The long-term objective of this proposal is to understand the mechanisms responsible for loss of consciousness (LOC) under general anesthesia. Previous invasive studies in animal models have identified candidate mechanisms, but translating those findings to human consciousness remains approximate. More precise determinations of states of consciousness are feasible in human subjects, but non-invasive measures of brain activity (fMRI, EEG, MEG) can only indirectly assess the underlying neural circuitry. This proposal will overcome these limitations by taking advantage of the unique opportunity to directly record from the human brain. Using electrocorticography in neurosurgical patients, we will investigate neural networks modulated by general anesthesia. Our overarching goal is to identify patterns of activity and connectivity in cortical networks that track changes in contents of consciousness (i.e. awareness) under anesthesia and during sleep. Our approach is to identify changes in the networks underlying auditory predictive coding that occur upon LOC. Predictive coding minimizes the differences between internally generated constructs and empirical data, subserved by ongoing interaction between sensory and higher-order cortical regions. This model is ideal for this project because it engages the crucial interplay between predictions of the world and sensory observations of the world, a fundamental function of consciousness. The scientific premise of this project is that at a systems level, disruption of predictive coding subserved by large-scale cortical networks represents a signature of anesthetic-induced unconsciousness. To accomplish our goals, we will pursue three specific aims.
The first aim seeks to refine our understanding of the cortical networks involved in auditory predictive coding in awake behaving subjects.
This aim will focus on identifying the connectivity of the networks subserving predictive coding over short and long time scales, as effects of LOC on these networks are believed to be distinct.
The second aim examines changes in network structure upon anesthesia LOC. This will be achieved by recording brain activity from subjects during induction of general anesthesia. The generality of the findings will be tested using two different anesthetic agents.
Aim 3 seeks to identify common electrophysiological signatures for LOC under anesthesia and during sleep. This will be achieved by measuring brain activity in the same subjects during natural sleep. The results will have broad clinical applicability to defining and interpreting prognostic signs in patients with altered mental status (e.g. chronic vegetative and minimally conscious states), mental illness (e.g. delirium and schizophrenia) and development of novel algorithms for use in monitoring depth of anesthesia.

Public Health Relevance

Despite the central role general anesthetics play in surgical and medical practice, a systems-level account of how they cause loss of consciousness remains unknown. This proposal seeks to understand these mechanisms using intracranial electrophysiological recordings from human patients who undergo clinical evaluation for surgical remediation of their medically intractable epilepsy. Knowledge gained from this project will be of high impact for the development of more accurate non-invasive monitors of awareness for patients undergoing surgery and those in vegetative or minimally conscious states, and development of novel general anesthetic agents with fewer side effects than those currently in use.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM109086-07S1
Application #
10136866
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Justinova, Zuzana
Project Start
2014-02-15
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Nourski, Kirill V; Steinschneider, Mitchell; Rhone, Ariane E et al. (2018) Auditory Predictive Coding across Awareness States under Anesthesia: An Intracranial Electrophysiology Study. J Neurosci 38:8441-8452
Nourski, Kirill V; Steinschneider, Mitchell; Rhone, Ariane E et al. (2018) Processing of auditory novelty across the cortical hierarchy: An intracranial electrophysiology study. Neuroimage 183:412-424
Banks, M I; Moran, N S; Krause, B M et al. (2018) Altered stimulus representation in rat auditory cortex is not causal for loss of consciousness under general anaesthesia. Br J Anaesth 121:605-615
Banks, M I; Murphy, C; Sanders, R D (2017) Correlational studies of unconsciousness under anaesthesia: how far can preclinical studies take us? Br J Anaesth 119:1079-1081
Nourski, Kirill V; Banks, Matthew I; Steinschneider, Mitchell et al. (2017) Electrocorticographic delineation of human auditory cortical fields based on effects of propofol anesthesia. Neuroimage 152:78-93
Sanders, R D; Raz, A; Banks, M I et al. (2016) Is consciousness fragile? Br J Anaesth 116:1-3
Nir, Yuval; Vyazovskiy, Vladyslav V; Cirelli, Chiara et al. (2015) Auditory responses and stimulus-specific adaptation in rat auditory cortex are preserved across NREM and REM sleep. Cereb Cortex 25:1362-78
Raz, Aeyal; Grady, Sean M; Krause, Bryan M et al. (2014) Preferential effect of isoflurane on top-down vs. bottom-up pathways in sensory cortex. Front Syst Neurosci 8:191