Subanesthetic Ketamine Suppresses Locus Coeruleus-Mediated Alertness Effects: A 7T fMRI Study

Abstract

Background: The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior.

Methods: We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes.

Results: We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction.

Conclusion: The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.

Keywords: Ketamine; LC functional connectivity; alertness; locus coeruleus; ultra-high field MRI.

Figure 1.

The LC functional connectivity mixed design ANOVA comparing sessions (ketamine (blue boxplots), placebo (red boxplots) and time (baseline, administration) reveals changes to bilateral thalamus (left thalamus cluster size = 279, FDR P < .001; right thalamus cluster size = 163, FDR P < .001); a, b), brainstem regions (cluster size = 122, FDR P < .001; c) and cerebellum (d, cluster size = 279, FDR P < .001).

Figure 2.

LC functional connectivity paired t test reveals decoupling of the LC to the bilateral thalamus, brainstem regions and cerebellum during the ketamine administration condition compared with the corresponding baseline session (left thalamus cluster size = 260, FDR P < .001; right thalamus cluster size = 84, FDR P < .001; cerebellum (cluster size = 305, P < .001); brainstem regions (cluster size = 134, P < .001).

Figure 3.

(a) A paired t test reveals a significant decrease of ALFF within the left thalamus (cluster size = 55, FDR P < .001) in the ketamine infusion condition compared with the placebo infusion. (b) The extracted beta weights from the significant decreased LC fc to the left thalamus are correlated to the ALFF decrease of the left thalamic cluster (mixed design ANOVA; Pearson correlation P = .014), with lower LC-thalamic connectivity (measured by fc) relating to lower thalamic activity (measured by ALFF).

Figure 4.

(a) In the attention network task we found a significantly diminished alerting effect in the ketamine condition compared with the placebo condition (P = .04, F = 63.003, mean difference: −10.817s). Neither orienting nor executive control showed any significant effects. (b) Whole brain LC functional connectivity ANCOVA shows correlations of alertness in the placebo administration condition within the bilateral thalamus (left thalamus cluster size = 134, FDR P<.001; right thalamus cluster size = 60, FDR P = .009).