Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network
De Boer, P., London, M., Mueller, F., Musso, F., Winterer, G., Zacharias, N.
This randomised, double-blind, placebo-controlled cross-over study (n=17) investigates the effects of subanesthetic ketamine (105 mg/70kg) on resting-state functional connectivity in healthy male subjects and found an increase of connectivity between the executive control network (i.e. prefrontal cortex ) and other resting-state networks, such as the anterior cingulum and the frontal gyrus, and decreased connectivity between executive control network and salience network. Increased connectivity is taken to reflect positive psychotic symptoms (e.g. delusions, conceptional disorganization, hallucinatory behavior), whereas the decreased connectivity was taken to reflect negative psychotic symptoms (e.g. difficulties in abstract thinking, withdrawal) and as a sign of decreased visual perception in these subjects.
Abstract
Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state.Method: Seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction −10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC).Results: In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4).Conclusion: Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms.