Propofol-induced Loss Of Consciousness Research Articles

Paraventricular thalamus controls consciousness transitions during propofol anaesthesia in mice

BackgroundThe neuronal mechanisms underlying propofol-induced modulation of consciousness are poorly understood. Neuroimaging studies suggest a potential role for non-specific thalamic nuclei in propofol-induced loss of consciousness. We investigated the contribution of the paraventricular thalamus (PVT), a midline thalamic nucleus that has been implicated in arousal control and general anaesthesia with inhaled anaesthetics, to loss and recovery of consciousness during propofol anaesthesia. MethodsPolysomnographic recordings and righting reflex test were used to determine the transitions of loss and recovery of righting reflex, used as a measure of consciousness in mice, during propofol anaesthesia in mice under conditions mimicking clinical propofol administration. PVT neuronal activities were monitored using fibre photometry and regulated using optogenetic and chemogenetic methods. ResultsPopulation activities of PVT glutamatergic neurones began to decrease before propofol-induced loss of consciousness and rapidly increased to a peak at the onset of recovery of consciousness. Chemogenetic inhibition of PVT calretinin-expressing (PVTCR) neurones shortened onset (from 176 [35] to 127 [26] s; P=0.001) and prolonged return (from 1568 [611] to 3126 [1616] s; P=0.002) of righting reflex. Conversely, chemogenetic activation of PVTCR neurones exerted opposite effects. Furthermore, optogenetic silencing of PVTCR neurones accelerated transitions to loss of consciousness (from 205 [35] to 158 [44] s; P=0.027) and slowed transitions to recovery of consciousness (from 230 [78] to 370 [99] s; P=0.041). During a steady period of unconsciousness maintained with continuous propofol infusion, brief optical activation of PVTCR neurones restored cortical activity and arousal with a latency of about 5 s. ConclusionsThe paraventricular thalamus contributes to the control of consciousness transitions in propofol anaesthesia in mice. This provides a potential neuroanatomical target for controlling consciousness to reduce anaesthetic dose requirements and side effects.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia.

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Role of adenosine A2A receptors in the loss of consciousness induced by propofol anesthesia.

The mechanism of propofol-anesthesia-induced loss of consciousness (LOC) remains largely unknown. We speculated that the adenosine A2A receptor serves as a vital molecular target in regulating LOC states under propofol anesthesia. c-Fos staining helped observe the changes in the neuronal activity in the nucleus accumbens (NAc). Initially, the adenosine signals in the NAc were measured under propofol anesthesia using fiber photometry recordings. Then, behavior tests and electrophysiological recordings were used to verify the effect of systemic A2A R agonist or antagonist treatment on propofol anesthesia. Next, the microinjection technique was used to clarify the role of the NAc A2A R under propofol anesthesia. Fiber photometry recordings were applied to assess the effect of A2A R agonist or antagonist systemic treatment on adenosine signal alterations in the NAc during propofol anesthesia. Then, as the GABAergic neurons are the main neurons in the NAc, we further measured the neuronal activity of GABAergic neurons. In our study, propofol anesthesia enhanced the neuronal activity in the NAc, and the adenosine signals were increased in the NAc. SCH58261 reduced the LOC time and sedative depth, while CGS21680 increased those via intraperitoneal injection. Additionally, CGS21680 increased the changes in delta, theta, alpha, beta, and low-gamma oscillations in the NAc. Moreover, microinjection of SCH58261 significantly shortened the LOC time, whereas microinjection of CGS21680 into the NAc significantly prolonged the LOC duration. The results illustrated that after A2A R agonist administration, the level of extracellular adenosine signals in the NAc was decreased and the neuronal activity of GABAergic neurons was enhanced, whereas after A2A R antagonist administration via intraperitoneal injection, the opposite occurred. This study reveals the vital role of the A2A R in propofol-induced LOC and that the A2A R could affect the maintenance of propofol anesthesia.

Altered functional and directed connectivity in propofol-induced loss of consciousness: A source-space resting-state EEG study

ObjectiveGeneral anesthesia might disrupt neuronal network communications measured by functional connectivity (FC; undirected connectivity) and directional information flow (directed connectivity). We sought to characterize the state-dependent effects of propofol on cortico-cortical undirected and directed FC. MethodsWe collected 256-channel high-density EEGs from 14 patients undergoing surgery while awake (AWA) or in propofol-induced moderate sedation (SED) or loss of consciousness (LOC) states. Using source-space EEG, we estimated neuronal oscillatory activity for 68 cortical regions of interest. FC was analyzed using the weighted phase lag index. Directed connectivity was computed using directed phase transfer entropy (dPTE) as a measure of information flow in the bilateral prefrontal, frontal, parietal, and occipital areas. ResultsFC strength evidently reduced during LOC compared with those during the AWA and SED states. The dPTE analysis showed significant propofol-induced changes in directed connectivity. In the alpha band, the prefrontal-to-frontal information flow was significantly stronger in the AWA than in the SED (p = 0.033) and LOC states (p = 0.033). The parietal-to-frontal dPTE was significantly weaker during LOC than during the AWA (p = 0.033) and SED states (p = 0.007). Finally, a loss of occipital-to-frontal connectivity occurred during LOC but not the AWA state (p = 0.001). In the beta band, the dominant occipital-to-frontal direction of information flow in the AWA state was gradually converted to a frontal-to-occipital direction during LOC. ConclusionsPropofol-induced unconsciousness is marked by a decrease in FC and posterior-to-anterior (feedforward) directed connectivity, which may be useful as a measure to discriminate different conscious states caused by propofol administration. SignificanceThe study demonstrates that propofol produces state-dependent effects on cortico-cortical undirected and directed FC, supporting the idea that propofol induces loss of consciousness may through disrupting network interactions and cortical coordination.

Propofol Anesthesia Alters Cortical Traveling Waves.

Oscillatory dynamics in cortex seem to organize into traveling waves that serve a variety of functions. Recent studies show that propofol, a widely used anesthetic, dramatically alters cortical oscillations by increasing slow-delta oscillatory power and coherence. It is not known how this affects traveling waves. We compared traveling waves across the cortex of non-human primates before, during, and after propofol-induced loss of consciousness (LOC). After LOC, traveling waves in the slow-delta (∼1 Hz) range increased, grew more organized, and traveled in different directions relative to the awake state. Higher frequency (8-30 Hz) traveling waves, by contrast, decreased, lost structure, and switched to directions where the slow-delta waves were less frequent. The results suggest that LOC may be due, in part, to increases in the strength and direction of slow-delta traveling waves that, in turn, alter and disrupt traveling waves in the higher frequencies associated with cognition.

This Month in Anesthesiology

This Month in Anesthesiology

Fast-spiking Interneurons Contribute to Propofol-induced Facilitation of Firing Synchrony in Pyramidal Neurons of the Rat Insular Cortex.

The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 μM propofol application. Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.

Largest scale dissociation of brain activity at propofol-induced loss of consciousness.

The brain is a functional unit made up of multilevel connected elements showing a pattern of synchronized activity that varies in different states. The wake-sleep cycle is a major variation of brain functional condition that is ultimately regulated by subcortical arousal- and sleep-promoting cell groups. We analyzed the evolution of functional MRI (fMRI) signal in the whole cortex and in a deep region including most sleep- and wake-regulating subcortical nuclei at loss of consciousness induced by the hypnotic agent propofol. Optimal data were obtained in 21 of the 30 healthy participants examined. A dynamic analysis of fMRI time courses on a time-scale of seconds was conducted to characterize consciousness transition, and functional connectivity maps were generated to detail the anatomy of structures showing different dynamics. Inside the magnet, loss of consciousness was marked by the participants ceasing to move their hands. We observed activity synchronization after loss of consciousness within both the cerebral cortex and subcortical structures. However, the evolution of fMRI signal was dissociated, showing a transient reduction of global cortico-subcortical coupling that was restored during the unconscious state. An exception to cortico-subcortical decoupling was a brain network related to self-awareness (i.e. the default mode network) that remained connected to subcortical brain structures. Propofol-induced unconsciousness is thus characterized by an initial, transitory dissociated synchronization at the largest scale of brain activity. Such cortico-subcortical decoupling and subsequent recoupling may allow the brain to detach from waking activity and reorganize into a functionally distinct state.

Dynamics of Ketamine-induced Loss and Return of Consciousness across Primate Neocortex.

Ketamine is a noncompetitive N-methyl-D-aspartate antagonist and is known for unique electrophysiologic profiles in electroencephalography. However, the mechanisms of ketamine-induced unconsciousness are not clearly understood. The authors have investigated neuronal dynamics of ketamine-induced loss and return of consciousness and how multisensory processing is modified in the primate neocortex. The authors performed intracortical recordings of local field potentials and single unit activity during ketamine-induced altered states of consciousness in a somatosensory and ventral premotor network. The animals were trained to perform a button holding task to indicate alertness. Air puff to face or sound was randomly delivered in each trial regardless of their behavioral response. Ketamine was infused for 60 min. Ketamine-induced loss of consciousness was identified during a gradual evolution of the high beta-gamma oscillations. The slow oscillations appeared to develop at a later stage of ketamine anesthesia. Return of consciousness and return of preanesthetic performance level (performance return) were observed during a gradual drift of the gamma oscillations toward the beta frequency. Ketamine-induced loss of consciousness, return of consciousness, and performance return are all identified during a gradual change of the dynamics, distinctive from the abrupt neural changes at propofol-induced loss of consciousness and return of consciousness. Multisensory responses indicate that puff evoked potentials and single-unit firing responses to puff were both preserved during ketamine anesthesia, but sound responses were selectively diminished. Units with suppressed responses and those with bimodal responses appeared to be inhibited under ketamine and delayed in recovery. Ketamine generates unique intracortical dynamics during its altered states of consciousness, suggesting fundamentally different neuronal processes from propofol. The gradually shifting dynamics suggest a continuously conscious or dreaming state while unresponsive under ketamine until its deeper stage with the slow-delta oscillations. Somatosensory processing is preserved during ketamine anesthesia, but multisensory processing appears to be diminished under ketamine and through recovery.

Propofol-induced loss of consciousness is associated with a decrease in thalamocortical connectivity in humans

Although the molecular effects of many anaesthetics have been well characterized, a network-level explanation for how these changes lead to loss of consciousness remains unclear. Studies using electroencephalography have characterized changes in neural oscillations in the cortex at specific frequency bands during propofol-induced anaesthesia and modelling work suggests these changes result from changes in thalamocortical functional connectivity. However, it is unclear if the neurophysiological changes seen at the cortex are due to enhanced or disrupted thalamocortical communication. Direct recordings from these sites during anaesthesia that could be used to confirm such models are rare. We recorded local field potentials from the ventral intermediate nucleus of the thalamus and electrocorticography signals from the ipsilateral sensorimotor cortex in 10 patients undergoing deep brain stimulation surgery. Signals were acquired during induction of propofol anaesthesia while subjects were resting. After confirming direct structural connectivity between the thalamus and the cortical recording site, we investigated propofol-associated changes in thalamic and cortical local power as well as thalamocortical functional connectivity, as measured with coherence, debiased weighted phase lag index, and phase amplitude coupling. Propofol anaesthesia resulted in local power increases at α frequencies (8-12 Hz) across both thalamic and cortical areas. At sensorimotor cortices, there was a broadband power increase (12-100 Hz), while the power of this same broad frequency band was suppressed within the thalamus. Despite the increase in local α power both within the thalamus and cortex, thalamocortical coherence and debiased weighted phase lag index in the α/low β frequencies (8-16 Hz, which was present in the awake state) significantly decreased with propofol administration (P < 0.05, two group test of coherence). Likewise, propofol administration resulted in decreased phase amplitude coupling between the phase of α/low β in the thalamus and the amplitude of broadband gamma (50-200 Hz) in the cortex (P = 0.031, Wilcoxon signed-rank test). We also report phase amplitude coupling between the phase of slow wave oscillations (0.1-1 Hz) and amplitude of broadband frequencies (8-200 Hz) within the cortex and across thalamocortical connections, during anaesthesia, both following a peak-max pattern. While confirming α-power increases with propofol administration both in thalamus and cortex, we observed decreased thalamocortical connectivity, contradicting models that suggest increasing cortical low frequency power is necessarily related to increased thalamocortical coherence but in support of the theory that propofol-induced loss of consciousness is associated with disrupted thalamocortical communication.

Investigating dynamic functional network patterns after propofol-induced loss of consciousness

ObjectiveWe investigated the changes of dynamic brain functional network from awaken state to the anesthesia level suitable for surgery. Methods60-channel EEG data of 22 subjects are acquired at wakefulness, light anesthesia and deep anesthesia. The activity of 68 cortical regions are obtained by using EEG source imaging. Sliding window analysis is employed to obtain a dynamic sequence of brain functional network. K-means clustering algorithm is then employed to identify the common brain functional network patterns. ResultsFive common brain functional network patterns were identified across all conscious levels. The occurrence of each meta-stable network pattern was associated with the level of anesthesia. A transition functional network pattern was found to transfer to the anesthesia dominating or wakefulness dominating network pattern depending on the conscious level. Furthermore, a functional network pattern persisted during both wakefulness and anesthesia is found to be supported by the anatomical connectivity. ConclusionsDynamic changes of brain functional network exist in both awaken and anesthesia state. SignificanceThese findings suggest that dynamic brain functional network analysis plays a critical role in decoding the mechanism of general anesthesia. The obtained five metastable network patterns may be employed for monitoring the depth of anesthesia.

Modulated spontaneous hemodynamic response to loss of consciousness

Event Abstract Back to Event Modulated spontaneous hemodynamic response to loss of consciousness Guorong Wu1, 2, Carol Di Perri3, 4, Vanessa Charland-Verville4, Charlotte Martial5, Steven Laureys5 and Daniele Marinazzo2* 1 Chongqing University, China 2 Ghent University, Faculty of Psychology and Pedagogical Sciences - Department of Data Analysis, Belgium 3 Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, United Kingdom 4 GIGA Consciousness, University of Liège, Belgium 5 GIGA-Neurosciences, University of Liège, Belgium Resting state functional connectivity MRI is playing a crucial role to explore the consciousness related functional integration, successfully complementing PET, another widely used neuroimaging technique. Here we apply a signal processing technique to retrieve a proxy of the hemodynamic response function from resting state fMRI recordings (rsHRF). rsHRF is useful to characterize resting state brain activity giving information on the local metabolism (neurovascular coupling), and to improve the time-resolved activity and connectivity measures based on BOLD fMRI. This voxel-wise measure is then used to investigate the loss of consciousness under Propofol anesthesia and unresponsive wakefulness syndrome. The dysfunction of hemodynamic response in precuneus and posterior cingulate is found to be a common principle underlying loss of consciousness in both conditions. The thalamus appears to be less obviously modulated by Propofol, compared with frontoparietal regions. However, a significant increase in spontaneous thalamic hemodynamic response was found in patients in unresponsive wakefulness syndrome compared with healthy control. Our results ultimately show that anesthesia or pathology induced neurovascular coupling could be tracked by modulated spontaneous hemodynamic response derived from resting state fMRI. References Boveroux, P., Vanhaudenhuyse, A., Bruno, M.A., Noirhomme, Q., Lauwick, S., Luxen, A., Degueldre, C., Plenevaux, A., Schnakers, C., Phillips, C., Brichant, J.F., Bonhomme, V., Maquet, P., Greicius, M.D., Laureys, S., Boly, M., 2010. Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology 113, 1038-1053. Rangaprakash, D., Wu, G.R., Marinazzo, D., Hu, X., Deshpande, G., 2018. Hemodynamic response function (HRF) variability confounds resting‐state fMRI functional connectivity. Magnetic resonance in medicine. 2018 Apr 15. doi: 10.1002/mrm.27146. [Epub ahead of print] Wu, G.R., Liao, W., Stramaglia, S., Ding, J.R., Chen, H., Marinazzo, D., 2013. A blind deconvolution approach to recover effective connectivity brain networks from resting state fMRI data. Med Image Anal 17, 365-374. https://github.com/compneuro-da/rsHRF Keywords: fMRI — functional magnetic resonance imaging, Hemodynamic response function (HRF), Consciousness, Anesthesia, Signal processing Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018. Presentation Type: e-posters Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE Citation: Wu G, Di Perri C, Charland-Verville V, Martial C, Laureys S and Marinazzo D (2019). Modulated spontaneous hemodynamic response to loss of consciousness. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00025 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Aug 2018; Published Online: 17 Jan 2019. * Correspondence: Prof. Daniele Marinazzo, Ghent University, Faculty of Psychology and Pedagogical Sciences - Department of Data Analysis, Ghent, B-9000, Belgium, daniele.marinazzo@ugent.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Guorong Wu Carol Di Perri Vanessa Charland-Verville Charlotte Martial Steven Laureys Daniele Marinazzo Google Guorong Wu Carol Di Perri Vanessa Charland-Verville Charlotte Martial Steven Laureys Daniele Marinazzo Google Scholar Guorong Wu Carol Di Perri Vanessa Charland-Verville Charlotte Martial Steven Laureys Daniele Marinazzo PubMed Guorong Wu Carol Di Perri Vanessa Charland-Verville Charlotte Martial Steven Laureys Daniele Marinazzo Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Dynamics of Propofol-Induced Loss of Consciousness Across Primate Neocortex.

The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.

Evidence of Resting-state Activity in Propofol-anesthetized Patients with Intracranial Tumors

Resting-state (RS) networks, revealed by functional magnetic resonance imaging (fMRI) studies in healthy volunteers, have never been evaluated in anesthetized patients with brain tumors. Our purpose was to examine the presence of residual brain activity on the auditory network during propofol-induced loss of consciousness in patients with brain tumors. Twenty subjects with intracranial masses were prospectively studied by means of intraoperative RS-fMRI acquisitions before any craniectomy. After performing single-subject independent component analysis, spatial maps and time courses were assigned to an auditory RS network template from the literature and compared via spatial regression coefficients. All fMRI data were of sufficient quality for further postprocessing. In all but two patients, the RS functional activity of the auditory network could be successfully mapped. In almost all patients, contralateral activation of the auditory network was present. No significant difference was found between the mean distance of the RS activity clusters and the lesion periphery for tumors located in the temporal gyri vs. those in other brain regions. The spatial deviation between the activated cluster in our experiment and the template was significantly (P = 0.04) higher in patients with tumors located in the temporal gyri than in patients with tumors located in other regions. Propofol-induced anesthesia in patients with intracranial lesions does not alter the blood-oxygenation level-depended signal, and independent component analysis of intraoperative RS-fMRI may allow assessment of the auditory network in a clinical setting.

The ventrolateral preoptic nucleus is required for propofol-induced inhibition of locus coeruleus neuronal activity.

The mechanisms underlying the unconsciousness of general anesthesia are not completely understood. Accumulating evidence indicates the ventrolateral preoptic nucleus (VLPO) in the endogenous sleep circuits may contribute to loss of consciousness (LOC) induced by GABA-enhancing anesthetics. However, there are few studies that look into distinct sleep pathway in the sleep-wake system. In the neural pathway from VLPO to the locus coeruleus (LC), we compared the inhibition effect of propofol on the LC activity before and after VLPO lesion in vivo rats. Systemic administration of propofol (20 mg/kg, i.p.) in normal rats caused a fast and obvious inhibition of LC neurons spontaneous firing (from 0.24 ± 0.06 to 0.12 ± 0.03 Hz). The LC neuronal firing rate of VLPO lesion rats only decreased to 0.18 ± 0.05 Hz (P = 0.021 vs. non-VLPO rats) after the propofol injection, and the time to reach the maximal inhibition level was also prolonged in VLPO lesion rats (2.3 ± 0.7 vs. 5.8 ± 1.2 min, P = 0.037). Microinjections of a selective GABAA receptor antagonist (SR95531) into the LC fully reversed the inhibitory effect of propofol on the LC neuronal activity, but did not significantly affect the latency to loss of righting reflex of rats after propofol administration (3.4 ± 0.9 vs. 3.7 ± 1.2 min, P = 0.639). Our results indicated that VLPO is necessary for the propofol-induced inhibition of LC activity, but the LC may not play an important role in the propofol-induced LOC.

Posterior cingulate cortex-related co-activation patterns: a resting state FMRI study in propofol-induced loss of consciousness.

BackgroundRecent studies have been shown that functional connectivity of cerebral areas is not a static phenomenon, but exhibits spontaneous fluctuations over time. There is evidence that fluctuating connectivity is an intrinsic phenomenon of brain dynamics that persists during anesthesia. Lately, point process analysis applied on functional data has revealed that much of the information regarding brain connectivity is contained in a fraction of critical time points of a resting state dataset. In the present study we want to extend this methodology for the investigation of resting state fMRI spatial pattern changes during propofol-induced modulation of consciousness, with the aim of extracting new insights on brain networks consciousness-dependent fluctuations.MethodsResting-state fMRI volumes on 18 healthy subjects were acquired in four clinical states during propofol injection: wakefulness, sedation, unconsciousness, and recovery. The dataset was reduced to a spatio-temporal point process by selecting time points in the Posterior Cingulate Cortex (PCC) at which the signal is higher than a given threshold (i.e., BOLD intensity above 1 standard deviation). Spatial clustering on the PCC time frames extracted was then performed (number of clusters = 8), to obtain 8 different PCC co-activation patterns (CAPs) for each level of consciousness.ResultsThe current analysis shows that the core of the PCC-CAPs throughout consciousness modulation seems to be preserved. Nonetheless, this methodology enables to differentiate region-specific propofol-induced reductions in PCC-CAPs, some of them already present in the functional connectivity literature (e.g., disconnections of the prefrontal cortex, thalamus, auditory cortex), some others new (e.g., reduced co-activation in motor cortex and visual area).ConclusionIn conclusion, our results indicate that the employed methodology can help in improving and refining the characterization of local functional changes in the brain associated to propofol-induced modulation of consciousness.

P35: Dominant change in intra-hemispheric information flow in fronto-parietal network in the gamma band during propofol-induced loss of consciousness

P35: Dominant change in intra-hemispheric information flow in fronto-parietal network in the gamma band during propofol-induced loss of consciousness

Statistical modeling of behavioral dynamics during propofol-induced loss of consciousness

Accurate quantitative analysis of the changes in responses to external stimuli is crucial for characterizing the timing of loss and recovery of consciousness induced by anesthetic drugs. We studied induction and emergence from unconsciousness achieved by administering a computer-controlled infusion of propofol to ten human volunteers. We evaluated loss and recovery of consciousness by having subjects execute every 4s two interleaved computer delivered behavioral tasks: responding to verbal stimuli (neutral words or the subject's name), or less salient stimuli of auditory clicks. We analyzed the data using state-space methods. For each stimulus type the observation model is a two-stage binomial model and the state model is two dimensional random walk in which one cognitive state governs the probability of responding and the second governs the probability of correctly responding given a response. We fit the model to the experimental data using Bayesian Monte Carlo methods. During induction subjects lost responsiveness to less salient clicks before losing responsiveness to the more salient verbal stimuli. During emergence subjects regained responsiveness to the more salient verbal stimuli before regaining responsiveness to the less salient clicks. The current state-space model is an extension of previous model used to analyze learning and behavioral performance. In this study, the probability of responding on each trial is obtained separately from the probability of behavioral performance. Our analysis provides a principled quantitative approach for defining loss and recovery of consciousness in experimental studies of general anesthesia.

Simultaneous Electroencephalographic and Functional Magnetic Resonance Imaging Indicate Impaired Cortical Top–Down Processing in Association with Anesthetic-induced Unconsciousness

In imaging functional connectivity (FC) analyses of the resting brain, alterations of FC during unconsciousness have been reported. These results are in accordance with recent electroencephalographic studies observing impaired top-down processing during anesthesia. In this study, simultaneous records of functional magnetic resonance imaging (fMRI) and electroencephalogram were performed to investigate the causality of neural mechanisms during propofol-induced loss of consciousness by correlating FC in fMRI and directional connectivity (DC) in electroencephalogram. Resting-state 63-channel electroencephalogram and blood oxygen level-dependent 3-Tesla fMRI of 15 healthy subjects were simultaneously registered during consciousness and propofol-induced loss of consciousness. To indicate DC, electroencephalographic symbolic transfer entropy was applied as a nonlinear measure of mutual interdependencies between underlying physiological processes. The relationship between FC of resting-state networks of the brain (z values) and DC was analyzed by a partial correlation. Independent component analyses of resting-state fMRI showed decreased FC in frontoparietal default networks during unconsciousness, whereas FC in primary sensory networks increased. DC indicated a decline in frontal-parietal (area under the receiver characteristic curve, 0.92; 95% CI, 0.68-1.00) and frontooccipital (0.82; 0.53-1.00) feedback DC (P<0.05 corrected). The changes of FC in the anterior default network correlated with the changes of DC in frontal-parietal (rpartial=+0.62; P=0.030) and frontal-occipital (+0.63; 0.048) electroencephalographic electrodes (P<0.05 corrected). The simultaneous propofol-induced suppression of frontal feedback connectivity in the electroencephalogram and of frontoparietal FC in the fMRI indicates a fundamental role of top-down processing for consciousness.

Dynamic Change of Global and Local Information Processing in Propofol-Induced Loss and Recovery of Consciousness

Whether unique to humans or not, consciousness is a central aspect of our experience of the world. The neural fingerprint of this experience, however, remains one of the least understood aspects of the human brain. In this paper we employ graph-theoretic measures and support vector machine classification to assess, in 12 healthy volunteers, the dynamic reconfiguration of functional connectivity during wakefulness, propofol-induced sedation and loss of consciousness, and the recovery of wakefulness. Our main findings, based on resting-state fMRI, are three-fold. First, we find that propofol-induced anesthesia does not bear differently on long-range versus short-range connections. Second, our multi-stage design dissociated an initial phase of thalamo-cortical and cortico-cortical hyperconnectivity, present during sedation, from a phase of cortico-cortical hypoconnectivity, apparent during loss of consciousness. Finally, we show that while clustering is increased during loss of consciousness, as recently suggested, it also remains significantly elevated during wakefulness recovery. Conversely, the characteristic path length of brain networks (i.e., the average functional distance between any two regions of the brain) appears significantly increased only during loss of consciousness, marking a decrease of global information-processing efficiency uniquely associated with unconsciousness. These findings suggest that propofol-induced loss of consciousness is mainly tied to cortico-cortical and not thalamo-cortical mechanisms, and that decreased efficiency of information flow is the main feature differentiating the conscious from the unconscious brain.