Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy Humans
Naomi R. Driesen, Peter Herman, Margaret A. Rowland, Garth J Thompson, Maolin Qiu, George He, Sarah K. Fineberg, Daniel S. Barron, Lars Helgeson, Cheryl Lacadie, Robert Chow, Ralitza Gueorguieva, Teo-Carlo Straun, John H. Krystal, Fahmeed Hyder
bioRxiv Preprint Server February 21, 2023 preprint DOI: 10.1101/2023.02.21.529425 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled |
|---|---|
| Population | Healthy subjects |
| Intervention | Ketamine |
| Dose | subanesthetic doses |
| Topics | Esketamine Ketamine |
| Keywords | Ketamine pharmacology Nmdar blocker Drug effects Drug impacts Brain metabolism Oxygen consumption Blood flow Brain energy use Cognitive neuroscience Cognition Working memory Brain function Cognitive impact Neuroimaging Advanced imaging Brain imaging |
| Citations | 5 |
| Key points | Ketamine increases cortical oxidative metabolism and cerebral blood flow, and higher basal CMRO2 is associated with greater working memory impairment and lower prefrontal activation. |
Abstract
Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a multimodal imaging design, combining gas-free calibrated functional magnetic resonance imaging (fMRI) measurement of oxidative metabolism (CMRO2), resting-state cortical functional connectivity assessed with fMRI, and WM-related fMRI. Healthy subjects participated in two scan sessions in a randomized, double-blind, placebo-controlled design. Ketamine increased CMRO2 and cerebral blood flow (CBF) in prefrontal cortex (PFC) and other cortical regions. However, resting-state cortical functional connectivity was not affected. Ketamine did not alter CBF-CMRO2 coupling brain-wide. Higher levels of basal CMRO2 were associated with lower task-related PFC activation and WM accuracy impairment under both saline and ketamine conditions. These observations suggest that CMRO2 and resting-state functional connectivity index distinct dimensions of neural activity. Ketamine’s impairment of WM-related neural activity and performance appears to be related to its ability to produce cortical metabolic activation. This work illustrates the utility of direct measurement of CMRO2 via calibrated fMRI in studies of drugs that potentially affect neurovascular and neurometabolic coupling.