A thalamocortical theory of propofol phase-amplitude coupling

Propofol is one of the most commonly used general anesthetics in the world, and yet precisely how it enables loss of consciousness still eludes us. It exhibits rich spectral characteristics on electroencephalogram (EEG) recordings from human patients, including alpha oscillations (8-14 Hz) and Slow Wave Oscillations (SWO, 0.5-2.0 Hz). Additionally, these two oscillations are phase-amplitude coupled (PAC) in a dose-dependent manner: low doses cause “trough-max” coupling where alpha power is maximal during the trough of the SWO cycle, while high doses cause “peak-max” coupling where alpha power is maximal during the peak of the SWO cycle. These propofol rhythms occur at the same frequencies as sleep spindles and sleep SWO, and likely use the same well-studied thalamocortical circuitry. The study of anesthesia therefore represents a safe method for investigating both how our brains sleep and the much-debated components of consciousness. In this dissertation, I use Hodgkin-Huxley-style computational models of both the thalamus and cortex to explain how the direct and indirect effects of propofol can generate such spectral phenomena. In the first part of this dissertation, I discuss results from a thalamic model. I illustrate how GABAA potentiation by propofol can create sustained alpha oscillations in the hyperpolarized thalamus by utilizing the same mechanisms used by sleep spindles. I then show how the thalamus, under artificial SWO conditions, can output trough-max or peak-max PAC depending on background excitation, GABAA potentiation, and H-current conductance. In the second part of this dissertation, I discuss results from a thalamocortical model. My analysis reveals how, in a simulated EEG signal, trough-max PAC can arise from competition between thalamocortical and intracortical synaptic currents, while peak-max PAC can arise from their cooperation. Furthermore, the coherence of cortical SWO rhythms can directly control whether the system expresses trough-max or peak-max PAC, while the indirect effects of propofol on acetylcholine are required for both PAC states. This culmination of years of work reveals just how complex the inner workings of anesthesia can be in enabling its profound effects