Thalamocortical control of propofol phase-amplitude coupling

Abstract

The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8–12 Hz), Slow Wave Oscillations (SWO, 0.1–1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABA _A inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABA _A potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABA _A potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.

Author summary

Anesthetics make patients lose consciousness, but how they affect brain dynamics is still unknown. Changes in EEG brainwaves are some of the few noninvasive signals we can use to learn about this. By analyzing such data, we can develop more targeted anesthetics, expand our knowledge of sleep circuits, and better understand how diseases impact these systems. The anesthetic propofol is known, among other effects, to increase synaptic inhibition, but it is unclear how these changes induce EEG alpha (8–12 Hz) oscillations and their interaction with slow wave (0.1–1.5 Hz) oscillations; these signals have been correlated with the state of propofol-infused consciousness. We simulated a network of thalamic cells to understand the mechanisms generating these signals. Propofol-potentiated inhibition produced a novel, sustained alpha rhythm in our network. Changes to the tonic level of depolarization enabled the alpha oscillations to occur at different phases in the slow wave oscillation, as seen clinically with increasing propofol dose. The thalamus may be critical to propofol-induced alpha oscillations and their coupling to slow wave oscillations. By understanding the mechanisms generating alpha, we may be able to design experiments to dissociate alpha from slow waves and determine their independent effects on levels of consciousness.