Functional connectivity of the amygdala subregions and the antidepressant effects of repeated ketamine infusions in major depressive disorder

Abstract

Background: Amygdala subregion-based network dysfunction has been determined to be centrally implicated in major depressive disorder (MDD). Little is known about whether ketamine modulates amygdala subarea-related networks. We aimed to investigate the relationships between changes in the resting-state functional connectivity (RSFC) of amygdala subregions and ketamine treatment and to identify important neuroimaging predictors of treatment outcomes.

Methods: Thirty-nine MDD patients received six doses of ketamine (0.5 mg/kg). Depressive symptoms were assessed, and magnetic resonance imaging (MRI) scans were performed before and after treatment. Forty-five healthy controls underwent one MRI scan. Seed-to-voxel RSFC analyses were performed on the amygdala subregions, including the centromedial amygdala (CMA), laterobasal amygdala (LBA), and superficial amygdala subregions.

Results: Abnormal RSFC between the left LBA and the left precuneus in MDD patients is related to the therapeutic efficacy of ketamine. There were significant differences in changes in bilateral CMA RSFC with the left orbital part superior frontal gyrus and in changes in the left LBA with the right middle frontal gyrus between responders and nonresponders following ketamine treatment. Moreover, there was a difference in the RSFC of left LBA and the right superior temporal gyrus/middle temporal gyrus (STG/MTG) between responders and nonresponders at baseline, which could predict the antidepressant effect of ketamine on Day 13.

Conclusions: The mechanism by which ketamine improves depressive symptoms may be related to its regulation of RSFC in the amygdala subregion. The RSFC between the left LBA and right STG/MTG may predict the response to the antidepressant effect of ketamine.

Keywords: amygdala subregion; antidepressant; functional connectivity; ketamine; major depressive disorder.

Figure 1.

Flowchart. DSM-5, diagnostic and statistical manual of mental diseases-5; fMRI, functional magnetic resonance imaging; HAMD-17, 17-item Hamilton Depression Scale; MDD, major depressive disorder; MRI, magnetic resonance imaging.

Figure 2.

(A–E) Differences in the RSFC of amygdala subregions between HCs and MDD patients. HCs, healthy controls; MDD, major depressive disorder; RSFC, resting-state functional connectivity.

Figure 3.

Correlations between improvements of depressive symptoms on Day 13 (A) and 19 (B) after ketamine treatment and abnormal amygdala subregion RSFC at baseline. HAMD-17, 17-item Hamilton Depression Scale; LBA, laterobasal; r, correlation coefficient; RSFC, resting-state functional connectivity.

Figure 4.

(A) Differences in the RSFC of the amygdala subregion between responders and nonresponders at baseline. (B) Correlation between the difference in amygdala subregion RSFC at baseline between responders and nonresponders and the reduction in depressive symptoms after ketamine treatment. (C) ROC curve analysis. The ROC curve showed an area under the curve (AUC) of 0.918 (95% confidence interval [CI] = 0.382–1.000, p < 0.001) for the RSFC of the left LBA and the right STG/MTG, with a sensitivity of 89.5% and specificity of 85.0%. (D) The difference in the RSFC of the left LBA and the right STG/MTG between nonresponders before and after treatment. AUC, area under the curve; HAMD-17, 17-item Hamilton Depression Scale; LBA, laterobasal; ROC, receiver operating characteristics; RSFC, resting-state functional connectivity; STG/MTG, superior temporal gyrus/middle temporal gyrus; r, correlation coefficient. *p-value < 0.05.