Abstract
Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brainstem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low beta and slow rhythm, as well as their interactions.
Our model suggests propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta frequency spiking in thalamus (C-state), while in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha co-localizes to the peak of the slow; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brainstem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state.
New & Noteworthy GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We construct a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brainstem neuromodulation.
Competing Interest Statement
Massachusetts General Hospital has licensed intellectual property for EEG monitoring developed by Drs. Brown and Purdon to Masimo Corporation. Drs. Purdon and Brown have a financial interest in PASCALL Systems, Inc., a company developing closed loop physiological control systems for anesthesiology. Dr. Purdon and Dr. Brown's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies.
Footnotes
↵* Co-senior authors
↵+ Co-first authors
Contributions: Austin E. Soplata: Conceptualization, Data curation, Investigation, Methodology, Software, Analysis, Validation, Visualization, Writing, Editing. Elie M. Adam: Software, Visualization, Analysis, Writing, Editing. Emery N. Brown: Funding acquisition, Project administration, Supervision, Editing. Patrick Purdon: Funding acquisition, Data curation, Project administration, Supervision, Editing. Michelle M. McCarthy: Conceptualization, Analysis, Writing, Editing. Nancy Kopell: Conceptualization, Analysis, Funding acquisition, Project administration, Supervision, Writing, Editing.
Entire work has been re-written, plots changed, more comprehensive and different simulations run, author order changed, and more. These changes were in response to helpful reviewer feedback.