Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy Humans
Naomi R. Driesen, Peter Herman, Margaret A. Rowland, Garth Thompson, Maolin Qiu, George He, Sarah 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 via bioRxiv
Summary
AI-generated from the abstractKetamine, an NMDAR antagonist, increased oxidative metabolism (CMRO2) and cerebral blood flow in the prefrontal cortex and other cortical regions, but did not alter resting-state cortical functional connectivity or brain-wide CBF-CMRO2 coupling. Higher baseline CMRO2 was associated with lower task-related prefrontal activation and greater working memory accuracy impairment under both saline and ketamine conditions. These findings suggest that CMRO2 and resting-state functional connectivity index distinct dimensions of neural activity, and that ketamine's impairment of working memory-related neural activity and performance relates to its induction of cortical metabolic activation.
Study at a glance
| Characteristics | Randomized, double-blind, placebo-controlled |
|---|---|
| Population | Healthy subjects |
| Intervention | Ketamine |
| Dose | subanesthetic doses |
| Keywords | Ketamine pharmacology Nmdar blocker Drug effects Drug impacts Brain metabolism |
| Citations | 5 |
| Key finding | 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.