Brain state identification and neuromodulation to promote recovery of consciousness

Brain Communications, Journal Year: 2024, Volume and Issue: 6(5)

Published: Jan. 1, 2024

Abstract Experimental and clinical studies of consciousness identify brain states (i.e. quasi-stable functional cerebral organization) in a non-systematic manner largely independent the research into state modulation. In this narrative review, we synthesize advances identification associated with animal models physiological (sleep), pharmacological (anaesthesia) pathological (disorders consciousness) altered humans. We show that reduced frequencies which operates are slowed down pattern communication is sparser, less efficient, complex. The results also highlight damaged resting-state networks, particular default mode network, decreased connectivity long-range connections especially thalamocortical loops. Next, therapeutic approaches to treat disorders consciousness, through pharmacology (e.g. amantadine, zolpidem), (non-) invasive stimulation transcranial direct current stimulation, deep stimulation) have shown partial effectiveness promoting recovery. Although some features conscious may improve response neuromodulation, targeting often remains non-specific does not always lead (behavioural) improvements. fields neuromodulation relation showing fascinating developments that, when integrated, might propel development new better-targeted techniques for consciousness. here propose framework modulation facilitate interaction between two fields. should be identified predictive setting, followed by theoretical empirical testing models, under anaesthesia patients disorder promote line such predictions. This further helps where challenges opportunities lay maturation context It will become apparent one angle opportunity provided addition computational modelling. Finally, it aids recognizing possibilities obstacles translation these diagnostic treatment options across both multimodal multi-species outlined throughout review.

Language: Английский

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A probabilistic model of behavioural emergence from general anaesthesia in mice

British Journal of Anaesthesia, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Time to emergence from general anaesthesia is highly variable between individuals. This variability has been attributed individual differences in anaesthetic sensitivity. However, this hypothesis not verified experimentally. We explicitly test by quantifying repeatedly the same individuals over time. Genetically identical adult (12-24 weeks old) male (n=40) and female (n=20) C57BL/6J mice were exposed 2 h of isoflurane (0.90 vol%) on 10 separate occasions. was measured using return righting reflex. Predictions standard effect-site pharmacokinetic-pharmacodynamic (PK-PD) model neuronal dynamics stochastic fluctuations awake anaesthetised states fit observed times. Repeated steady-state assessments reflex obtained during last a 4-h exposure 0.3, 0.4, 0.6, or 0.7 vol% (n=20 per concentration) used determine probabilities losing reflex, which defined as an individual's Emergence times varied at least two orders magnitude after exposure. did find consistent inter-individual Instead, we found that across trials each large different correlated Consistent with previous work, identified sensitivity persisted time scale 1 week. A PK-PD failed reproduce inter-trial variability. In contrast, reproduced both population- individual-level Stochastic state switching contributes inherent anaesthesia. Delayed occurred small proportion exposures genetically homogeneous population. The predicts will be probabilistically long, might explain delayed clinical settings.

Language: Английский

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The Inhibition of Reactive Oxygen Species Modulator 1 Attenuates Sevoflurane-Induced Neural Injury via Reducing Apoptosis and Oxidative Stress

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(4)

Published: Oct. 16, 2024

Language: Английский

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How does the brain emerge from anesthesia and regain consciousness

Chinese Medical Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Herein, we first discuss advancements in our understanding of the mechanisms involved induction anesthesia. This includes fundamentals anesthesia as shaped by three influential theories: non-specific lipid theory, specific protein target and neural circuit theory. We then traditional identification purely passive recovery from due to elimination anesthetics body brain. is followed a recent study that has revealed common mechanism based on brain's intrinsic ability actively reboot consciousness Finally, novel theory how brain emerges regains presented. Advancements whereby loses or after General was used patients 1840s for clinical surgery. Since then, reversible loss (LOC) induced still unclear been complex elusive subject scientific challenge debate. Anesthesia-induced LOC model investigate neurobiological basis and, more recently, general principles function, including nature consciousness. The lipid, target, theories. These hypotheses provide explanations different perspectives levels induce There are pharmacological targets diverse As an overarching principle, it logical propose disrupt activity integrity function circuits responsible signal transmission conscious perception/subjective experience binding molecular through membrane-mediated targets.[1–5] However, there significant knowledge gaps process inhibition neuronal activity, disruption blocking information various anesthetics, For instance, some reagents act blockers/antagonists γ-aminobutyric acid type A (GABAARs) N-methyl-d-aspartate (NMDARs) receptors were initially believed LOC. this not case.[1] It hypothesized cognitive process, contrast anesthesia, which depends anesthetic hypothesis lacks solid experimental support does explain long delay emergence full have major challenges practice. Over past 20 years, extensive evidence animal studies shown artificial manipulation certain cortical subcortical nuclei along with arousal pathways can either reverse deepen accelerate its emergence. glutamatergic, GABAergic, cholinergic, noradrenergic, dopaminergic, orexigenic efferent circuitries nuclei, e.g., prefrontal cortex, basal forebrain, locus coeruleus, ventral tegmental area, etc., may play important roles emergence.[1,6–8] demonstrated dynamic controllable process. emerge LOC, considered until recently published study.[9] paradox plays decisive role regaining Molecular "active reboot" Under addition behavioral manifestations, such forms reflexes, undergoes changes at cellular levels. During anesthesia-induced subsequent recovery, power occurs between proposed apparent contradictions, these effects be characterized dynamic. contradictory proposals follows, external force leading internal cause Typically, pair contradictions dominant determines final outcome. Does regain LOC? provided showing active rebooting anesthesia.[9] When forced into minimum responsive state (MRS) rapid downregulation K+/Cl− cotransporter 2 (KCC2) posteromedial nucleus (VPM) thalamus serves Ubiquitin proteasomal degradation KCC2 downregulation, driven ubiquitin ligase Fbxl4. phosphorylation Thr1007 promotes interaction leads GABAAR-mediated disinhibition, enabling accelerated VPM excitability inhibition. intermediate step en route key points anesthesia[9] include following: first, distinct much earlier than observed discontinuation. almost simultaneously parallel induction, beginning when MRS continuing during exits state. Second, anesthetic-induced action. KCC2, neuron-specific isoform cotransporter, transports Cl− out cell.[10] Normal expression essential maintenance inhibitory GABAAR responses. under impairs reduces Third, mediated ubiquitin-proteasomal degradation, but previously recognized NMDAR–Ca2+–calpain brain-derived neurotrophic factor (BDNF)–tropomyosin receptor kinase B (TrkB) activation.[11–15] Activity-dependent via NMDAR-Ca2+–calpain BDNF–TrkB activation context increased excitability; however, decreased excitability. Fourth, independent highlighted targets. KCC2-Thr1007 causes KCC2. Although ketamine produces acting NMDARs propofol; pentobarbital isoflurane produce GABAARs, increases ketamine, propofol, pentobarbital, occur NMDAR activity. Changes EGABA occurred independently GABAAR. Propofol, activating GABAARs. propofol KCC2-phosphorylation HEK293 cells overexpressing (wild-type [WT] mutant), whereas no expressed cells. supports notion isoflurane, their proteins, NMDARs.[9] successfully downregulation-independent continues. later depend clearance body; reversal patterns anesthetic-related nuclei; targets, neurotransmitter systems, circuits, other unknown mechanisms.[1] Novel Based progress studies, previous assumptions, inferences about following analogy conceptualized; neurons serve "power generators" connected networks, lines" exchange signals. Anesthesia disrupts outage". Ubiquitin-proteasomal "reboot" within neuron restore thalamocortical activation. Thus, balance if allow would without effective work generators", could even termination removal anesthetics. Conversely, sustained high enough concentrations, anesthesia-interrupted lines", regardless speed intensity worked. Artificial anesthesia-inhibited systems help therefore synergistically interact all necessary resulting unconsciousness concept illustrated Figure 1. while significantly innovative, further research reliable basis.Figure 1: An illustrative diagram thalamus. LOC: Loss consciousness; MRS: Mini­mum state; VPM: Ventral nucleus; KCC2: 2.Acknowledgments thank William Song University Pennsylvania Perelman Medical School his thoughtful comments suggestions. Funding partly supported grant National Natural Science Foundation China (No. 82350710225). Conflicts interest None.

Language: Английский

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VCP controls KCC2 degradation through FAF1 recruitment and accelerates emergence from anesthesia

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 122(1)

Published: Dec. 30, 2024

Ubiquitin-proteasomal degradation of K + /Cl − cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) has been demonstrated to serve as a common mechanism by which brain emerges from anesthesia and regains consciousness. KCC2 during is driven E3 ligase Fbxl4. However, ubiquitinated targeted proteasome not elucidated. We report cultured neuro-2a cells that valosin-containing protein (VCP) transported mice vivo experiments inhibition VCP restored expression VPM enhanced effects anesthesia. In cells, propofol-induced was inhibited inhibitor DBeQ knockout plasmid sgRNA(VCP). Propofol-induced interaction between Fbxl4 or Fas-associated factor 1 (FAF1). studies, pharmacological genetic significantly prevented propofol anesthesia; these were abrogated antagonist VU0463271. These results demonstrate controls ubiquitin-proteasomal dependent on FAF1 recruitment serves for KCC2, responsible subsequent emergence

Language: Английский

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