The overall goal of our research is to understand the mechanism of general anesthesia at an integrative level with respect to the loss of consciousness (LOC). The general hypothesis is that LOC is due to the disruption of functional connectivity (FC) of neuronal activity among primary sensory and fronto-parietal association cortices which are involved in the integration of sensory information. In this work, two clinically used volatile anesthetics, isoflurane and desflurane and one clinically used intravenous anesthetic, propofol will be used to seek the common, agent-invariant effects on FC in chronically instrumented, freely moving rats. FC will be characterized by the statistical parameter mutual information as estimated from measurements of intracortical local field potentials and unit activities at gamma frequency (20-80 Hz) using chronically implanted high- density microelectrode arrays. The loss of righting reflex will be used as the primary behavioral index of LOC assessed simultaneously with the electrophysiological recordings. Three specific hypotheses that we will test are: (1) anesthetics will preferentially suppress neuronal feedback FC from frontal to visual cortex at anesthetic concentrations that produces unconsciousness, (2) inactivation of the frontal cortex by local cooling will suppress neuronal feedback FC as revealed by the suppression of long-latency flash-evoked potentials in visual cortex, (3) generalized cortical activation by electrical or neurochemical (glutamate, norepinephrine and neurotensin) stimulation of specific forebrain and brainstem nuclei (n. Basalis of Meynert and n. Cuneiformis) will reverse the suppressive effects of anesthetics on FC and consciousness. Public Health: This research should advance our understanding of the neurobiological basis of consciousness and of the mechanism of hypnotic effect of general anesthetic agents. It should help develop novel methods for monitoring the state of consciousness based on established neurobiological mechanisms and of new anesthetic agents with more specific hypnotic effects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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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
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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
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
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; 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; 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
Pillay, Siveshigan; Liu, Xiping; Baracskay, P├ęter et al. (2014) Brainstem stimulation increases functional connectivity of basal forebrain-paralimbic network in isoflurane-anesthetized rats. Brain Connect 4:523-34
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
Liu, Xiaolin; Li, Shi-Jiang; Hudetz, Anthony G (2014) Increased precuneus connectivity during propofol sedation. Neurosci Lett 561:18-23

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