Ketamine normalizes brain activity during emotionally valenced attentional processing in depression

Abstract

Background: An urgent need exists for faster-acting pharmacological treatments in major depressive disorder (MDD). The glutamatergic modulator ketamine has been shown to have rapid antidepressant effects, but much remains unknown about its mechanism of action. Functional MRI (fMRI) can be used to investigate how ketamine impacts brain activity during cognitive and emotional processing.

Methods: This double-blind, placebo-controlled, crossover study of 33 unmedicated participants with MDD and 26 healthy controls (HCs) examined how ketamine affected fMRI activation during an attentional bias dot probe task with emotional face stimuli across multiple time points. A whole brain analysis was conducted to find regions with differential activation associated with group, drug session, or dot probe task-specific factors (emotional valence and congruency of stimuli).

Results: A drug session by group interaction was observed in several brain regions, such that ketamine had opposite effects on brain activation in MDD versus HC participants. Additionally, there was a similar finding related to emotional valence (a drug session by group by emotion interaction) in a large cluster in the anterior cingulate and medial frontal cortex.

Conclusions: The findings show a pattern of brain activity in MDD participants following ketamine infusion that is similar to activity observed in HCs after placebo. This suggests that ketamine may act as an antidepressant by normalizing brain function during emotionally valenced attentional processing.

Clinical trial: NCT#00088699: https://www.clinicaltrials.gov/ct2/show/NCT00088699.

Keywords: Attentional processing; Depression; Dot probe; Emotion; Functional magnetic resonance imaging (fMRI); Ketamine.

Figures

Fig. 1

Graphic representation of the study design. This was a randomized, placebo-controlled, crossover study. It included five fMRI scans per participant; the timepoints at which these were conducted are noted in the figure. Information about the number of participants with usable data for each scan session is also provided.

Fig. 2

Schematic representation of the dot probe task. In this task, a fixation cross was presented for 500 ms, followed by the presentation of faces for 500 ms, then the dot probe on the left or right for 200 ms, and then a 1300 ms interstimulus interval. The trial types in the analysis included angry congruent (example shown on top), angry incongruent, happy congruent, and happy incongruent (example shown on bottom).

Fig. 3

Main effect of emotion (angry > happy). Crosshairs are located at coordinates [−4–10 49], the center of mass of the largest cluster, which extends into the bilateral cingulate, medial frontal, and precentral gyri (scale: Z-score; left = right).

Fig. 4

Effect of emotion (angry > happy) in the major depressive disorder (MDD) and healthy control (HC) groups, displayed separately for each group. Crosshairs for both images are located at coordinates [7–4 38], the center of mass of the cingulate gyrus cluster in the MDD group (scale: Z-score).

Fig. 5

Drug session (post-ketamine versus post-placebo) by group interaction. Crosshairs are located at the center of mass of each cluster: [50 4 35] for right precentral gyrus; [7 18 39] for right cingulate gyrus; and [−29–89-12] for left inferior occipital gyrus. Error bars on graphs indicate +/−1 standard error (scale: Z-score; left = right).

Fig. 6

Drug session (post-ketamine versus post-placebo) by emotion by group interaction. Crosshairs are located at coordinates [2 39 29], the center of mass of the bilateral medial frontal gyri/anterior cingulate cluster. Error bars on the graph indicate +/−1 standard error (scale: Z-score; left = right).

Fig. 7

Interaction between emotion and percent change in Montgomery-Asberg Depression Rating Scale (MADRS) score on blood oxygen-level-dependent (BOLD) signal during post-ketamine scans in participants with major depressive disorder (MDD). Crosshairs located at [−19 6–13], the center of mass of the left parahippocampal gyrus/amygdala cluster (scale: Z-score, left = right).

Supplementary Fig. S1

Main effect of session. Crosshairs are located at coordinates [2 -67 2], the center of mass of the large occipital/temporal cluster. Error bars on the graph indicate +/- 1 standard error (Int = interim scan; scale: F value; left = right).

Supplementary Fig. S2

Effect of drug session (ketamine > placebo on left in yellow; ketamine

Supplementary Fig. S3

Session by emotion interaction effect. Crosshairs are located at coordinates [0 36 1], the center of mass of the bilateral anterior cingulate cluster (scale: F value, left = right).

Supplementary Fig. S4

Effect of group (major depressive disorder (MDD) vs. healthy control (HC)) at baseline. Crosshairs are located at coordinates [8 -17 10], the center of the mass of the large cluster extending from the bilateral thalamus into the caudate and posterior cingulate (scale: Z-score; left = right).