Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study

• Published in: Psychopharmacology Vol. 232; no. 24; pp. 4515 - 4524
• Main Authors: Pollak, T. A., De Simoni, S., Barimani, B., Zelaya, F. O., Stone, J. M., Mehta, M. A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2015; Springer Nature B.V
• Subjects: Adult; Antagonist drugs; Biomedical and Life Sciences; Biomedicine; Brain; Cerebrovascular Circulation - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Gyrus Cinguli - drug effects; Humans; Ketamine - pharmacology; Male; Medical imaging; Neuropsychological Tests; Neurosciences; Original Investigation; Perception - drug effects; Pharmacology/Toxicology; Phenomenology; Psychiatry; Psychopharmacology; Spin Labels; Thinking - drug effects; Young Adult; Neuroimaging; Glutamate receptor; Cerebral blood flow; NMDA Receptor
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-015-4078-8

Rationale
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.
Objectives
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.
Methods
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).
Results
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.
Conclusions
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.