenzyme Q analog ubiquinone-5 (Ub5) and aimed to characterize its anesthetic phenotype in the mouse and elucidate the source of Ub5-induced mitochondrial leak. METHODS: Anesthetic phenotype was assessed in vivo in the mouse using behavioral and neurophysiological approaches. The authors measured biologic activity in isolated mitochondria using polarography and spectrophotometry and identified source of proton leak using pharmacologic inhibitors, mutant mouse strains, and transport activity assays in proteoliposomes. Finally, they assessed cardiotoxic effects in the isolated-perfused mouse heart ex vivo . RESULTS: Coenzyme Q analogs caused uncompensated proton leak in developing cardiomyocyte mitochondria and reversible cardiotoxicity in a manner reminiscent of propofol. Tail vein injection of Ub5 induced short-lived loss of righting, electroencephalogram changes consistent with a deep state of anesthesia, and reversible decreases in neuronal calcium transients and mitochondrial membrane potential in vivo . Precipitous decline in mitochondrial membrane potential played a role in Ub5-induced unconsciousness, and the authors identified the aspartate-glutamate carrier Aralar as a functional target and source of Ub5-mediated proton leak. CONCLUSIONS: The data indicate that uncompensated mitochondrial proton leak is an important mechanistic contributor to the anesthetic response in addition to electron transport inhibition. These findings advance the authors' understanding of how anesthetics induce hypnosis and lay the foundation for next-generation drug discovery.

Reanimation of rodents: an animal model for cognitive recovery from anaesthesia

British Journal of Anaesthesia · 2025-08-01