The overall goal of this project is to understand the systems-level neural mechanisms by which general anesthetics suppress consciousness and allow its return during emergence in the human brain. Our fundamental hypothesis is that consciousness emerges from brain function as a network phenomenon, and that general anesthetics suppress consciousness by disrupting the communication across large-scale neuronal networks that support information integration in the brain. Our previous findings suggest that anesthetics alter the functional connectivity of thalamocortical systems, particularly in the """"""""nonspecific"""""""" thalamocortical division, as well as in other intrinsic cortical cognitive networks. Here, we build on our decade-long developments in blood-oxygen level-dependent (BOLD) functional MRI (fMRI) and resting-state functional connectivity MRI (R- fcMRI) methods with high spatial and temporal resolution applied to test specific hypotheses about the anesthetic modulation of cognitive functioning, network organization, reorganization, and information integration during wakefulness and at graded levels of suppressed consciousness.
In Specific Aim 1, we will employ concurrent behavioral and BOLD fMRI assessment of semantic discrimination to test the hypotheses that deepening anesthesia with propofol will suppress conscious awareness by diminishing integrative functional networks of the brain in a graded, top-down manner, suppressing the most complex systems first and the simplest systems last and that these changes can be characterized by the anesthetics'effect on the behavioral response and neural activity to a series of tasks that depend on different levels of information integration.
In Specific Aim 2, we will test the hypotheses that propofol confers differential changes in resting- state (baseline) functional connectivity, modularity and network integration in thalamocortical and cortical intrinsic networks, particularly those involved with attention, executive control, and salience, vs. others, such as the default mode and sensory networks. Finally, in Specific Aim 3, we will test the hypotheses that anesthetic- induced loss and subsequent return of consciousness are mediated in part by different neural mechanisms that show prior state dependency, as reflected by various brain network interaction measures and that the restoration of consciousness from anesthesia requires additional neural resources over those required for the maintenance of consciousness, reflecting the reconfiguration capability of the brain as a self-organizing system for resource management and functional resilience. The proposed work should advance our understanding of the neural mechanisms of anesthesia with respect to its effect on human consciousness at an integrative level. The work should reveal the order in which cognitive functions are lost during sedation and anesthesia and the degree of residual cognitive functions based on direct, noninvasive detection of neural events. It should illuminate how anesthetics alter resting-state intrinsic brain networks and how the latter may reconfigure to cope with anesthetic challenge. Novel quantitative approaches to assess residual cognitive functions by fMRI network analysis may eventually be extendable to neurological patients with disordered consciousness. In a wider context, the findings should facilitate our understanding of the scientific basis of human consciousness, including its aspects for sensory awareness and voluntary action.

Public Health Relevance

This research project should help us better understand what happens to the thinking brain when the patient is anesthetized. The project will use cognitive testing and noninvasive functional magnetic resonance imaging of the brain to help understand how general anesthetics suppress consciousness in the anesthetized patient, and how consciousness returns after the termination of anesthesia. Using anesthetic drugs as investigational tools, the knowledge gained should help better understand the neuronal mechanisms of anesthesia and of human consciousness and help develop novel approaches to assess residual cognitive functioning during anesthesia with possible implications to neurological patients with disordered consciousness.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Cole, Alison E
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Medical College of Wisconsin
Schools of Medicine
United States
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