PT - JOURNAL ARTICLE AU - Soplata, Austin E. AU - McCarthy, Michelle M. AU - Adam, Elie M. AU - Purdon, Patrick L. AU - Brown, Emery N. AU - Kopell, Nancy TI - Neuromodulation due to propofol affects anesthetic oscillatory coupling AID - 10.1101/2022.02.17.480766 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.02.17.480766 4099 - http://biorxiv.org/content/early/2022/02/20/2022.02.17.480766.short 4100 - http://biorxiv.org/content/early/2022/02/20/2022.02.17.480766.full AB - The anesthetic propofol produces prominent oscillatory signatures on the EEG. Despite the strong correlation between oscillations and the anesthetic state, the fundamental mechanisms of this unconsciousness remain unknown. On the EEG, propofol elicits alpha oscillations (8-14 Hz), slow oscillations (0.5-2.0 Hz), and dose-dependent phase-amplitude coupling (PAC) between these rhythms. A low enough dose causes “trough-max” PAC, where alpha oscillation amplitude is consistently maximal during slow troughs; this occurs at the same time as arousable unconsciousness. A high enough dose causes consistent “peak-max” PAC, where alpha amplitude is maximal during the slow peak, at the same time as unarousable unconsciousness. Much of the anesthetic state is dominated by a mixture of both states. Using thalamocortical Hodgkin-Huxley simulations, we show that, in addition to propofol effects on GABAA synapses and thalamocortical H-currents, propofol-induced changes to neuromodulation may generate LFP oscillations and their dose-dependent coupling. We show this for acetylcholine specifically, though other neuromodulators may produce the same effects. We find that LFP- and EEG-relevant synapses of local thalamocortical circuits stochastically display either trough-max or peak-max PAC on any given slow cycle. Trough-max PAC signals are present only in thalamocortical synaptic currents, and not identifiable via membrane potentials alone. PAC preference depends critically on the neuromodulatory state, which is dose-dependent: high doses are associated with statistically more peak-max than trough-max, and vice-versa. This is caused by increased cortical synchronization at higher doses. Our results have important consequences for analyzing LFP/EEG data, in that local network trough-or peak-max may only be seen on a cycle-by-cycle basis, and not when averaging. We hypothesize that this increased cortical synchronization leads to an inability to process signals in a flexible manner needed for awake cognition.New & Noteworthy We simulate biophysical neural networks to investigate how the anesthetic propofol enables alpha and slow oscillations to emerge and interact. Direct effects of propofol on inhibition and indirect effects on acetylcholine level are necessary for dose-dependent emergence and coupling of these rhythms. Local groups of anesthetized cells behave with more complexity than global EEG would suggest. Higher doses are associated with more cortical synchrony, which may underlie the reduced ability to respond to stimuli.Competing Interest StatementMassachusetts General Hospital has licensed intellectual property for EEG monitoring developed by Drs. Brown and Purdon to Masimo Corporation. Drs. Brown and Purdon hold interests in, and Dr. Purdon is a co-founder of, PASACALL Systems, Inc., a start-up company developing EEG-based anesthetic state control systems for anesthesiology.