Although the field of anesthesiology has played a leadership role in promoting patient safety, there is still no standard monitor for the target orga of general anesthesia: the brain. The lack of reliable neurophysiologic monitoring can result in patient complications because of insufficient anesthesia (e.g., awareness and post- traumatic stress disorder) as well as excessive anesthesia (e.g., delayed emergence, delirium, neurotoxicity). A number of commercially-available brain monitors are currently used in the operating room, but such devices have shown limited utility and are often based on proprietary or empirical algorithms. Recent advances in neurobiology herald the possibility of a more sophisticated era of brain monitoring and improved patient safety. What is urgently needed is the identification of measurable neurophysiologic features of general anesthesia that are informed by the neurobiology of consciousness and that can be explained by neurochemical mechanisms. We have recently performed both human and animal studies that identify preferential inhibition of frontal-to-parietal feedback connectivity in the brain as a candidate neurophysiologic correlate of general anesthesia. However, it is still unclear how cortical feedback inhibition during anesthesia is best measured, how sensitive it is to changing states of consciousness, and what the underlying mechanisms are. Our long-term goal is to develop a neurophysiologic monitor for general anesthesia that improves patient safety. The objective of the proposed studies is to demonstrate that preferential inhibition of frontoparietal feedback connectivity is a reliable measure of general anesthesia in humans as well as to elucidate its neurochemical mechanisms in an animal model. Our central hypothesis is that frontoparietal feedback inhibition is a common network-level mechanism of general anesthesia that is regulated by acetylcholine activity in the prefrontal cortex. The rationale for the proposed research is that understanding anesthetic- induced changes in frontoparietal connectivity will significantly impact clinical practice by improved patient monitoring. Furthermore, a mechanistic understanding of the role of acetylcholine in network connectivity will advance the anesthetic care of patients at risk for dementia or delirium, both of which are thought to involve cholinergic neurotransmission. Finally, this fundamental work on feedback connectivity will help advance the understanding of pathologic states of unconsciousness, because selective feedback inhibition has recently been shown to be associated with vegetative states.

Public Health Relevance

This project is relevant to public health because it seeks to understand how general anesthetics affect the brain and how this can best be measured. Gaining a more detailed knowledge of anesthesia and the brain will help improve patient care through better monitoring in the operating room and the development of safer anesthetic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098578-01A1
Application #
8369549
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2012-08-01
Project End
2016-03-31
Budget Start
2012-08-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$295,450
Indirect Cost
$105,450
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Kim, Minkyung; Mashour, George A; Moraes, Stefanie-Blain et al. (2016) Functional and Topological Conditions for Explosive Synchronization Develop in Human Brain Networks with the Onset of Anesthetic-Induced Unconsciousness. Front Comput Neurosci 10:1
Pal, Dinesh; Silverstein, Brian H; Lee, Heonsoo et al. (2016) Neural Correlates of Wakefulness, Sleep, and General Anesthesia: An Experimental Study in Rat. Anesthesiology 125:929-942
Hudetz, Anthony G; Mashour, George A (2016) Disconnecting Consciousness: Is There a Common Anesthetic End Point? Anesth Analg 123:1228-1240
Tarnal, Vijay; Vlisides, Phillip E; Mashour, George A (2016) The Neurobiology of Anesthetic Emergence. J Neurosurg Anesthesiol 28:250-5
Pal, Dinesh; Jones, Julie M; Wisidagamage, Stella et al. (2015) Reduced Nav1.6 Sodium Channel Activity in Mice Increases In Vivo Sensitivity to Volatile Anesthetics. PLoS One 10:e0134960
Pal, D; Hambrecht-Wiedbusch, V S; Silverstein, B H et al. (2015) Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousness. Br J Anaesth 114:979-89
Moon, Joon-Young; Lee, UnCheol; Blain-Moraes, Stefanie et al. (2015) General relationship of global topology, local dynamics, and directionality in large-scale brain networks. PLoS Comput Biol 11:e1004225
Blain-Moraes, Stefanie; Tarnal, Vijay; Vanini, Giancarlo et al. (2015) Neurophysiological correlates of sevoflurane-induced unconsciousness. Anesthesiology 122:307-16
Lee, UnCheol; Blain-Moraes, Stefanie; Mashour, George A (2015) Assessing levels of consciousness with symbolic analysis. Philos Trans A Math Phys Eng Sci 373:

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