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 #
2R01GM056398-13
Application #
8295719
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
2012-04-02
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
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
Hudetz, Anthony G; Liu, Xiping; Pillay, Siveshigan (2015) Dynamic repertoire of intrinsic brain states is reduced in propofol-induced unconsciousness. Brain Connect 5:22-Oct
Pillay, Siveshigan; Vizuete, Jeannette; Liu, Xiping et al. (2014) Brainstem stimulation augments information integration in the cerebral cortex of desflurane-anesthetized rats. Front Integr Neurosci 8:8
Pillay, Siveshigan; Liu, Xiping; Baracskay, Péter et al. (2014) Brainstem stimulation increases functional connectivity of basal forebrain-paralimbic network in isoflurane-anesthetized rats. Brain Connect 4:523-34
Liu, Xiping; Pillay, Siveshigan; Li, Rupeng et al. (2013) Multiphasic modification of intrinsic functional connectivity of the rat brain during increasing levels of propofol. Neuroimage 83:581-92
Liu, Xiaolin; Lauer, Kathryn K; Ward, B Douglas et al. (2013) Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: a functional magnetic resonance imaging study. Anesthesiology 118:59-69
Pillay, Siveshigan; Vizuete, Jeannette A; McCallum, J Bruce et al. (2011) Norepinephrine infusion into nucleus basalis elicits microarousal in desflurane-anesthetized rats. Anesthesiology 115:733-42
Hudetz, Anthony G; Vizuete, Jeannette A; Pillay, Siveshigan (2011) Differential effects of isoflurane on high-frequency and low-frequency ýý oscillations in the cerebral cortex and hippocampus in freely moving rats. Anesthesiology 114:588-95
Pawela, Christopher P; Biswal, Bharat B; Hudetz, Anthony G et al. (2010) Interhemispheric neuroplasticity following limb deafferentation detected by resting-state functional connectivity magnetic resonance imaging (fcMRI) and functional magnetic resonance imaging (fMRI). Neuroimage 49:2467-78
Hudetz, Judith A; Patterson, Kathleen M; Iqbal, Zafar et al. (2009) Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 23:651-7
Hudetz, J A; Iqbal, Z; Gandhi, S D et al. (2009) Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand 53:864-72

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