Publications by authors named "George A Mashour"

227 Publications

Repurposing Propofol as a Prognostic Probe for Return of Consciousness.

Am J Respir Crit Care Med 2021 Nov 24. Epub 2021 Nov 24.

University of Michigan Michigan Medicine, 21614, Anesthesiology, Ann Arbor, Michigan, United States.

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http://dx.doi.org/10.1164/rccm.202111-2504EDDOI Listing
November 2021

Distinct and Dissociable EEG Networks Are Associated With Recovery of Cognitive Function Following Anesthesia-Induced Unconsciousness.

Front Hum Neurosci 2021 14;15:706693. Epub 2021 Sep 14.

School of Physical and Occupational Therapy, McGill University, Montreal, QC, Canada.

The temporal trajectories and neural mechanisms of recovery of cognitive function after a major perturbation of consciousness is of both clinical and neuroscientific interest. The purpose of the present study was to investigate network-level changes in functional brain connectivity associated with the recovery and return of six cognitive functions after general anesthesia. High-density electroencephalograms (EEG) were recorded from healthy volunteers undergoing a clinically relevant anesthesia protocol (propofol induction and isoflurane maintenance), and age-matched healthy controls. A battery of cognitive tests (motor praxis, visual object learning test, fractal-2-back, abstract matching, psychomotor vigilance test, digital symbol substitution test) was administered at baseline, upon recovery of consciousness (ROC), and at half-hour intervals up to 3 h following ROC. EEG networks were derived using the strength of functional connectivity measured through the weighted phase lag index (wPLI). A partial least squares (PLS) analysis was conducted to assess changes in these networks: (1) between anesthesia and control groups; (2) during the 3-h recovery from anesthesia; and (3) for each cognitive test during recovery from anesthesia. Networks were maximally perturbed upon ROC but returned to baseline 30-60 min following ROC, despite deficits in cognitive performance that persisted up to 3 h following ROC. Additionally, during recovery from anesthesia, cognitive tests conducted at the same time-point activated distinct and dissociable functional connectivity networks across all frequency bands. The results highlight that the return of cognitive function after anesthetic-induced unconsciousness is task-specific, with unique behavioral and brain network trajectories of recovery.
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http://dx.doi.org/10.3389/fnhum.2021.706693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477048PMC
September 2021

Neurophysiologic Complexity in Children Increases with Developmental Age and Is Reduced by General Anesthesia.

Anesthesiology 2021 11;135(5):813-828

From the Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; the Center for Consciousness Science, University of Michigan Medical School, Ann Arbor, Michigan.

Background: Neurophysiologic complexity in the cortex has been shown to reflect changes in the level of consciousness in adults but remains incompletely understood in the developing brain. This study aimed to address changes in cortical complexity related to age and anesthetic state transitions. This study tested the hypotheses that cortical complexity would (1) increase with developmental age and (2) decrease during general anesthesia.

Methods: This was a single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists physical status I or II) children (n = 50) of age 8 to 16 undergoing surgery with general anesthesia at Michigan Medicine. This age range was chosen because it reflects a period of substantial brain network maturation. Whole scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Cortical complexity was measured using the Lempel-Ziv algorithm and analyzed during the baseline, premedication, maintenance of general anesthesia, and clinical recovery periods. The effect of spectral power on Lempel-Ziv complexity was analyzed by comparing the original complexity value with those of surrogate time series generated through phase randomization that preserves power spectrum.

Results: Baseline spatiotemporal Lempel-Ziv complexity increased with age (yr; slope [95% CI], 0.010 [0.004, 0.016]; P < 0.001); when normalized to account for spectral power, there was no significant age effect on cortical complexity (0.001 [-0.004, 0.005]; P = 0.737). General anesthesia was associated with a significant decrease in spatiotemporal complexity (median [25th, 75th]; baseline, 0.660 [0.620, 0.690] vs. maintenance, 0.459 [0.402, 0.527]; P < 0.001), and spatiotemporal complexity exceeded baseline levels during postoperative recovery (0.704 [0.642, 0.745]; P = 0.009). When normalized, there was a similar reduction in complexity during general anesthesia (baseline, 0.913 [0.887, 0.923] vs. maintenance 0.851 [0.823, 0.877]; P < 0.001), but complexity remained significantly reduced during recovery (0.873 [0.840, 0.902], P < 0.001).

Conclusions: Cortical complexity increased with developmental age and decreased during general anesthesia. This association remained significant when controlling for spectral changes during anesthetic-induced perturbations in consciousness but not with developmental age.

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http://dx.doi.org/10.1097/ALN.0000000000003929DOI Listing
November 2021

Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19.

Proc Natl Acad Sci U S A 2021 09;118(36)

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109;

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.
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http://dx.doi.org/10.1073/pnas.2105815118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433531PMC
September 2021

Inactivation of Prefrontal Cortex Delays Emergence From Sevoflurane Anesthesia.

Front Syst Neurosci 2021 9;15:690717. Epub 2021 Jul 9.

Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States.

Studies aimed at investigating brain regions involved in arousal state control have been traditionally limited to subcortical structures. In the current study, we tested the hypothesis that inactivation of prefrontal cortex, but not two subregions within parietal cortex-somatosensory barrel field and medial/lateral parietal association cortex-would suppress arousal, as measured by an increase in anesthetic sensitivity. Male and female Sprague Dawley rats were surgically prepared for recording electroencephalogram and bilateral infusion into prefrontal cortex ( = 13), somatosensory barrel field (N = 10), or medial/lateral parietal association cortex ( = 9). After at least 10 days of post-surgical recovery, 156 μM tetrodotoxin or saline was microinjected into one of the cortical sites. Ninety minutes after injection, rats were anesthetized with 2.5% sevoflurane and the time to loss of righting reflex, a surrogate for loss of consciousness, was measured. Sevoflurane was stopped after 45 min and the time to return of righting reflex, a surrogate for return of consciousness, was measured. Tetrodotoxin-mediated inactivation of all three cortical sites decreased ( < 0.05) the time to loss of righting reflex. By contrast, only inactivation of prefrontal cortex, but not somatosensory barrel field or medial/lateral parietal association cortex, increased ( < 0.001) the time to return of righting reflex. Burst suppression ratio was not altered following inactivation of any of the cortical sites, suggesting that there was no global effect due to pharmacologic lesion. These findings demonstrate that prefrontal cortex plays a causal role in emergence from anesthesia and behavioral arousal.
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http://dx.doi.org/10.3389/fnsys.2021.690717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299111PMC
July 2021

Role of CTSA institutes and academic medical centers in facilitating preapproval access to investigational agents and devices during the COVID-19 pandemic.

J Clin Transl Sci 2021 Feb 26;5(1):e94. Epub 2021 Feb 26.

Michigan Institute for Clinical & Health Research, University of Michigan, Ann Arbor, MI, USA.

Introduction: With no approved treatments for COVID-19 initially available, the Food and Drug Administration utilized multiple preapproval pathways to provide access to investigational agents and/or medical devices: Expanded Access, Emergency Use Authorizations, and Clinical Trials. Regulatory units within an Academic Medical Center (AMC), including those part of the Clinical and Translational Science Award (CTSA) consortium, have provided support for clinicians in navigating these options prior to the pandemic. As such, they were positioned to be a resource for accessing therapies during the COVID-19 public health emergency.

Methods: A small survey and a follow-on poll of the national Investigational New Drug (IND)/Investigational Device Exemption (IDE) Workgroup were conducted in October and December 2020 to determine whether CTSA regulatory units assisted in facilitating access to COVID-19 therapies and the extent of pandemic-related challenges these units faced.

Results: Fifteen survey and 21 poll responses were received, which provided insights into the demands placed on these regulatory support units due to the pandemic and the changes required to provide critical support during this and future crises. Key changes and lessons learned included the importance of regulatory knowledge to support the institutional response, the critical need for electronic submission capacity for Food and Drug Administration (FDA) documents, and the nimble reallocation of regulatory and legal resources to support patient access to investigational agents and/or medical devices during the pandemic.

Conclusion: AMC- and CTSA-based regulatory units played a meaningful role in the COVID-19 pandemic but further unit modifications are needed for enabling more robust regulatory support in the future.
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http://dx.doi.org/10.1017/cts.2021.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134898PMC
February 2021

Neural Dynamics in Primate Cortex during Exposure to Subanesthetic Concentrations of Nitrous Oxide.

eNeuro 2021 Jul-Aug;8(4). Epub 2021 Jul 14.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109

Nitrous oxide (NO) is a hypnotic gas with antidepressant and psychedelic properties at subanesthetic concentrations. Despite long-standing clinical use, there is insufficient understanding of its effect on neural dynamics and cortical processing, which is important for mechanistic understanding of its therapeutic effects. We administered subanesthetic (70%), inhaled NO and studied the dynamic changes of spiking rate, spectral content, and somatosensory information representation in primary motor cortex (M1) in two male rhesus macaques implanted with Utah microelectrode arrays in the hand area of M1. The average sorted multiunit spiking rate in M1 increased from 8.1 ± 0.99 to 10.6 ± 1.3 Hz in Monkey W (<0.001) and from 5.6 ± 0.87 to 7.0 ± 1.1 Hz in Monkey N (=0.003). Power spectral densities increased in beta- and gamma-band power. To evaluate somatosensory content in M1 as a surrogate of information transfer, fingers were lightly brushed and classified using a naive Bayes classifier. In both monkeys, the proportion of correctly classified fingers dropped from 0.50 ± 0.06 before NO inhalation to 0.34 ± 0.03 during NO inhalation (=0.018), although some fingers continued to be correctly classified (=0.005). The decrease in correct classifications corresponded to decreased modulation depth for the population (=0.005) and fewer modulated units (=0.046). However, the increased single-unit firing rate was not correlated with its modulation depth ( < 0.001, =0.93). These data suggest that NO degrades information transfer, although no clear relationship was found between neuronal tuning and NO-induced changes in firing rate.
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http://dx.doi.org/10.1523/ENEURO.0479-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281265PMC
August 2021

Differential classification of states of consciousness using envelope- and phase-based functional connectivity.

Neuroimage 2021 08 15;237:118171. Epub 2021 May 15.

Montreal General Hospital, McGill University Health Centre, 1650 Cedar Ave, Montreal, QC, Canada; School of Physical and Occupational Therapy, McGill University, 3654 Promenade Sir-William-Osler Montreal, Quebec H3G 1Y5, Canada. Electronic address:

The development of sophisticated computational tools to quantify changes in the brain's oscillatory dynamics across states of consciousness have included both envelope- and phase-based measures of functional connectivity (FC), but there are very few direct comparisons of these techniques using the same dataset. The goal of this study was to compare an envelope-based (i.e. Amplitude Envelope Correlation, AEC) and a phase-based (i.e. weighted Phase Lag Index, wPLI) measure of FC in their classification of states of consciousness. Nine healthy participants underwent a three-hour experimental anesthetic protocol with propofol induction and isoflurane maintenance, in which five minutes of 128-channel electroencephalography were recorded before, during, and after anesthetic-induced unconsciousness, at the following time points: Baseline; light sedation with propofol (Light Sedation); deep unconsciousness following three hours of surgical levels of anesthesia with isoflurane (Unconscious); five minutes prior to the recovery of consciousness (Pre-ROC); and three hours following the recovery of consciousness (Recovery). Support vector machine classification was applied to the source-localized EEG in the alpha (8-13 Hz) frequency band in order to investigate the ability of AEC and wPLI (separately and together) to discriminate i) the four states from Baseline; ii) Unconscious ("deep" unconsciousness) vs. Pre-ROC ("light" unconsciousness); and iii) responsiveness (Baseline, Light Sedation, Recovery) vs. unresponsiveness (Unconscious, Pre-ROC). AEC and wPLI yielded different patterns of global connectivity across states of consciousness, with AEC showing the strongest network connectivity during the Unconscious epoch, and wPLI showing the strongest connectivity during full consciousness (i.e., Baseline and Recovery). Both measures also demonstrated differential predictive contributions across participants and used different brain regions for classification. AEC showed higher classification accuracy overall, particularly for distinguishing anesthetic-induced unconsciousness from Baseline (83.7 ± 0.8%). AEC also showed stronger classification accuracy than wPLI when distinguishing Unconscious from Pre-ROC (i.e., "deep" from "light" unconsciousness) (AEC: 66.3 ± 1.2%; wPLI: 56.2 ± 1.3%), and when distinguishing between responsiveness and unresponsiveness (AEC: 76.0 ± 1.3%; wPLI: 63.6 ± 1.8%). Classification accuracy was not improved compared to AEC when both AEC and wPLI were combined. This analysis of source-localized EEG data demonstrates that envelope- and phase-based FC provide different information about states of consciousness but that, on a group level, AEC is better able to detect relative alterations in brain FC across levels of anesthetic-induced unconsciousness compared to wPLI.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118171DOI Listing
August 2021

Recovery of consciousness and cognition after general anesthesia in humans.

Elife 2021 05 10;10. Epub 2021 May 10.

Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory.
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http://dx.doi.org/10.7554/eLife.59525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163502PMC
May 2021

Anterior insula regulates brain network transitions that gate conscious access.

Cell Rep 2021 05;35(5):109081

Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Consciousness Science, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Conscious access to sensory information is likely gated at an intermediate site between primary sensory and transmodal association cortices, but the structure responsible remains unknown. We perform functional neuroimaging to determine the neural correlates of conscious access using a volitional mental imagery task, a report paradigm not confounded by motor behavior. Titrating propofol to loss of behavioral responsiveness in healthy volunteers creates dysfunction of the anterior insular cortex (AIC) in association with an impairment of dynamic transitions of default-mode and dorsal attention networks. Candidate subcortical regions mediating sensory gating or arousal (thalamus, basal forebrain) fail to show this association. The gating role of the AIC is consistent with findings in awake participants, whose conscious access is predicted by pre-stimulus AIC activity near perceptual threshold. These data support the hypothesis that AIC, situated at an intermediate position of the cortical hierarchy, regulates brain network transitions that gate conscious access.
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http://dx.doi.org/10.1016/j.celrep.2021.109081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157795PMC
May 2021

The Effects of Intraoperative Caffeine on Postoperative Opioid Consumption and Related Outcomes After Laparoscopic Surgery: A Randomized Controlled Trial.

Anesth Analg 2021 07;133(1):233-242

From the Department of Anesthesiology.

Background: Surgical patients are vulnerable to opioid dependency and related risks. Clinical-translational data suggest that caffeine may enhance postoperative analgesia. This trial tested the hypothesis that intraoperative caffeine would reduce postoperative opioid consumption. The secondary objective was to assess whether caffeine improves neuropsychological recovery postoperatively.

Methods: This was a single-center, randomized, placebo-controlled trial. Participants, clinicians, research teams, and data analysts were all blinded to the intervention. Adult (≥18 years old) surgical patients (n = 65) presenting for laparoscopic colorectal and gastrointestinal surgery were randomized to an intravenous caffeine citrate infusion (200 mg) or dextrose 5% in water (40 mL) during surgical closure. The primary outcome was cumulative opioid consumption through postoperative day 3. Secondary outcomes included subjective pain reporting, observer-reported pain, delirium, Trail Making Test performance, depression and anxiety screens, and affect scores. Adverse events were reported, and hemodynamic profiles were also compared between the groups.

Results: Sixty patients were included in the final analysis, with 30 randomized to each group. The median (interquartile range) cumulative opioid consumption (oral morphine equivalents, milligrams) was 77 mg (33-182 mg) for caffeine and 51 mg (15-117 mg) for placebo (estimated difference, 55 mg; 95% confidence interval [CI], -9 to 118; P = .092). After post hoc adjustment for baseline imbalances, caffeine was associated with increased opioid consumption (87 mg; 95% CI, 26-148; P = .005). There were otherwise no differences in prespecified pain or neuropsychological outcomes between the groups. No major adverse events were reported in relation to caffeine, and no major hemodynamic perturbations were observed with caffeine administration.

Conclusions: Caffeine appears unlikely to reduce early postoperative opioid consumption. Caffeine otherwise appears well tolerated during anesthetic emergence.
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http://dx.doi.org/10.1213/ANE.0000000000005532DOI Listing
July 2021

Asymmetric neural dynamics characterize loss and recovery of consciousness.

Neuroimage 2021 08 10;236:118042. Epub 2021 Apr 10.

Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Consciousness Science, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Anesthetics are known to disrupt neural interactions in cortical and subcortical brain circuits. While the effect of anesthetic drugs on consciousness is reversible, the neural mechanism mediating induction and recovery may be different. Insight into these distinct mechanisms can be gained from a systematic comparison of neural dynamics during slow induction of and emergence from anesthesia. To this end, we used functional magnetic resonance imaging (fMRI) data obtained in healthy volunteers before, during, and after the administration of propofol at incrementally adjusted target concentrations. We analyzed functional connectivity of corticocortical and subcorticocortical networks and the temporal autocorrelation of fMRI signal as an index of neural processing timescales. We found that en route to unconsciousness, temporal autocorrelation across the entire brain gradually increased, whereas functional connectivity gradually decreased. In contrast, regaining consciousness was associated with an abrupt restoration of cortical but not subcortical temporal autocorrelation and an abrupt boost of subcorticocortical functional connectivity. Pharmacokinetic effects could not account for the difference in neural dynamics between induction and emergence. We conclude that the induction and recovery phases of anesthesia follow asymmetric neural dynamics. A rapid increase in the speed of cortical neural processing and subcorticocortical neural interactions may be a mechanism that reboots consciousness.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310457PMC
August 2021

Neural Correlates of the Shamanic State of Consciousness.

Front Hum Neurosci 2021 18;15:610466. Epub 2021 Mar 18.

Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States.

Psychedelics have been recognized as model interventions for studying altered states of consciousness. However, few empirical studies of the shamanic state of consciousness, which is anecdotally similar to the psychedelic state, exist. We investigated the neural correlates of shamanic trance using high-density electroencephalography (EEG) in 24 shamanic practitioners and 24 healthy controls during rest, shamanic drumming, and classical music listening, followed by an assessment of altered states of consciousness. EEG data were used to assess changes in absolute power, connectivity, signal diversity, and criticality, which were correlated with assessment measures. We also compared assessment scores to those of individuals in a previous study under the influence of psychedelics. Shamanic practitioners were significantly different from controls in several domains of altered states of consciousness, with scores comparable to or exceeding that of healthy volunteers under the influence of psychedelics. Practitioners also displayed increased gamma power during drumming that positively correlated with elementary visual alterations. Furthermore, shamanic practitioners had decreased low alpha and increased low beta connectivity during drumming and classical music and decreased neural signal diversity in the gamma band during drumming that inversely correlated with insightfulness. Finally, criticality in practitioners was increased during drumming in the low and high beta and gamma bands, with increases in the low beta band correlating with complex imagery and elementary visual alterations. These findings suggest that psychedelic drug-induced and non-pharmacologic alterations in consciousness have overlapping phenomenal traits but are distinct states of consciousness, as reflected by the unique brain-related changes during shamanic trance compared to previous literature investigating the psychedelic state.
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http://dx.doi.org/10.3389/fnhum.2021.610466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012721PMC
March 2021

Glutamatergic Neurons in the Preoptic Hypothalamus Promote Wakefulness, Destabilize NREM Sleep, Suppress REM Sleep, and Regulate Cortical Dynamics.

J Neurosci 2021 04 4;41(15):3462-3478. Epub 2021 Mar 4.

Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109-5615

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study, we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. We also demonstrate, for the first time, that activation of these preoptic glutamatergic neurons causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, decreases body temperature, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons can initiate, but not maintain, arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the hypothesis that the preoptic area causally contributes to the regulation of both sleep and wakefulness. Historically, the preoptic area of the hypothalamus has been considered a key site for sleep generation. However, emerging modeling and empirical data suggest that this region might play a dual role in sleep-wake control. We demonstrate that chemogenetic stimulation of preoptic glutamatergic neurons produces brief arousals that fragment sleep, persistently suppresses REM sleep, causes hypothermia, and shifts EEG patterns toward a "lighter" NREM sleep state. We propose that preoptic glutamatergic neurons can initiate, but not maintain, arousal from sleep and gate REM sleep generation, possibly to block REM-like intrusions during NREM-to-wake transitions. In contrast to the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic, we provide further evidence that preoptic neurons also generate wakefulness.
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http://dx.doi.org/10.1523/JNEUROSCI.2718-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051693PMC
April 2021

Brain network motifs are markers of loss and recovery of consciousness.

Sci Rep 2021 02 16;11(1):3892. Epub 2021 Feb 16.

School of Physical and Occupational Therapy, McGill University, Montreal, Canada.

Motifs are patterns of inter-connections between nodes of a network, and have been investigated as building blocks of directed networks. This study explored the re-organization of 3-node motifs during loss and recovery of consciousness. Nine healthy subjects underwent a 3-h anesthetic protocol while 128-channel electroencephalography (EEG) was recorded. In the alpha (8-13 Hz) band, 5-min epochs of EEG were extracted for: Baseline; Induction; Unconscious; 30-, 10- and 5-min pre-recovery of responsiveness; 30- and 180-min post-recovery of responsiveness. We constructed a functional brain network using the weighted and directed phase lag index, on which we calculated the frequency and topology of 3-node motifs. Three motifs (motifs 1, 2 and 5) were significantly present across participants and epochs, when compared to random networks (p < 0.05). The topology of motifs 1 and 5 changed significantly between responsive and unresponsive epochs (p-values < 0.01; Kendall's W = 0.664 (motif 1) and 0.529 (motif 5)). Motif 1 was constituted of long-range chain-like connections, while motif 5 was constituted of short-range, loop-like connections. Our results suggest that anesthetic-induced unconsciousness is associated with a topological re-organization of network motifs. As motif topological re-organization may precede (motif 5) or accompany (motif 1) the return of responsiveness, motifs could contribute to the understanding of the neural correlates of consciousness.
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http://dx.doi.org/10.1038/s41598-021-83482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887248PMC
February 2021

Instantaneous amplitude and shape of postrhinal theta oscillations differentially encode running speed.

Behav Neurosci 2020 Dec;134(6):516-528

Department of Psychology.

Hippocampal theta oscillations have a temporally asymmetric waveform shape, but it is not known if this theta asymmetry extends to all other cortical regions involved in spatial navigation and memory. Here, using both established and improved cycle-by-cycle analysis methods, we show that theta waveforms in the postrhinal cortex are also temporally asymmetric. On average, the falling phase of postrhinal theta cycles lasts longer than the subsequent rising phase. There are, however, rapid changes in both the instantaneous amplitude and instantaneous temporal asymmetry of postrhinal theta cycles. These rapid changes in amplitude and asymmetry are very poorly correlated, indicative of a mechanistic disconnect between these theta cycle features. We show that the instantaneous amplitude and asymmetry of postrhinal theta cycles differentially encode running speed. Although theta amplitude continues to increase at the fastest running speeds, temporal asymmetry of the theta waveform shape plateaus after medium speeds. Our results suggest that the amplitude and waveform shape of individual postrhinal theta cycles may be governed by partially independent mechanisms and emphasize the importance of employing a single cycle approach to understanding the genesis and behavioral correlates of cortical theta rhythms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000416DOI Listing
December 2020

Carbachol and Nicotine in Prefrontal Cortex Have Differential Effects on Sleep-Wake States.

Front Neurosci 2020 20;14:567849. Epub 2020 Nov 20.

Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States.

The role of the brainstem cholinergic system in the regulation of sleep-wake states has been studied extensively but relatively little is known about the role of cholinergic mechanisms in prefrontal cortex in the regulation of sleep-wake states. In a recent study, we showed that prefrontal cholinergic stimulation in anesthetized rat can reverse the traits associated with anesthesia and restore a wake-like state, thereby providing evidence for a causal role for prefrontal cholinergic mechanisms in modulating level of arousal. However, the effect of increase in prefrontal cholinergic tone on spontaneous sleep-wake states has yet to be demonstrated. Therefore, in this study, we tested the hypothesis that delivery of cholinergic agonists - carbachol or nicotine - into prefrontal cortex of rat during slow wave sleep (SWS) would produce behavioral arousal and increase the time spent in wake state. We show that unilateral microinjection (200 nL) of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex during SWS decreased the latency to the onset of wake state ( = 0.03 for carbachol, = 0.03 for nicotine) and increased the latency to the onset of rapid eye movement sleep ( = 0.008 for carbachol, = 0.006 for nicotine). Although the infusion of 1 mM carbachol increased the time spent in wake state ( = 0.01) and decreased the time spent in SWS ( = 0.01), infusion of 10 or 100 mM nicotine did not produce any statistically significant change in sleep-wake architecture. These data demonstrate a differential role of prefrontal cholinergic receptors in modulating spontaneous sleep-wake states.
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http://dx.doi.org/10.3389/fnins.2020.567849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714754PMC
November 2020

Greater Somatosensory Afference With Acupuncture Increases Primary Somatosensory Connectivity and Alleviates Fibromyalgia Pain via Insular γ-Aminobutyric Acid: A Randomized Neuroimaging Trial.

Arthritis Rheumatol 2021 07 31;73(7):1318-1328. Epub 2021 May 31.

University of Michigan, Ann Arbor.

Objective: Acupuncture is a complex multicomponent treatment that has shown promise in the treatment of fibromyalgia (FM). However, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. The present study was undertaken to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved.

Methods: Seventy-six patients with FM were randomized to receive either electroacupuncture (EA), with somatosensory afference, or mock laser acupuncture (ML), with no somatosensory afference, twice a week over 8 treatments. Patients with FM in each treatment group were assessed for pain severity levels, measured using Brief Pain Inventory (BPI) scores, and for levels of functional brain network connectivity, assessed using resting state functional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy in the right anterior insula, before and after treatment.

Results: Fibromyalgia patients who received EA therapy experienced a greater reduction in pain severity, as measured by the BPI, compared to patients who received ML therapy (mean difference in BPI from pre- to posttreatment was -1.14 in the EA group versus -0.46 in the ML group; P for group × time interaction = 0.036). Participants receiving EA treatment, as compared to ML treatment, also exhibited resting functional connectivity between the primary somatosensory cortical representation of the leg (S1 ; i.e. primary somatosensory subregion activated by EA) and the anterior insula. Increased S1 -anterior insula connectivity was associated with both reduced levels of pain severity as measured by the BPI (r = -0.44, P = 0.01) and increased levels of γ-aminobutyric acid (GABA+) in the anterior insula (r = 0.48, P = 0.046) following EA therapy. Moreover, increased levels of GABA+ in the anterior insula were associated with reduced levels of pain severity as measured by the BPI (r = -0.59, P = 0.01). Finally, post-EA treatment changes in levels of GABA+ in the anterior insula mediated the relationship between changes in S1 -anterior insula connectivity and pain severity on the BPI (bootstrap confidence interval -0.533, -0.037).

Conclusion: The somatosensory component of acupuncture modulates primary somatosensory functional connectivity associated with insular neurochemistry to reduce pain severity in FM.
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http://dx.doi.org/10.1002/art.41620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197768PMC
July 2021

Altered network architecture of functional brain communities in chronic nociplastic pain.

Neuroimage 2021 02 24;226:117504. Epub 2020 Oct 24.

Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Center for Consciousness Science, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117504DOI Listing
February 2021

Genetic mutations associated with susceptibility to perioperative complications in a longitudinal biorepository with integrated genomic and electronic health records.

Br J Anaesth 2020 12 3;125(6):986-994. Epub 2020 Sep 3.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Existing genetic information can be leveraged to identify patients with susceptibilities to conditions that might impact their perioperative care, but clinicians generally have limited exposure and are not trained to contextualise this information. We identified patients with genetic susceptibilities to anaesthetic complications using a perioperative biorepository and characterised the concordance with existing diagnoses.

Methods: Adult patients undergoing surgery within Michigan Medicine from 2012 to 2017 were consented for genotyping. Genotypes were integrated with the electronic health record (EHR). We retrospectively characterised frequencies of variants associated with butyrylcholinesterase deficiency, factor V Leiden, and malignant hyperthermia, three pharmacogenetic factors with perioperative implications. We calculated the percentage homozygous and heterozygous for each that had been diagnosed previously and searched for EHR findings consistent with a predisposition.

Results: Analysis of genetic data revealed that 25 out of 40 769 (0.1%) patients were homozygous and 1918 (4.7%) were heterozygous for mutations associated with butyrylcholinesterase deficiency. Of the homozygous individuals, 14 (56%) carried a pre-existing diagnosis. For factor V Leiden, 29 (0.1%) were homozygous and 2153 (5.3%) heterozygous. Of the homozygous individuals, three (10%) were diagnosed by EHR-derived phenotype and six (21%) by clinician review. Malignant hyperthermia was assessed in a subset of patients. We detected two patients with associated mutations. Neither carried clinical diagnoses.

Conclusions: We identified patients with genetic susceptibility to perioperative complications using an open source script designed for clinician use. We validated this application in a retrospective analysis for three conditions with well-characterised inheritance, and showed that not all genetic susceptibilities were documented in the EHR.
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http://dx.doi.org/10.1016/j.bja.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729841PMC
December 2020

State-Dependent and Bandwidth-Specific Effects of Ketamine and Propofol on Electroencephalographic Complexity in Rats.

Front Syst Neurosci 2020 11;14:50. Epub 2020 Aug 11.

Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States.

There is an ongoing debate as to whether ketamine anesthesia suppresses neurophysiologic complexity at doses sufficient for surgical anesthesia, with previous human studies reporting surrogates of both suppressed and preserved levels of cortical complexity. However, these studies have not assessed cortical dynamics in higher gamma frequencies, which have previously been demonstrated to correlate with the level of consciousness during anesthesia. In this study, we used Lempel-Ziv complexity (LZc) to characterize frontal and parietal electroencephalographic complexity (0.5-175 Hz, 0.5-55 Hz, 65-175 Hz) before, during, and after ketamine or propofol anesthesia in the rat. To control for the potential influence of spectral changes in complexity estimation, LZc was normalized with phase-shuffled surrogate data. We demonstrate that ketamine and propofol anesthesia were characterized by a significant reduction in broadband (0.5-175 Hz) LZc. Further analysis showed that while the reduction of LZc during ketamine anesthesia was significant in 65-175 Hz range, during propofol anesthesia, a significant decrease was observed in 0.5-55 Hz bandwidth. LZc in broadband and 0.5-55 Hz range showed a significant increase during emergence from ketamine anesthesia. Phase-shuffled normalized LZc revealed that (1) decrease in complexity during ketamine and propofol anesthesia-not increase in complexity during emergence-were dissociable from the influence of spectral changes, and (2) reduced LZc during ketamine anesthesia was present across all three bandwidths. Ketamine anesthesia was characterized by reduced complexity in high gamma bandwidth, as reflected in both raw and phase-shuffled normalized LZc, which suggests that reduced high gamma complexity is a neurophysiological feature of ketamine anesthesia.
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http://dx.doi.org/10.3389/fnsys.2020.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431468PMC
August 2020

Alpha band frontal connectivity is a state-specific electroencephalographic correlate of unresponsiveness during exposure to dexmedetomidine and propofol.

Br J Anaesth 2020 10 7;125(4):518-528. Epub 2020 Aug 7.

Department of Anesthesiology, Center for Consciousness Science, University of Michigan Medical School, Ann Arbor, MI, USA.

Background: Coherent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity.

Methods: Forty-seven healthy males received either dexmedetomidine (n=23) or propofol (n=24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontal-frontal and anterior-posterior functional connectivity in the alpha band (8-14 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI).

Results: Prefrontal-frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontal-frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: -0.13 to -0.40) in contrast to baseline (dPLI: 0.01-0.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anterior-posterior connectivity in the alpha band did not differentiate LOR and ROR.

Conclusions: Local prefrontal-frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents.

Clinical Trial Registration: NCT01889004.
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http://dx.doi.org/10.1016/j.bja.2020.05.068DOI Listing
October 2020

Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19.

bioRxiv 2020 Dec 7. Epub 2020 Dec 7.

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10-15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 17 dose-responsive compounds with antiviral efficacy in human liver Huh7 cells and confirmed antiviral efficacy in human colon carcinoma Caco-2, human prostate adenocarcinoma LNCaP, and in a physiologic relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection . Notably, we discovered that lactoferrin, a glycoprotein classically found in secretory fluids, including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.
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http://dx.doi.org/10.1101/2020.05.27.117184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302203PMC
December 2020

Perioperative Care of Patients at High Risk for Stroke During or After Non-cardiac, Non-neurological Surgery: 2020 Guidelines From the Society for Neuroscience in Anesthesiology and Critical Care.

J Neurosurg Anesthesiol 2020 Jul;32(3):210-226

Department of Anesthesiology.

Perioperative stroke is associated with considerable morbidity and mortality. Stroke recognition and diagnosis are challenging perioperatively, and surgical patients receive therapeutic interventions less frequently compared with stroke patients in the outpatient setting. These updated guidelines from the Society for Neuroscience in Anesthesiology and Critical Care provide evidence-based recommendations regarding perioperative care of patients at high risk for stroke. Recommended areas for future investigation are also proposed.
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http://dx.doi.org/10.1097/ANA.0000000000000686DOI Listing
July 2020

Altered Global Brain Signal during Physiologic, Pharmacologic, and Pathologic States of Unconsciousness in Humans and Rats.

Anesthesiology 2020 06;132(6):1392-1406

From the Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China (J.Z., Y.C., J.X.) the Department of Anesthesiology and Center for Consciousness Science, University of Michigan, Ann Arbor, Michigan (S.T., Z.H., G.A.M., A.G.H.) Institute of Mental Health Research (S.F., G.N.) School of Psychology (S.F.), University of Ottawa, Ottawa, Canada Department of Psychology, University of Montreal, Montreal, Canada (S.F., J.D.) Functional Neuroimaging Unit, Institute of Geriatrics, University of Montréal, Montréal, Canada (S.F., J.D.) McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Canada (J.D.) Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China (J.W., X.W., Y.M.) Mental Health Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (J.Z., G.N.) School of Psychology, South China Normal University, Guangzhou, Guangdong, China (P.Q.).

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.
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http://dx.doi.org/10.1097/ALN.0000000000003197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218242PMC
June 2020

Temporal circuit of macroscale dynamic brain activity supports human consciousness.

Sci Adv 2020 03 11;6(11):eaaz0087. Epub 2020 Mar 11.

Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

The ongoing stream of human consciousness relies on two distinct cortical systems, the default mode network and the dorsal attention network, which alternate their activity in an anticorrelated manner. We examined how the two systems are regulated in the conscious brain and how they are disrupted when consciousness is diminished. We provide evidence for a "temporal circuit" characterized by a set of trajectories along which dynamic brain activity occurs. We demonstrate that the transitions between default mode and dorsal attention networks are embedded in this temporal circuit, in which a balanced reciprocal accessibility of brain states is characteristic of consciousness. Conversely, isolation of the default mode and dorsal attention networks from the temporal circuit is associated with unresponsiveness of diverse etiologies. These findings advance the foundational understanding of the functional role of anticorrelated systems in consciousness.
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http://dx.doi.org/10.1126/sciadv.aaz0087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065875PMC
March 2020

Conscious Processing and the Global Neuronal Workspace Hypothesis.

Neuron 2020 03;105(5):776-798

Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France; Cognitive Neuroimaging Unit, CEA, INSERM, Université Paris-Sud, Université Paris-Saclay, NeuroSpin Center, 91191 Gif/Yvette, France. Electronic address:

We review the central tenets and neuroanatomical basis of the global neuronal workspace (GNW) hypothesis, which attempts to account for the main scientific observations regarding the elementary mechanisms of conscious processing in the human brain. The GNW hypothesis proposes that, in the conscious state, a non-linear network ignition associated with recurrent processing amplifies and sustains a neural representation, allowing the corresponding information to be globally accessed by local processors. We examine this hypothesis in light of recent data that contrast brain activity evoked by either conscious or non-conscious contents, as well as during conscious or non-conscious states, particularly general anesthesia. We also discuss the relationship between the intertwined concepts of conscious processing, attention, and working memory.
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http://dx.doi.org/10.1016/j.neuron.2020.01.026DOI Listing
March 2020
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