PROJECT 4: MODELING STUDIES OF ANESTHETIC ACTION General anesthesia is a fascinating man-made, neurophysiological phenomenon that has been developed empirically over many years to enable safe and humane performance of surgical and non-surgical procedures. Specifically it is a drug-induced condition consisting of unconsciousness, amnesia, analgesia and immobility, along with physiological stability. General anesthesia is administered daily to 60,000 patients in the United States, the mechanisms for how anesthetics act in the brain to create the states of anesthesia are not well understood. Significant progress has been made recently in characterizing the molecular sites that anesthetics target. However, how actions at specific molecular targets lead to the behavioral states is less well understood. Addressing this issue requires a systems neuroscience approach to define how actions of the drugs at specific molecular targets and neural circuits lead to a behavioral state of general anesthesia. In this program project entitled, Integrated Systems Neuroscience Studies of Anesthesia, we will develop an integrated systems neuroscience program consisting of human, non-human primate, rodent and modeling studies of four anesthetics: the GABAA agents, propofol and sevoflurane; the alpha-2 adrenergic agonist, dexmedetomidine; and the NMDA receptor antagonist, ketamine. The program project will also include a DATA ANALYSIS CORE, which will provide assistant with data analysis and conduct research on statistical methods.
The Specific Aims are to understand how the actions of the anesthetics at specific molecular targets and neural circuits produce the oscillatory dynamics (EEG rhythms, changes in LFPs and neural spiking activity) that are likely a primary common mechanism through which anesthetics create altered states of arousal (sedation, hallucination, unconsciousness). The goal of the modeling research will be to develop detailed, circuit-level descriptions of the neurophysiological mechanisms underlying each brain state of each anesthetic. The modeling will provide a systematic way to organize and integrate information across all of the three experimental projects and thereby, allow us to develop precise statements about anesthetic mechanisms of action. As the research proceeds, the modeling will enable us to make predictions that can be tested with experiments. In addition to providing new insights into the systems neuroscience of anesthetic states, these studies will also provide fundamental new quantitative knowledge about the neurophysiology of the brain's arousal circuits that will be relevant to studies of other neuropsychological problems such as coma, pain, sleep and depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM118269-03
Application #
9624794
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Cornelissen, L; Kim, S E; Lee, J M et al. (2018) Electroencephalographic markers of brain development during sevoflurane anaesthesia in children up to 3 years old. Br J Anaesth 120:1274-1286
Brown, Emery N; Pavone, Kara J; Naranjo, Marusa (2018) Multimodal General Anesthesia: Theory and Practice. Anesth Analg 127:1246-1258
Sherfey, Jason S; Soplata, Austin E; Ardid, Salva et al. (2018) DynaSim: A MATLAB Toolbox for Neural Modeling and Simulation. Front Neuroinform 12:10
Lewis, Laura D; Piantoni, Giovanni; Peterfreund, Robert A et al. (2018) A transient cortical state with sleep-like sensory responses precedes emergence from general anesthesia in humans. Elife 7:
Walsh, Elisa C; Lee, Johanna M; Terzakis, Kristina et al. (2018) Age-Dependent Changes in the Propofol-Induced Electroencephalogram in Children With Autism Spectrum Disorder. Front Syst Neurosci 12:23
Brown, E N; Purdon, P L; Akeju, O et al. (2018) Using EEG markers to make inferences about anaesthetic-induced altered states of arousal. Br J Anaesth 121:325-327
Akeju, Oluwaseun; Hobbs, Lauren E; Gao, Lei et al. (2018) Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study. Clin Neurophysiol 129:69-78
Flores, Francisco J; Hartnack, Katharine E; Fath, Amanda B et al. (2017) Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness. Proc Natl Acad Sci U S A 114:E6660-E6668
Song, Andrew H; Kucyi, Aaron; Napadow, Vitaly et al. (2017) Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Ceruleus in Humans. J Neurosci 37:6938-6945
Soplata, Austin E; McCarthy, Michelle M; Sherfey, Jason et al. (2017) Thalamocortical control of propofol phase-amplitude coupling. PLoS Comput Biol 13:e1005879

Showing the most recent 10 out of 12 publications