PT - JOURNAL ARTICLE AU - Alexander D Shaw AU - Suresh D Muthukumaraswamy AU - Neeraj Saxena AU - Natalie Adams AU - Rosalyn J Moran AU - Krish D Singh TI - <em>In-silico</em> evidence that increased cortico-thalamic connectivity and superficial pyramidal disinhibition underlie broadband task-related spectral changes induced by ketamine AID - 10.1101/688044 DP - 2019 Jan 01 TA - bioRxiv PG - 688044 4099 - http://biorxiv.org/content/early/2019/07/02/688044.short 4100 - http://biorxiv.org/content/early/2019/07/02/688044.full AB - 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 capable of recapitulating broadband spectral responses. Compared with placebo, ketamine was found to increase the decay rate of NMDA receptor currents, decrease the decay rate of GABA-B receptor currents, but had no effect on AMPA or GABA-A currents. Furthermore, ketamine decreased the inhibitory self-modulation of superficial pyramidal populations, increased the inhibitory self-modulation of inhibitory interneurons and increased the strength of the cortico-thalamic projection from layer 6 into thalamus. In-silico rectification of each of these parameters to their placebo state revealed the accompanying spectral changes. Similar broadband effects were demonstrated for the NMDA constant and intrinsic connectivity changes, whereby rectification resulted in normalising the amplitude of alpha (increased) and gamma (decreased). While supporting theories of superficial pyramidal disinhibition following ketamine administration, our results suggest a role for altered cortico-thalamic connectivity relevant to understanding ketamine induced cortical responses and potentially identifies a system-level mechanism contributing to its antidepressant effects.