Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine

Abstract

Background: Most patients with major depressive disorder (MDD) experience a period of lengthy trial and error when trying to find optimal antidepressant treatment; identifying biomarkers that could predict response to antidepressant treatment would be of enormous benefit. We tested the hypothesis that pretreatment anterior cingulate cortex (ACC) activity could be a putative biomarker of rapid antidepressant response to ketamine, in line with previous findings that investigated the effects of conventional antidepressants. We also investigated patterns of ACC activity to rapid presentation of fearful faces compared with the normal habituation observed in healthy subjects.

Methods: We elicited ACC activity in drug-free patients with MDD (n = 11) and healthy control subjects (n = 11) by rapidly presenting fearful faces, a paradigm known to activate rostral regions of the ACC. Spatial-filtering analyses were performed on magnetoencephalographic (MEG) recordings, which offer the temporal precision necessary to estimate ACC activity elicited by the rapid presentation of stimuli. Magnetoencephalographic recordings were obtained only once for both patients and control subjects. Patients were subsequently administered a single ketamine infusion followed by assessment of depressive symptoms 4 hours later.

Results: Although healthy subjects had decreased neuromagnetic activity in the rostral ACC across repeated exposures, patients with MDD showed robust increases in pretreatment ACC activity. Notably, this increase was positively correlated with subsequent rapid antidepressant response to ketamine. Exploratory analyses showed that pretreatment amygdala activity was negatively correlated with change in depressive symptoms.

Conclusions: Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamine's antidepressant effects.

Figure 1

ACC shows contrasting changes in activity (i.e., increasing or decreasing for 120 repeated presentations) in patients with MDD versus healthy controls for the average of both faces (A), and separately for the first face (B) but not the second face (C). Sagittal images show the omnibus F statistics for the 2 × 4 interaction between group and block (blocks 1,2,3,4) between 125–175ms post-stimulus onset (p < .001); insets show the t statistics for the linear contrast across blocks in the patient group (p < .002). Bar graphs show average power increase averaged across 125 voxels within an ACC region of interest (BA 24,32) as a function of group and blocks. Errors bars are standard errors of the means.

Figure 2

(A) Nonparametric correlation between increased ACC activity (thresholded at p < .05) over repeated exposure to a fearful face and change in depressive symptoms 230 minutes after ketamine infusion; and (B) for ACC activity to the last 30 exposures only (i.e., block 4). Scatterplots with least squares lines display ACC activity values, averaged across all post-stimulus time windows, at the location of maximal correlations. Change in depressive symptoms is expressed by the percentage change in MADRS score, with positive percentages representing reductions in depressive symptoms. Dotted lines represent the 50% criterion for defining treatment-responders. Images are in radiological orientation (left=right, right=left).

Figure 3

Nonparametric correlation between decreased right amygdala activity (thresholded at p < .05) over repeated exposure to a fearful face and change in depressive symptoms 230 minutes after ketamine infusion (left), and for right amygdala activity to the last 30 exposures only (right). Scatterplots with least squares lines display right amygdala activity values, averaged across all post-stimulus time windows, at the location of maximal negative correlations. Images are in radiological orientation (left=right, right=left).