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Acute and Delayed Effects of Ketamine On Brain Activation and Glutamatergic Neurotransmission


Scheidegger M, Lehmann M, Henning,  A
Department High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Max Planck Society;

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Grimm, S., Scheidegger M, Lehmann M, Henning, A., Walter M, Boeker H, Weigand A, Bajbouj, M., & Seifritz, E. (2012). Acute and Delayed Effects of Ketamine On Brain Activation and Glutamatergic Neurotransmission. Poster presented at 18th Annual Meeting of the Organization for Human Brain Mapping (OHBM 2012), Beijing, China.

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Introduction: Increasing preclinical and clinical evidence underscores the role of glutamate in the pathophysiology of major depressive disorder (Sanacora et al., 2008; Machado- Vieira et al., 2009; Zarate et al., 2010). Glutamatergic dysfunction in depression is further supported by pharmacological benefits of glutamate-modulating substances. Ketamine, known as a potent glutamatergic NMDA receptor antagonist, is used for premedication, sedation, and induction and maintenance of general anesthesia. In subanesthetic doses, ketamine appears to be the first medication to produce a rapid, although short-lasting, antidepressant effect (Zarate et al., 2006; Phelps et al., 2009; Salvadore et al., 2010) and thus provides a valuable research tool for the investigation of the neurobiology of MDD. Methods: Acute ketamine effects were investigated in 23 healthy subjects, who completed two separate fMRI sessions (baseline and pharmacological intervention respectively). Since the antidepressant effect of ketamine is most prominent after 24h, a further investigation in 19 healthy subjects focused on alterations 24 hours post ketamine infusion. Here, subjects completed four scan sessions in a randomized, double-blind, placebo-controlled crossover design. S-ketamine was administered as an intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h over 60 minutes. Multimodal measurements on a Philips 3T MR unit included functional and resting state magnetic resonance imaging (fMRI/rsfMRI), arterial spin labeling (ASL) and proton magnetic resonance spectroscopy. Analyses focused on fMRI-BOLD responses during an emotional processing task as well as during a working memory task and their relationship to glutamatergic metabolite concentrations. Results: Acute ketamine administration had no effect on working memory performance. A valence- specific significant difference in task induced BOLD signal amplitude for negative stimuli could be found following ketamine administration in right, but not in left dorsolateral prefrontal cortex. Furthermore, reduced BOLD signal amplitudes for negative stimuli could be observed in posterior cingulate cortex and left anterior insula. During emotional processing there was a brain region-specific increase in negative BOLD responses following ketamine administration. The most significant BOLD differences were found in predominantly limbic brain areas associated with the processing of emotional information and higher-order mental functions. In the pregenual anterior cingulate, changes in negative BOLD responses correlated with glutamine to glutamate ratios as a putative marker of glutamatergic neurotransmission after ketamine administration compared to baseline. No significant differences in task induced BOLD amplitudes or metabolite levels compared to the baseline assessment could be found 24 hours after the administration of ketamine. Conclusions: The specific ketamine effect on BOLD signal in regions implicated in altered emotional and cognitive processing in mood disorders might be related to its rapid antidepressant properties. The relationship of negative BOLD responses in the pregenual anterior cingulate with glutamine to glutamate ratios is most likely interpreted in terms of an increased glutamate-glutamine-cycling rate after ketamine administration. Thus, the antidepressant effect of ketamine might be linked to a beneficial short-term influence on glutamatergic neurotransmission. Results assessed 24 hours after the administration of ketamine suggest that a healthy organism is able to reestablish the neurosystemic balance of the baseline state. Imaging Methods: BOLD fMRI