S-Ketamine's Effect Changes the Cortical Electrophysiological Activity Related to Semantic Affective Dimension of Pain: A Placebo- Controlled Study in Healthy Male Individuals

André Schwertner, Maxciel Zortea, Felipe Vasconcelos Torres, Leticia Ramalho, Camila Fernanda da Silveira Alves, Guilherme Lannig, Iraci L S Torres, Felipe Fregni, Gustavo Gauer, Wolnei Caumo, André Schwertner, Maxciel Zortea, Felipe Vasconcelos Torres, Leticia Ramalho, Camila Fernanda da Silveira Alves, Guilherme Lannig, Iraci L S Torres, Felipe Fregni, Gustavo Gauer, Wolnei Caumo

Abstract

Background: Previous studies using the electroencephalogram (EEG) technique pointed out that ketamine decreases the amplitude of cortical electrophysiological signal during cognitive tasks, although its effects on the perception and emotional-valence judgment of stimuli are still unknown.

Objective: We evaluated the effect of S-ketamine on affective dimension of pain using EEG and behavioral measures. The hypothesis was that S-ketamine would be more effective than placebo, both within and between groups, to attenuate the EEG signal elicited by target and non-target words.

Methods: This double-blind parallel placebo-controlled study enrolled 24 healthy male volunteers between 19 and 40 years old. They were randomized to receive intravenous S-ketamine (n = 12) at a plasmatic concentration of 60 ng/ml or placebo (n = 12). Participants completed a computerized oddball paradigm containing written words semantically related to pain (targets), and non-pain related words (standard). The volunteers had to classify the words either as "positive," "negative" or "neutral" (emotional valence judgment). The paradigm consisted in 6 blocks of 50 words each with a fixed 4:1 target/non-target rate presented in a single run. Infusion started during the interval between the 3rd and 4th blocks, for both groups. EEG signal was registered using four channels (Fz, Pz, Pz, and Oz, according to the 10-20 EEG system) with a linked-earlobe reference. The area under the curve (AUC) of the N200 (interval of 100-200 ms) and P300 (300-500 ms) components of event-related potentials (ERPs) was measured for each channel.

Results: S-ketamine produced substantial difference (delta) in the AUC of grand average ERP components N200 (P = 0.05) and P300 (P = 0.02) at Pz during infusion period when compared to placebo infusion for both targets and non-targets. S-ketamine was also associated with a decrease in the amount of pain-related words judged as negative from before to after infusion [mean = 0.83 (SD = 0.09) vs. mean = 0.73 (SD = 0.11), respectively; P = 0.04].

Conclusion: Our findings suggest that S-ketamine actively changed the semantic processing of written words. There was an increase in electrophysiological response for pain-related stimuli and a decrease for standard stimuli, as evidenced by the increased delta of AUCs. Behaviorally, S-ketamine seems to have produced an emotional and discrimination blunting effect for pain-related words.

Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03915938.

Keywords: ERPs; P300; ketamine; oddball; pain.

Copyright © 2019 Schwertner, Zortea, Torres, Ramalho, Alves, Lannig, Torres, Fregni, Gauer and Caumo.

Figures

FIGURE 1
FIGURE 1
Procedures. (A) Representation of subject positioning, monitoring and generation of ERPs. Twenty-four healthy men were randomized to receive an infusion of S-ketamine or placebo. (B) Sequence of procedures. All participants completed six runs, grouped into three blocks. A block was made up of a single run consisting in 50 words (10 target, 40 neutral) interrupted by a 30-seconds resting trace. After completion of the first 3 blocks, infusion was initiated (S-ketamine or placebo), and participants rested for 3 min. Following the third block, euphoria and sedation ratings were scored in each block intervals (∗). (C) Semantic oddball paradigm. Each trial began with a fixation cross in the center of a black screen, after which the stimuli were presented for 1000 ms each. Participants were instructed to classify each presented word as “positive,” “negative,” or “neutral” according to their subjective interpretation. The participants pressed the “left arrow” key if the word was negative, “up arrow” if neutral or “right arrow” if positive. Interstimulus interval was randomized in 1500 ± 500 ms during which the fixation cross appeared on the screen.
FIGURE 2
FIGURE 2
(A) Grand averaged P300 ERP waveforms of target and non-target words during placebo and S-ketamine infusions at Pz, Fz, Cz, and Oz. (B) Grand averaged difference between pre and post infusion periods (delta) in group S-ketamine (blue) and placebo (black); Gray-shaded areas denote statistically significant differences. (C) Comparison of delta AUCs between groups placebo and S-ketamine. Asterisk indicates statistical significance (∗p < 0.05).

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