Authors: John H Abel, Marcus A Badgeley, Benyamin Meschede-Krasa...

In current anesthesiology practice, anesthesiologists infer the state of unconsciousness without directly monitoring the brain. Drug- and patient-specific electroencephalographic (EEG) signatures of anesthesia-induced unconsciousness have been identified previously. We applied machine learning approaches to construct classification models for real-time tracking of unconscious state during anesthesia-induced unconsciousness. We used cross-validation to select and train the best performing models using 33,159 2s segments of EEG data recorded from 7 healthy volunteers who received increasing infusions of propofol while responding to stimuli to directly assess unconsciousness. Cross-validated models of unconsciousness performed very well when tested on 13,929 2s EEG segments from 3 left-out volunteers collected under the same conditions (median volunteer AUCs 0.99-0.99). Models showed strong generalization when tested on a cohort of 27 surgical patients receiving solely propofol collected in a separate clinical dataset under different circumstances and using different hardware (median patient AUCs 0.95-0.98), with model predictions corresponding with actions taken by the anesthesiologist during the cases. Performance was also strong for 17 patients receiving sevoflurane (alone or in addition to propofol) (median AUCs 0.88-0.92). These results indicate that EEG spectral features can predict unconsciousness, even when tested on a different anesthetic that acts with a similar neural mechanism. With high performance predictions of unconsciousness, we can accurately monitor anesthetic state, and this approach may be used to engineer infusion pumps to intelligibly respond to patients' neural activity.

Topics: Anesthetics, Intravenous; Brain; Electroencephalography; Humans; Machine Learning; Male; Sevoflurane; Signal Processing, Computer-Assisted; Unconsciousness

PubMed: 33956800
DOI: 10.1371/journal.pone.0246165

Clinical Trial

Authors: Sandya Subramanian, Patrick L Purdon, Riccardo Barbieri...

During general anesthesia, both behavioral and autonomic changes are caused by the administration of anesthetics such as propofol. Propofol produces unconsciousness by creating highly structured oscillations in brain circuits. The anesthetic also has autonomic effects due to its actions as a vasodilator and myocardial depressant. Understanding how autonomic dynamics change in relation to propofol-induced unconsciousness is an important scientific and clinical question since anesthesiologists often infer changes in level of unconsciousness from changes in autonomic dynamics. Therefore, we present a framework combining physiology-based statistical models that have been developed specifically for heart rate variability and electrodermal activity with a robust statistical tool to compare behavioral and multimodal autonomic changes before, during, and after propofol-induced unconsciousness. We tested this framework on physiological data recorded from nine healthy volunteers during computer-controlled administration of propofol. We studied how autonomic dynamics related to behavioral markers of unconsciousness: 1) overall, 2) during the transitions of loss and recovery of consciousness, and 3) before and after anesthesia as a whole. Our results show a strong relationship between behavioral state of consciousness and autonomic dynamics. All of our prediction models showed areas under the curve greater than 0.75 despite the presence of non-monotonic relationships among the variables during the transition periods. Our analysis highlighted the specific roles played by fast versus slow changes, parasympathetic vs sympathetic activity, heart rate variability vs electrodermal activity, and even pulse rate vs pulse amplitude information within electrodermal activity. Further advancement upon this work can quantify the complex and subject-specific relationship between behavioral changes and autonomic dynamics before, during, and after anesthesia. However, this work demonstrates the potential of a multimodal, physiologically-informed, statistical approach to characterize autonomic dynamics.

Topics: Adult; Algorithms; Electroencephalography; Female; Humans; Male; Models, Neurological; Parasympathetic Nervous System; Propofol; Sympathetic Nervous System; Unconsciousness

PubMed: 34379623
DOI: 10.1371/journal.pone.0254053

Authors: Hetao Bian, Lei Huang, Bo Li...

Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.

Topics: Animals; Arousal; Benzoxazoles; Dioxanes; Ethanol; Hyperbaric Oxygenation; Ketamine; Male; Naphthyridines; Orexin Receptor Antagonists; Orexins; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Reflex, Righting; Unconsciousness; Up-Regulation; Urea

PubMed: 30895638
DOI: 10.1002/jnr.24414

Comparative Study Review

Authors: Benjamin F Gruenbaum

In order to understand general anaesthesia and certain seizures, a fundamental understanding of the neurobiology of unconsciousness is needed. This review article explores similarities in neuronal and network changes during general anaesthesia and seizure-induced unconsciousness. Both seizures and anaesthetics cause disruption in similar anatomical structures that presumably lead to impaired consciousness. Despite differences in behaviour and mechanisms, both of these conditions are associated with disruption of the functionality of subcortical structures that mediate neuronal activity in the frontoparietal cortex. These areas are all likely to be involved in maintaining normal consciousness. An assessment of the similarities in the brain network disruptions with certain seizures and general anaesthesia might provide fresh insights into the mechanisms of the alterations of consciousness seen in these particular unconscious states, allowing for innovative therapies for seizures and the development of anaesthetic approaches targeting specific networks.

Topics: Anesthetics; Animals; Brain; Electroencephalography; Humans; Rats; Seizures; Unconsciousness

PubMed: 32951841
DOI: 10.1016/j.bja.2020.07.056

Authors: Shengpei Wang, Yun Li, Shuang Qiu...

BACKGROUND

General anesthesia (GA) provides an invaluable experimental tool to understand the essential neural mechanisms underlying consciousness. Previous neuroimaging studies have shown the functional integration and segregation of brain functional networks during anesthetic-induced alteration of consciousness. However, the organization pattern of hubs in functional brain networks remains unclear. Moreover, comparisons with the well-characterized physiological unconsciousness can help us understand the neural mechanisms of anesthetic-induced unconsciousness.

METHODS

Resting-state functional magnetic resonance imaging was performed during wakefulness, mild propofol-induced sedation (m-PIS), and deep PIS (d-PIS) with clinical unconsciousness on 8 healthy volunteers and wakefulness and natural sleep on 9 age- and sex-matched healthy volunteers. Large-scale functional brain networks of each volunteer were constructed based on 160 regions of interest. Then, rich-club organizations in brain functional networks and nodal properties (nodal strength and efficiency) were assessed and analyzed among the different states and groups.

RESULTS

Rich-clubs in the functional brain networks were reorganized during alteration of consciousness induced by propofol. Firstly, rich-club nodes were switched from the posterior cingulate cortex (PCC), angular gyrus, and anterior and middle insula to the inferior parietal lobule (IPL), inferior parietal sulcus (IPS), and cerebellum. When sedation was deepened to unconsciousness, the rich-club nodes were switched to the occipital and angular gyrus. These results suggest that the rich-club nodes were switched among the high-order cognitive function networks (default mode network [DMN] and fronto-parietal network [FPN]), sensory networks (occipital network [ON]), and cerebellum network (CN) from consciousness (wakefulness) to propofol-induced unconsciousness. At the same time, compared with wakefulness, local connections were switched to rich-club connections during propofol-induced unconsciousness, suggesting a strengthening of the overall information commutation of networks. Nodal efficiency of the anterior and middle insula and ventral frontal cortex was significantly decreased. Additionally, from wakefulness to natural sleep, a similar pattern of rich-club reorganization with propofol-induced unconsciousness was observed: rich-club nodes were switched from the DMN (including precuneus and PCC) to the sensorimotor network (SMN, including part of the frontal and temporal gyrus). Compared with natural sleep, nodal efficiency of the insula, frontal gyrus, PCC, and cerebellum significantly decreased during propofol-induced unconsciousness.

CONCLUSIONS

Our study demonstrated that the rich-club reorganization in functional brain networks is characterized by switching of rich-club nodes between the high-order cognitive and sensory and motor networks during propofol-induced alteration of consciousness and natural sleep. These findings will help understand the common neurological mechanism of pharmacological and physiological unconsciousness.

Topics: Adult; Anesthesia, General; Cerebral Cortex; Connectome; Conscious Sedation; Female; Humans; Hypnotics and Sedatives; Magnetic Resonance Imaging; Male; Nerve Net; Propofol; Sleep; Unconsciousness; Young Adult

PubMed: 32018124
DOI: 10.1016/j.nicl.2020.102188

Authors: André M Bastos, Jacob A Donoghue, Scott L Brincat...

The specific circuit mechanisms through which anesthetics induce unconsciousness have not been completely characterized. We recorded neural activity from the frontal, parietal, and temporal cortices and thalamus while maintaining unconsciousness in non-human primates (NHPs) with the anesthetic propofol. Unconsciousness was marked by slow frequency (~1 Hz) oscillations in local field potentials, entrainment of local spiking to Up states alternating with Down states of little or no spiking activity, and decreased coherence in frequencies above 4 Hz. Thalamic stimulation 'awakened' anesthetized NHPs and reversed the electrophysiologic features of unconsciousness. Unconsciousness is linked to cortical and thalamic slow frequency synchrony coupled with decreased spiking, and loss of higher-frequency dynamics. This may disrupt cortical communication/integration.

Topics: Anesthetics, Intravenous; Animals; Cerebral Cortex; Female; Hypnotics and Sedatives; Macaca mulatta; Male; Propofol; Recovery of Function; Thalamus; Unconsciousness

PubMed: 33904411
DOI: 10.7554/eLife.60824

Authors: Emily P Stephen, Gladia C Hotan, Eric T Pierce...

A controversy has developed in recent years over the roles of frontal and posterior cortices in mediating consciousness and unconsciousness. Disruption of posterior cortex during sleep appears to suppress the contents of dreaming, yet activation of frontal cortex appears necessary for perception and can reverse unconsciousness under anesthesia. We used anesthesia to study how regional cortical disruption, mediated by slow wave modulation of broadband activity, changes during unconsciousness in humans. We found that broadband slow-wave modulation enveloped posterior cortex when subjects initially became unconscious, but later encompassed both frontal and posterior cortex when subjects were more deeply anesthetized and likely unarousable. Our results suggest that unconsciousness under anesthesia comprises several distinct shifts in brain state that disrupt the contents of consciousness distinct from arousal and awareness of those contents.

Topics: Adult; Anesthetics, Intravenous; Brain; Consciousness; Electroencephalography; Humans; Propofol; Unconsciousness; Young Adult

PubMed: 32792556
DOI: 10.1038/s41598-020-68756-y

Authors: Sean Tanabe, Zirui Huang, Jun Zhang...

BACKGROUND

Consciousness is supported by integrated brain activity across widespread functionally segregated networks. The functional magnetic resonance imaging-derived global brain signal is a candidate marker for a conscious state, and thus the authors hypothesized that unconsciousness would be accompanied by a loss of global temporal coordination, with specific patterns of decoupling between local regions and global activity differentiating among various unconscious states.

METHODS

Functional magnetic resonance imaging global signals were studied in physiologic, pharmacologic, and pathologic states of unconsciousness in human natural sleep (n = 9), propofol anesthesia (humans, n = 14; male rats, n = 12), and neuropathological patients (n = 21). The global signal amplitude as well as the correlation between global signal and signals of local voxels were quantified. The former reflects the net strength of global temporal coordination, and the latter yields global signal topography.

RESULTS

A profound reduction of global signal amplitude was seen consistently across the various unconscious states: wakefulness (median [1st, 3rd quartile], 0.46 [0.21, 0.50]) versus non-rapid eye movement stage 3 of sleep (0.30 [0.24, 0.32]; P = 0.035), wakefulness (0.36 [0.31, 0.42]) versus general anesthesia (0.25 [0.21, 0.28]; P = 0.001), healthy controls (0.30 [0.27, 0.37]) versus unresponsive wakefulness syndrome (0.22 [0.15, 0.24]; P < 0.001), and low dose (0.07 [0.06, 0.08]) versus high dose of propofol (0.04 [0.03, 0.05]; P = 0.028) in rats. Furthermore, non-rapid eye movement stage 3 of sleep was characterized by a decoupling of sensory and attention networks from the global network. General anesthesia and unresponsive wakefulness syndrome were characterized by a dissociation of the majority of functional networks from the global network. This decoupling, however, was dominated by distinct neuroanatomic foci (e.g., precuneus and anterior cingulate cortices).

CONCLUSIONS

The global temporal coordination of various modules across the brain may distinguish the coarse-grained state of consciousness versus unconsciousness, while the relationship between the global and local signals may define the particular qualities of a particular unconscious state.

Topics: Adult; Animals; Brain; Electroencephalography; Female; Humans; Hypnotics and Sedatives; Magnetic Resonance Imaging; Male; Models, Animal; Propofol; Rats; Sleep; Unconsciousness

PubMed: 32205548
DOI: 10.1097/ALN.0000000000003197

Observational Study

Authors: Feng-Fang Tsai, Shou-Zen Fan, Hsiao-Liang Cheng...

Under general anesthesia (GA), advanced analysis methods enhance the awareness of the electroencephalography (EEG) signature of transitions from consciousness to unconsciousness. For nonlinear and nonstationary signals, empirical mode decomposition (EMD) works as a dyadic filter bank to reserve local dynamical properties in decomposed components. Moreover, cross-frequency phase-amplitude coupling analysis illustrates that the coupling between the phase of low-frequency components and the amplitude of high-frequency components is correlated with the brain functions of sensory detection, working memory, consciousness, and attentional selection. To improve the functions of phase-amplitude coupling analysis, we utilized a multi-timescale approach based on EMD to assess changes in brain functions in anesthetic-induced unconsciousness using a measure of phase-amplitude coupling. Two groups of patients received two different anesthetic recipes (with or without ketamine) during the induction period of GA. Long-term (low-frequency) coupling represented a common transitional process of brain functions from consciousness to unconsciousness with a decay trend in both groups. By contrast, short-term coupling reflected a reverse trend to long-term coupling. However, the measures of short-term coupling also reflected a higher degree of coupling for the group with ketamine compared with that without ketamine. In addition, the coupling phase is a factor of interest. The phases for different combinations of coupling components showed significant changes in anesthetic-induced unconsciousness. The coupling between the delta-band phase and the theta-band amplitude changed from in-phase to out-phase coupling during the induction process from consciousness to unconsciousness. The changes in the coupling phase in EEG signals were abrupt and sensitive in anesthetic-induced unconsciousness.

Topics: Anesthetics, General; Brain; Case-Control Studies; Electroencephalography; Humans; Sevoflurane; Unconsciousness

PubMed: 31127152
DOI: 10.1038/s41598-019-44238-8

Authors: Jesus Javier Ballesteros, Jessica Blair Briscoe, Yumiko Ishizawa...

How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They generate unconsciousness selectively through α2-adrenergic receptors and related circuits. We studied intracortical neuronal dynamics during transitions of loss of consciousness (LOC) with the α2-adrenergic agonist dexmedetomidine and return of consciousness (ROC) in a functionally interconnecting somatosensory and ventral premotor network in non-human primates. LOC, ROC and full task performance recovery were all associated with distinct neural changes. The early recovery demonstrated characteristic intermediate dynamics distinguished by sustained high spindle activities. Awakening by the α2-adrenergic antagonist completely eliminated this intermediate state and instantaneously restored awake dynamics and the top task performance while the anesthetic was still being infused. The results suggest that instantaneous functional recovery is possible following anesthetic-induced unconsciousness and the intermediate recovery state is not a necessary path for the brain recovery.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Brain; Consciousness; Dexmedetomidine; Electroencephalography; Humans; Hypnotics and Sedatives; Imidazoles; Macaca; Male; Unconsciousness; Wakefulness

PubMed: 32857037
DOI: 10.7554/eLife.57670