Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine
bioRxiv Preprint Server – May 05, 2020
Source: bioRxiv
Summary
Ketamine dramatically shifts brain activity. To understand how, a sophisticated computer model of brain circuits was developed. This model successfully replicated ketamine's effect on brain waves – boosting high-frequency activity while reducing low-frequency patterns. The key finding: ketamine primarily enhances specific neural connections involving chemicals like NMDA, AMPA, and GABA-A, rather than altering receptor response times. This offers powerful computational insight into how ketamine modifies brain function.
Abstract
Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine’s ability to alter local coupling mediated by NMDA, AMPA and GABA-A.