Ketamine normalizes subgenual cingulate cortex hyper-activity in depression

Abstract

Mounting evidence supports the rapid antidepressant efficacy of the N-methyl-D-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven in part by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful antidepressant treatment. This study aimed to examine whether task-based sgACC activity was higher in patients with MDD compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol at baseline and following a 40 min infusion of ketamine (0.5 mg/kg). Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its antidepressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.

Fig. 1. Linking subgenual anterior cingulate cortex (sgACC) activation with distinct symptoms of depression.

Top: Subjects completed the incentive flanker task (IFT) during functional MRI. The task consisted of reward, loss, and neutral trials, which included a cue, followed by a flanker task (congruent/incongruent), followed by feedback (positive/negative). Positive and negative feedback was contrasted against no feedback (Nil). Bottom: Patients with major depressive disorder (MDD) showed higher activity within the sgACC region of interest (ROI) compared to healthy controls (HCs) to both positive (T₍₄₅₎ = 2.208, p = 0.032) and negative (T₍₄₂₎ = 3.036, p = 0.004) feedback. Higher sgACC activation to positive was associated with anhedonia (R = −0.34, p = 0.028), whereas higher activation to negative was associated with higher anxiety (R = 0.386, p = 0.012) across the full cohort.

Fig. 2. Hippocampus and subgenual anterior cingulate cortex (sgACC) connectivity in depression.

Patients with major depressive disorder (MDD) had increased resting-state functional connectivity between the hippocampus and sgACC, compared to healthy controls (HCs, t₍₄₄₎ = −2.2, p = 0.031). This connectivity was associated with higher sgACC activation to positive feedback (R = 0.33, p = 0.028).

Fig. 3. The influence of ketamine on subgenual anterior cingulate cortex (sgACC) activation.

Ketamine reduced sgACC activation to positive feedback in patients MDD (t₍₁₃₎ = 3.17, p = 0.007). Greater pre-ketamine sgACC activation was associated with greater improvement in anhedonia (TEPS total score) after single-dose ketamine (R = −0.437, p = 0.045).

Fig. 4. Putative subdivisions within subgenual anterior cingulate cortex (sgACC) relate to distinct symptomology.

The sgACC was divided based on architectonic boundaries of area 25 (posterior medial wall) and prelimbic area 32 (PL32). Exploratory analysis revealed area 25 was hyper-activate to positive feedback only (p = 0.054, p = 0.478), which was correlated with anhedonia (R = −0.346, p = 0.017), whereas PL32 was significantly hyper-active to negative feedback only (p = 0.048, p = 0.272), and correlated with anxiety (R = 0.359, p = 0.017).