The overall goal of this project is to understand the mechanisms by which general anesthetics remove consciousness and allow its return during emergence. Our general hypothesis is that anesthetics remove consciousness by disrupting the functional integration across cortical neuronal networks. The proposed project builds upon our decade-long investigation into the systems neuroscience mechanisms of anesthesia. In our previous work, we focused on the effect of volatile anesthetics on the power and coherence of gamma oscillations, and on their preferential role in cortico-cortical feedback vs. feedforward signaling as a putative neuronal correlate of unconsciousness. Here we extend this work to test the hypothesis for the first time that loss and return of consciousness (righting reflex) in anesthetized rats correlates with reversible, nonlinear transitions in functional connectivity, complexity, and information capacity of the neuronal network. To this end, we will study the concentration-dependent effect of three representative anesthetic agents with substantially different pharmacological profiles: desflurane, propofol, and dexmedetomidine to find a common, agent-invariant neuronal correlate of unconsciousness. As an alternative means of modulating the state of consciousness without changing the anesthetic drug effects, subcortical stimulation of the ascending activating system in the brainstem and basal forebrain will also be performed. Parallel spike trains and local field potentials will be recorded from visual and adjacent association cortices using chronically implanted multielectrode arrays in unrestrained rats, and excitatory and inhibitory connectivity, complexity and information capacity in neuronal networks during both spontaneous ongoing activity and during visual stimulation will be derived. The effect of anesthetics on avalanche dynamics of negative local field potential events will be determined. Local and long-range feedforward and feedback connectivity will be delineated with respect to their cortical layer-specificity. We hypothesize that the diversity of cortical states, ocal and interregional cortical connectivity, and interaction complexity are maximal in the awake, attentive state, reduced by anesthesia when consciousness is lost, reversed by cortical activation, and that the principal target of anesthetic action is feedback connectivity both within and among cortical regions. The proposed work should advance our understanding of the neural mechanism of anesthesia, and more generally, the neurobiological basis of consciousness at an integrative level. The findings should facilitate the development of novel methods for electrophysiological monitoring of the state of consciousness under anesthesia, and the development of new anesthetic agents with specific hypnotic effects.

Public Health Relevance

This research project should help us better understand how general anesthetics work, in particular, how they remove consciousness in the anesthetized patient. The knowledge gained should help develop safer anesthetics and better methods to determine the presence or absence of consciousness during anesthesia. Using anesthetic drugs as investigational tools, the project will also help understand how nerve cells in the brain collaborate to create human and animal consciousness.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056398-15
Application #
8609575
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1997-08-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
15
Fiscal Year
2014
Total Cost
$306,000
Indirect Cost
$106,000
Name
Medical College of Wisconsin
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Mashour, George A; Hudetz, Anthony G (2018) Neural Correlates of Unconsciousness in Large-Scale Brain Networks. Trends Neurosci 41:150-160
Pal, Dinesh; Silverstein, Brian H; Sharba, Lana et al. (2017) Propofol, Sevoflurane, and Ketamine Induce a Reversible Increase in Delta-Gamma and Theta-Gamma Phase-Amplitude Coupling in Frontal Cortex of Rat. Front Syst Neurosci 11:41
Mashour, George A; Hudetz, Anthony G (2017) Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness. Front Neural Circuits 11:44
Todorov, Mihail I; K├ękesi, Katalin A; Borhegyi, Zsolt et al. (2016) Retino-cortical stimulus frequency-dependent gamma coupling: evidence and functional implications of oscillatory potentials. Physiol Rep 4:
Hudetz, Anthony G; Mashour, George A (2016) Disconnecting Consciousness: Is There a Common Anesthetic End Point? Anesth Analg 123:1228-1240
Hudetz, Anthony G; Vizuete, Jeannette A; Pillay, Siveshigan et al. (2016) Repertoire of mesoscopic cortical activity is not reduced during anesthesia. Neuroscience 339:402-417
Hudetz, Anthony G; Liu, Xiping; Pillay, Siveshigan et al. (2016) Propofol anesthesia reduces Lempel-Ziv complexity of spontaneous brain activity in rats. Neurosci Lett 628:132-5
Hudetz, Anthony G; Vizuete, Jeannette A; Pillay, Siveshigan et al. (2015) Critical Changes in Cortical Neuronal Interactions in Anesthetized and Awake Rats. Anesthesiology 123:171-80
Hudetz, Anthony G; Liu, Xiping; Pillay, Siveshigan (2015) Dynamic repertoire of intrinsic brain states is reduced in propofol-induced unconsciousness. Brain Connect 5:10-22
Liu, Xiaolin; Li, Shi-Jiang; Hudetz, Anthony G (2014) Increased precuneus connectivity during propofol sedation. Neurosci Lett 561:18-23

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