Ketamine treatment modulates habenular and nucleus accumbens static and dynamic functional connectivity in major depression.

Dysfunctional reward processing in major depressive disorder (MDD) involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Ketamine elicits rapid antidepressant and alleviates anhedonia in MDD. To clarify how ketamine perturbs reward circuitry in MDD, we examined how serial ketamine infusions (SKI) modulate static and dynamic functional connectivity (FC) in Hb and NAc networks. MDD participants (n=58, mean age=40.7 years, female=28) received four ketamine infusions (0.5mg/kg) 2-3 times weekly. Resting-state fMRI scans and clinical assessments were collected at baseline and 24 hours post-SKI completion. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Paired t-tests examined changes in FC pre-to-post SKI, and correlations were used to determine relationships between FC changes with mood and anhedonia. Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in Hamilton Depression Rating Scale. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.