Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study
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The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine provides a pragmatic approach to address the link between glutamate-mediated changes in brain function and psychosis-like experiences. Most studies using PET or BOLD fMRI have assessed these symptoms broadly, which may limit inference about specific mechanisms.
The objective of this study is to identify the cerebral blood flow (CBF) correlates of ketamine-induced psychopathology, focusing on individual psychotomimetic symptom dimensions, which may have separable neurobiological substrates.
We measured validated psychotomimetic symptom factors following intravenous ketamine administration in 23 healthy male volunteers (10 given a lower dose and 13 a higher dose) and correlated ketamine-induced changes in symptoms with regional changes in CBF, measured non-invasively using arterial spin labelling (ASL).
The main effect of ketamine paralleled previous studies, with increases in CBF in anterior and subgenual cingulate cortex and decreases in superior and medial temporal cortex. Subjective effects were greater in the high-dose group. For this group, ketamine-induced anhedonia inversely related to orbitofrontal cortex CBF changes and cognitive disorganisation was positively correlated with CBF changes in posterior thalamus and the left inferior and middle temporal gyrus. Perceptual distortion was correlated with different regional CBF changes in the low- and high-dose groups.
Here, we provide evidence for the sensitivity of ASL to the effects of ketamine and the strength of subjective experience, suggesting plausible neural mechanisms for ketamine-induced anhedonia and cognitive disorganisation.
KeywordsGlutamate receptor NMDA Receptor Neuroimaging Cerebral blood flow
We thank Dr. David Alsop for making available to us the pCASL pulse sequences employed in this work, Professor Anthony Absalom for supplying the Stanpump software for the implementation of the Clements 250 infusion model and the radiographers at the Centre for Neuroimaging Sciences and Astrid Pauls for helping with the data collection.
Compliance with ethical standards
Conflict of interest
The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
TP was supported by the National Institute for Health Research (NIHR). JMS was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King’s College London, and by the Yale Center for Clinical Investigation (UL1RR024139), U.S. Department of Veterans Affairs via its support for the National Center for Post Traumatic Stress Disorder and Consortium to Alleviate PTSD, and the U.S. National Institute on Alcohol Abuse and Alcoholism (P50AA012879). He has received honoraria from Janssen Pharmaceuticals, Behrenberg Bank, AstraZeneca, Pfizer, Sunovion and Hoffman-La Roche Ltd. MAM has consulted for Cambridge Cognition and Lundbeck and received payment for contribution towards educational materials for Shire in the past 5 years. This study was supported by a grant from Eli Lilly and Company. We also thank the Wellcome Trust and EPSRC for continued funding of the Centre for Neuroimaging Sciences.
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