Large-scale neural recordings and biophysical models for inferring network mechanisms of ketamine anesthesia
Kowalski, Marek Mateusz
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Ketamine is an NMDA receptor antagonist with powerful anesthetic, antidepressant, and psychotomimetic effects. At all therapeutic doses, ketamine generates robust gamma oscillations between 30-80 Hz that are typical of active, structured cognition; yet, under ketamine, gamma oscillations persist into profound sedation and anesthetic unconsciousness. Here, I use experimental and computational approaches to characterize ketamine gamma oscillations, examine their mechanistic origins, and offer a potential explanation for their paradoxical ability to support unconsciousness. First, I analyze local field potentials and single unit activity from ketamine anesthesia in non-human primates to show that the neocortex under ketamine is hyperactive based on all common measures of neural activity. Furthermore, I demonstrate that spiking UP-states that underlie gamma bursts wax and wane in a synchronous fashion across the majority of the neocortex, entraining local field potentials in the intralaminar thalamus, a major subcortical regulator of arousal. While cortical gamma activity becomes hyper-coherent at the local level, globally synchronous beta oscillations from the awake state vanish entirely under ketamine. These phenomena may indicate an impaired local and long-range cortico-cortical communication, respectively, providing one explanation for loss of consciousness despite hyperexcitation. To examine the effect of ketamine on cortical circuits, I built a computational network model of pyramidal cells and fast-spiking interneurons connected via synapses that include an experimentally verified scheme of NMDA receptor kinetics. I show that increased trapping, a known molecular feature of ketamine binding to the NMDA receptor, inhibits both pyramidal cells and interneurons by proportionally decreasing the magnitude of their NMDAR currents during the receptor’s brief opening. Due to higher NMDAR conductance on the interneurons, this antagonism produces net disinhibition of pyramidal cells and initiates a gamma rhythm. Adding a homeostatic spike-rate adaptation variable to such a hyperactive network can produce fragmented spiking activity that resembles UP-DOWN states of ketamine anesthesia. Together, my findings (1) demonstrate that anesthesia is possible even with high and simultaneous spiking activity across most of the neocortex, and (2) provide the first model that accounts for both ketamine gamma oscillations at subanesthetic doses and their discontinuity during unconsciousness.