Cerebellar Purkinje cell firing promotes conscious recovery from anesthesia state through coordinating neuronal communications with motor cortex.

Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.

Consciousness and General Anesthesia: Challenges for Measuring the Depth of Anesthesia.

The optimal consciousness level required for general anesthesia with surgery is unclear, but in existing practice, anesthetic oblivion, may be incomplete. This article discusses the concept of consciousness, how it is altered by anesthetics, the challenges for assessing consciousness, currently used technologies for assessing anesthesia levels, and future research directions. Wakefulness is marked by a subjective experience of existence (consciousness), perception of input from the body or the environment (connectedness), the ability for volitional responsiveness, and a sense of continuity in time. Anesthetic drugs may selectively impair some of these components without complete extinction of the subjective experience of existence. In agreement with Sanders et al. (2012), the authors propose that a state of disconnected consciousness is the optimal level of anesthesia, as it likely avoids both awareness and the possible dangers of oversedation. However, at present, there are no reliably tested indices that can discriminate between connected consciousness, disconnected consciousness, and complete unconsciousness.

Criticality supports cross-frequency cortical-thalamic information transfer during conscious states.

Consciousness is thought to be regulated by bidirectional information transfer between the cortex and thalamus, but the nature of this bidirectional communication - and its possible disruption in unconsciousness - remains poorly understood. Here, we present two main findings elucidating mechanisms of corticothalamic information transfer during conscious states. First, we identify a highly preserved spectral channel of cortical-thalamic communication that is present during conscious states, but which is diminished during the loss of consciousness and enhanced during psychedelic states. Specifically, we show that in humans, mice, and rats, information sent from either the cortex or thalamus via δ/θ/α waves (∼1-13 Hz) is consistently encoded by the other brain region by high γ waves (52-104 Hz); moreover, unconsciousness induced by propofol anesthesia or generalized spike-and-wave seizures diminishes this cross-frequency communication, whereas the psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) enhances this low-to-high frequency interregional communication. Second, we leverage numerical simulations and neural electrophysiology recordings from the thalamus and cortex of human patients, rats, and mice to show that these changes in cross-frequency cortical-thalamic information transfer may be mediated by excursions of low-frequency thalamocortical electrodynamics toward/away from edge-of-chaos criticality, or the phase transition from stability to chaos. Overall, our findings link thalamic-cortical communication to consciousness, and further offer a novel, mathematically well-defined framework to explain the disruption to thalamic-cortical information transfer during unconscious states.

Efficacy of remimazolam tosilate versus propofol for total intravenous anaesthesia in urological surgery: A randomised clinical trial.

BACKGROUND: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that acts on the gamma-aminobutyric acid type A receptor (GABAAR). OBJECTIVE: To compare the efficacies of remimazolam (RMZ), and propofol (PROP) combined with remifentanil and cisatracurium for total intravenous anaesthesia (TIVA) in patients undergoing urological surgery. DESIGN: A prospective, single-blind, randomised, noninferiority clinical trial. SETTING: Single centre from 1 January 2022 to 30 March 2022. PATIENTS: A total of 146 adult patients undergoing elective urological surgery. INTERVENTION: Patients were randomly allocated in a 1 : 1 ratio to the PROP or RMZ groups. In the PROP group, anaesthesia was induced with propofol at 100 mg min -1 to reach a bispectral index score (BIS) of 40 to 60. After loss of consciousness (LOC), intravenous fentanyl 3 µg kg -1 was administered, followed by cisatracurium 0.3 mg kg -1 . Patients were intubated 3 min after cisatracurium administration. Anaesthesia was maintained with the combination of propofol (plasma concentration: 2.5 to 4 µg ml -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). In the RMZ group, anaesthesia was induced with remimazolam tosilate starting at 10 mg kg -1  h -1 to reach a BIS of 40 to 60 and maintained between 0.2 and 2 mg kg -1  h -1 . After LOC, fentanyl and cisatracurium were administered and intubation was performed as in the PROP group. Anaesthesia was maintained with a combination of remimazolam (0.2 to 2 mg kg -1  h -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). MAIN OUTCOME MEASURES: The primary outcome was the TIVA success rate. The predefined noninferiority margin considered an absolute difference of 6% in the primary outcome between the groups. The secondary outcomes were vital signs, anaesthesia and surgery characteristics, and adverse events. RESULTS: All patients completed the trial. The success rates of TIVA with remimazolam and propofol were 100 and 98.6%, respectively. The incidence of hypotension during anaesthesia was lower in the RMZ group (26%) than in the PROP group (46.6%) ( P  = 0.016). The median [IQR] total consumption of ephedrine during anaesthesia was higher in the PROP group 10 [0 to 12.5] mg than in the RMZ group 0 [0 to 10] mg ( P  = 0.0002). The incidence of injection pain was significantly higher in the PROP group (76.7%) than in the RMZ group (0; P  < 0.001). No significant differences in the controllability of the anaesthesia depth, anaesthesia and surgery characteristics, or vital signs were observed between the groups. CONCLUSION: Remimazolam demonstrated noninferior efficacy to propofol combined with remifentanil and cisatracurium for TIVA in patients undergoing urological surgery. TRIAL REGISTRATION: Chictr.org.cn, identifier: ChiCTR2100050923. CLINICAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100050923, Principal investigator: Xuehai Guan, Date of registration: 8 November 2021, https://www.chictr.org.cn/showproj.html?proj=133466 ).

Impact of antithrombotic therapy on acute and delayed intracranial haemorrhage and evaluation of the need of short-term hospitalisation based on CT findings after mild traumatic brain injury: experience from an oral and maxillofacial surgery unit.

PURPOSE: The primary aim was to compare the prevalence of acute and delayed intracranial haemorrhage (ICH) following mild traumatic brain injury (mTBI) in patients on antithrombotic medication referred to a clinic for oral and plastic maxillofacial surgery. The secondary aim was to evaluate the need for short-term hospitalisation based on initial radiological and clinical findings. METHODS: This was an observational retrospective single-centre study of all patients on antithrombotic medication who were admitted to our department of oral and plastic maxillofacial surgery with mTBI over a 5 year period. Demographic and anamnesis data, injury characteristics, antithrombotic medication, radiological findings, treatment, and outcome were analysed. Patients were divided into the following four groups based on their antithrombotic medication: (1) single antiplatelet users, (2) vitamin K antagonist users, (3) direct oral anticoagulant users, and (4) double antithrombotic users. All patients underwent an emergency cranial CT (CT0) at admission. Based on clinical and radiological evaluation, different treatment protocols were applied. Patients with positive CT0 findings and patients with secondary neurological deterioration received a control CT (CT1) before discharge. Acute and delayed ICH and patient's outcome during hospitalisation were evaluated using descriptive statistical analysis. RESULTS: A total of 696 patients (mean age, 71.6 years) on antithrombotic medication who presented at our department with mTBI were included in the analysis. Most injuries were caused by a ground-level fall (76.9%). Thirty-six patients (5.1%) developed an acute traumatic ICH, and 47 intracerebral lesions were detected by radiology-most of these in patients taking acetylsalicylic acid. No association was detected between ICH and antithrombotic medication (p = 0.4353). In total, 258 (37.1%) patients were admitted for 48 h in-hospital observation. The prevalence of delayed ICH was 0.1%, and the mortality rate was 0.1%. Multivariable analysis identified a Glasgow Coma Scale (GCS) of < 15, loss of consciousness, amnesia, headache, dizziness, and nausea as clinical characteristics significantly associated with an increased risk of acute ICH, whereas age, sex, and trauma mechanism were not associated with ICH prevalence. Of the 39 patients who underwent a control CT1, most had a decreasing or at least constant intracranial lesion; in three patients, intracranial bleeding increased but was not clinically relevant. CONCLUSION: According to our experience, antithrombotic therapy does not increase the rate of ICH after mTBI. A GCS of < 15, loss of consciousness, amnesia, headache, dizziness, and nausea are indicators of higher ICH risk. A second CT scan is more effective in patients with secondary neurological deterioration. Initial CT findings were not clinically relevant and should not indicate in-hospital observation.

Propofol-mediated Unconsciousness Disrupts Progression of Sensory Signals through the Cortical Hierarchy.

A critical component of anesthesia is the loss of sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of nonhuman primates before and during propofol-mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-related synchronization between brain areas in the local field potential of Awake animals. By contrast, propofol-mediated unconsciousness eliminated stimulus-related synchrony and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in Awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just because of asynchronous Down states. Rather, both Down states and Up states reflect disrupted dynamics.

Activation of glutamatergic neurones in the pedunculopontine tegmental nucleus promotes cortical activation and behavioural emergence from sevoflurane-induced unconsciousness in mice.

BACKGROUND: The neural mechanisms underlying sevoflurane-induced loss of consciousness and recovery of consciousness after anaesthesia remain unknown. We investigated whether glutamatergic pedunculopontine tegmental nucleus (PPT) neurones are involved in the regulation of states of consciousness under sevoflurane anaesthesia. METHODS: In vivo fibre photometry combined with electroencephalography (EEG)/electromyography recording was used to record changes in the activity of glutamatergic PPT neurones under sevoflurane anaesthesia. Chemogenetic and cortical EEG recordings were used to explore their roles in the induction of and emergence from sevoflurane anaesthesia. Optogenetic methods combined with EEG recordings were used to explore the roles of glutamatergic PPT neurones and of the PPT-ventral tegmental area pathway in maintenance of anaesthesia. RESULTS: The population activity of glutamatergic PPT neurones was reduced before sevoflurane-induced loss of righting reflex and gradually recovered after return of righting reflex. Chemogenetic inhibition of glutamatergic PPT neurones accelerated induction of anaesthesia (hM4Di-CNO vs mCherry-CNO, 76 [17] vs 121 [27] s, P<0.0001) and delayed emergence from sevoflurane anaesthesia (278 [98] vs 145 [53] s, P<0.0001) but increased sevoflurane sensitivity. Optogenetic stimulation of glutamatergic PPT neurons or of the PPT-ventral tegmental area pathway promoted cortical activation and behavioural emergence during steady-state sevoflurane anaesthesia, reduced the depth of anaesthesia, and caused cortical arousal during sevoflurane-induced EEG burst suppression. CONCLUSIONS: Glutamatergic PPT neurones regulate induction and emergence of sevoflurane anaesthesia.

State-related Electroencephalography Microstate Complexity during Propofol- and Esketamine-induced Unconsciousness.

BACKGROUND: Identifying the state-related "neural correlates of consciousness" for anesthetics-induced unconsciousness is challenging. Spatiotemporal complexity is a promising tool for investigating consciousness. The authors hypothesized that spatiotemporal complexity may serve as a state-related but not drug-related electroencephalography (EEG) indicator during an unconscious state induced by different anesthetic drugs (e.g., propofol and esketamine). METHODS: The authors recorded EEG from patients with unconsciousness induced by propofol (n = 10) and esketamine (n = 10). Both conventional microstate parameters and microstate complexity were analyzed. Spatiotemporal complexity was constructed by microstate sequences and complexity measures. Two different EEG microstate complexities were proposed to quantify the randomness (type I) and complexity (type II) of the EEG microstate series during the time course of the general anesthesia. RESULTS: The coverage and occurrence of microstate E (prefrontal pattern) and the duration of microstate B (right frontal pattern) could distinguish the states of preinduction wakefulness, unconsciousness, and recovery under both anesthetics. Type I EEG microstate complexity based on mean information gain significantly increased from awake to unconsciousness state (propofol: from mean ± SD, 1.562 ± 0.059 to 1.672 ± 0.023, P < 0.001; esketamine: 1.599 ± 0.051 to 1.687 ± 0.013, P < 0.001), and significantly decreased from unconsciousness to recovery state (propofol: 1.672 ± 0.023 to 1.537 ± 0.058, P < 0.001; esketamine: 1.687 ± 0.013 to 1.608 ± 0.028, P < 0.001) under both anesthetics. In contrast, type II EEG microstate fluctuation complexity significantly decreased in the unconscious state under both drugs (propofol: from 2.291 ± 0.771 to 0.782 ± 0.163, P < 0.001; esketamine: from 1.645 ± 0.417 to 0.647 ± 0.252, P < 0.001), and then increased in the recovery state (propofol: 0.782 ± 0.163 to 2.446 ± 0.723, P < 0.001; esketamine: 0.647 ± 0.252 to 1.459 ± 0.264, P < 0.001). CONCLUSIONS: Both type I and type II EEG microstate complexities are drug independent. Thus, the EEG microstate complexity measures that the authors proposed are promising tools for building state-related neural correlates of consciousness to quantify anesthetic-induced unconsciousness.

Electroencephalographic signatures of consciousness: uncovering the fake news.

Amongst electroencephalographic markers of anaesthetic-induced unresponsiveness, those that estimate loss of frontoparietal functional connectivity detect loss of sensory perceptual connection with the outside world, rather than full phenomenological unconsciousness. This transition to unconsciousness is manifest as further incremental changes in indices of electroencephalographic complexity.

EEG spectral slope: A reliable indicator for continuous evaluation of consciousness levels during propofol anesthesia.

The level of consciousness undergoes continuous alterations during anesthesia. Prior to the onset of propofol-induced complete unconsciousness, degraded levels of behavioral responsiveness can be observed. However, a reliable index to monitor altered consciousness levels during anesthesia has not been sufficiently investigated. In this study, we obtained 60-channel EEG data from 24 healthy participants during an ultra-slow propofol infusion protocol starting with an initial concentration of 1 µg/ml and a stepwise increase of 0.2 µg/ml in concentration. Consecutive auditory stimuli were delivered every 5 to 6 s, and the response time to the stimuli was used to assess the responsiveness levels. We calculated the spectral slope in a time-resolved manner by extracting 5-second EEG segments at each auditory stimulus and estimated their correlation with the corresponding response time. Our results demonstrated that during slow propofol infusion, the response time to external stimuli increased, while the EEG spectral slope, fitted at 15-45 Hz, became steeper, and a significant negative correlation was observed between them. Moreover, the spectral slope further steepened at deeper anesthetic levels and became flatter during anesthesia recovery. We verified these findings using an external dataset. Additionally, we found that the spectral slope of frontal electrodes over the prefrontal lobe had the best performance in predicting the response time. Overall, this study used a time-resolved analysis to suggest that the EEG spectral slope could reliably track continuously altered consciousness levels during propofol anesthesia. Furthermore, the frontal spectral slope may be a promising index for clinical monitoring of anesthesia depth.

Alterations in rat brain modular organization during unconsciousness are dependent on communication efficiency and metabolic cost.

Spontaneous brain activity exhibits a highly structured modular organization that varies across individuals and reconfigures over time. Although it has been proposed that brain organization is shaped by an economic trade-off between minimizing costs and facilitating efficient information transfer, it remains untested whether modular variability and its changes during unconscious conditions might be constrained by the economy of brain organization. We acquired functional MRI and FDG-PET in rats under three different levels of consciousness induced by propofol administration. We examined alterations in brain modular variability during loss of consciousness from mild sedation to deep anesthesia. We also investigated the relationships between modular variability with glucose metabolism and functional connectivity strength as well as their alterations during unconsciousness. We observed that modular variability increased during loss of consciousness. Critically, across-individual modular variability is oppositely associated with functional connectivity strength and cerebral metabolism, and with deepening dosage of anesthesia, becoming increasingly dependent on basal metabolism over functional connectivity. These results suggested that, propofol-induced unconsciousness may lead to brain modular reorganization, which are putatively shaped by re-negotiations between energetic resources and communication efficiency.

Differential cortical network engagement during states of un/consciousness in humans.

What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing we`re reduced, while variability increased in any type of unconscious state. These changes were more pronounced during anesthesia than sleep and involved different cortical engagement. During sleep, changes were mostly uniformly distributed across the brain, whereas during anesthesia, the prefrontal cortex was the most disrupted, suggesting that the lack of arousability during anesthesia results not from just altered overall physiology but from a disconnection between the prefrontal and other brain areas. These findings provide direct evidence for different neural dynamics during loss of consciousness compared with loss of arousability.

Analogous cortical reorganization accompanies entry into states of reduced consciousness during anesthesia and sleep.

Theories of consciousness suggest that brain mechanisms underlying transitions into and out of unconsciousness are conserved no matter the context or precipitating conditions. We compared signatures of these mechanisms using intracranial electroencephalography in neurosurgical patients during propofol anesthesia and overnight sleep and found strikingly similar reorganization of human cortical networks. We computed the "effective dimensionality" of the normalized resting state functional connectivity matrix to quantify network complexity. Effective dimensionality decreased during stages of reduced consciousness (anesthesia unresponsiveness, N2 and N3 sleep). These changes were not region-specific, suggesting global network reorganization. When connectivity data were embedded into a low-dimensional space in which proximity represents functional similarity, we observed greater distances between brain regions during stages of reduced consciousness, and individual recording sites became closer to their nearest neighbors. These changes corresponded to decreased differentiation and functional integration and correlated with decreases in effective dimensionality. This network reorganization constitutes a neural signature of states of reduced consciousness that is common to anesthesia and sleep. These results establish a framework for understanding the neural correlates of consciousness and for practical evaluation of loss and recovery of consciousness.

Slow-wave modulation analysis during states of unconsciousness using the novel tau-modulation method.

Objective. Slow-wave modulation occurs during states of unconsciousness and is a large-scale indicator of underlying brain states. Conventional methods typically characterize these large-scale dynamics by assuming that slow-wave activity is sinusoidal with a stationary frequency. However, slow-wave activity typically has an irregular waveform shape with a non-stationary frequency, causing these methods to be highly unpredictable and inaccurate. To address these limitations, we developed a novel method using tau-modulation, which is more robust than conventional methods in estimating the modulation of slow-wave activity and does not require assumptions on the shape or stationarity of the underlying waveform.Approach. We propose a novel method to estimate modulatory effects on slow-wave activity. Tau-modulation curves are constructed from cross-correlation between slow-wave and high-frequency activity. The resultant curves capture several aspects of modulation, including attenuation or enhancement of slow-wave activity, the temporal synchrony between slow-wave and high-frequency activity, and the rate at which the overall brain activity oscillates between states.Main results. The method's performance was tested on an open electrocorticographic dataset from two monkeys that were recorded during propofol-induced anesthesia, with electrodes implanted over the left hemispheres. We found a robust propagation of slow-wave modulation along the anterior-posterior axis of the lateral aspect of the cortex. This propagation preferentially originated from the anterior superior temporal cortex and anterior cingulate gyrus. We also found the modulation frequency and polarity to track the stages of anesthesia. The algorithm performed well, even with non-sinusoidal activity and in the presence of real-world noise.Significance. The novel method provides new insight into several aspects of slow-wave modulation that have been previously difficult to evaluate across several brain states. This ability to better characterize slow-wave modulation, without spurious correlations induced by non-sinusoidal signals, may lead to robust and physiologically-plausible diagnostic tools for monitoring brain functions during states of unconsciousness.

Modulatory dynamics mark the transition between anesthetic states of unconsciousness.

Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta-alpha (SDA) oscillations transition into burst suppression. This is a marker of a state of profound brain inactivation during which isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state-space methods, we characterize the dynamic evolution of brain activity from SDA to burst suppression and back during unconsciousness maintained with propofol or sevoflurane in volunteer subjects and surgical patients. We uncover two dynamical processes that continuously modulate the SDA oscillations: alpha-wave amplitude and slow-wave frequency modulation. We present an alpha modulation index and a slow modulation index which characterize how these processes track the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively. Our biophysical model reveals that these dynamics track the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. Our characterization of the modulatory dynamics mediated by GABAergic anesthetics offers insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia.

Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model.

Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brain stem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low-beta and slow rhythm, as well as their interactions. Our model suggests that propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta-frequency spiking in thalamus (C-state), whereas in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha colocalizes to the peak of the slow oscillation; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brain stem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state.NEW & NOTEWORTHY GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We constructed a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brain stem neuromodulation.

P2X7 Receptor in Microglia Contributes to Propofol-induced Unconsciousness by Regulating Synaptic Plasticity in Mice.

Propofol infusion is processed through the wake-sleep cycle in neural connections, and the ionotropic purine type 2X7 receptor (P2X7R) is a nonspecific cation channel implicated in sleep regulation and synaptic plasticity through its regulation of electric activity in the brain. Here, we explored the potential roles of P2X7R of microglia in propofol-induced unconsciousness. Propofol induced loss of the righting reflex in male C57BL/6 wild-type mice and increased spectral power of the slow wave and delta wave of the medial prefrontal cortex (mPFC), all of which were reversed with P2X7R antagonist A-740003 and strengthened with P2X7R agonist Bz-ATP. Propofol increased the P2X7R expression level and P2X7R immunoreactivity with microglia in the mPFC, induced mild synaptic injury and increased GABA release in the mPFC, and these changes were less severe when treated with A-740003 and were more obvious when treated with Bz-ATP. Electrophysiological approaches showed that propofol induced a decreased frequency of sEPSCs and an increased frequency of sIPSCs, A-740003 decrease frequency of sEPSCs and sIPSCs and Bz-ATP increase frequency of sEPSCs and sIPSCs under propofol anesthesia. These findings indicated that P2X7R in microglia regulates synaptic plasticity and may contribute to propofol-mediated unconsciousness.

Different Alterations of Hippocampal and Reticulo-Thalamic GABAergic Parvalbumin-Expressing Interneurons Underlie Different States of Unconsciousness.

We traced the changes in GABAergic parvalbumin (PV)-expressing interneurons of the hippocampus and reticulo-thalamic nucleus (RT) as possible underlying mechanisms of the different local cortical and hippocampal electroencephalographic (EEG) microstructures during the non-rapid-eye movement (NREM) sleep compared with anesthesia-induced unconsciousness by two anesthetics with different main mechanisms of action (ketamine/diazepam versus propofol). After 3 h of recording their sleep, the rats were divided into two experimental groups: one half received ketamine/diazepam anesthesia and the other half received propofol anesthesia. We simultaneously recorded the EEG of the motor cortex and hippocampus during sleep and during 1 h of surgical anesthesia. We performed immunohistochemistry and analyzed the PV and postsynaptic density protein 95 (PSD-95) expression. PV suppression in the hippocampus and at RT underlies the global theta amplitude attenuation and hippocampal gamma augmentation that is a unique feature of ketamine-induced versus propofol-induced unconsciousness and NREM sleep. While PV suppression resulted in an increase in hippocampal PSD-95 expression, there was no imbalance between inhibition and excitation during ketamine/diazepam anesthesia compared with propofol anesthesia in RT. This increased excitation could be a consequence of a lower GABA interneuronal activity and an additional mechanism underlying the unique local EEG microstructure in the hippocampus during ketamine/diazepam anesthesia.

Beyond alpha power: EEG spatial and spectral gradients robustly stratify disorders of consciousness.

Neurophysiological markers can overcome the limitations of behavioural assessments of Disorders of Consciousness (DoC). EEG alpha power emerged as a promising marker for DoC, although long-standing literature reported alpha power being sustained during anesthetic-induced unconsciousness, and reduced during dreaming and hallucinations. We hypothesized that EEG power suppression caused by severe anoxia could explain this conflict. Accordingly, we split DoC patients (n = 87) in postanoxic and non-postanoxic cohorts. Alpha power was suppressed only in severe postanoxia but failed to discriminate un/consciousness in other aetiologies. Furthermore, it did not generalize to an independent reference dataset (n = 65) of neurotypical, neurological, and anesthesia conditions. We then investigated EEG spatio-spectral gradients, reflecting anteriorization and slowing, as alternative markers. In non-postanoxic DoC, these features, combined in a bivariate model, reliably stratified patients and indexed consciousness, even in unresponsive patients identified as conscious by an independent neural marker (the Perturbational Complexity Index). Crucially, this model optimally generalized to the reference dataset. Overall, alpha power does not index consciousness; rather, its suppression entails diffuse cortical damage, in postanoxic patients. As an alternative, EEG spatio-spectral gradients, reflecting distinct pathophysiological mechanisms, jointly provide a robust, parsimonious, and generalizable marker of consciousness, whose clinical application may guide rehabilitation efforts.

Study on the effectiveness and safety of ciprofol in anesthesia in gynecological day surgery: a randomized double-blind controlled study.

BACKGROUD: ciprofol is a new type of intravenous anesthetic, which is a tautomer of propofol, with the characteristics of less injection pain, less respiratory depression and higher potency, but little clinical experience. The aim of this study was to observe the efficacy and safety of the application of ciprofol in ambulatory surgery anesthesia in gynecology. METHODS: 128 patients were selected to undergo gynecological day surgery under general anesthesia, and the patients were randomly divided into the ciprofol group and the propofol group, with 64 cases in each group. During anesthesia induction, the ciprofol group was infused at a time limit of 0.5 mg/kg for one minute, and the propofol group was infused at a time limit of 2 mg/kg for 1 min. The overall incidence of adverse events was the primary outcome for this study, while secondary outcomes included the success rate of anesthesia induction, the time of loss of consciousness, the time of awakening,top-up dose and frequency of use of rescue drugs. RESULTS: The overall incidence of adverse events was significantly lower in the ciprofol group compared with the propofol group (56.2% vs. 92.2%,P < 0.05). The success rate of anesthesia induction of ciprofol and propofol group was 100.0%. The time of loss of consciousness of the ciprofol group was longer than that of the propofol group (1.6 ± 0.4 min vs. 1.4 ± 0.2 min, P < 0.05). The time of awakening was not statistically significant (5.4 ± 2.8 min vs. 4.6 ± 1.6 min, P > 0.05). The number of drug additions and resuscitation drugs used were not statistically significant. CONCLUSIONS: Compared with propofol, ciprofol had a similar anesthetic effect in gynecological ambulatory surgery, and the incidence of adverse events in the ciprofol group was lower.