Modulation of habenular and nucleus accumbens functional connectivity by ketamine in major depression

• Published in: Brain and behavior 2024-06, Vol.14 (6), p.e3511-n/a
• Main Authors: Taraku, Brandon, Loureiro, Joana R., Sahib, Ashish K., Zavaliangos‐Petropulu, Artemis, Al‐Sharif, Noor, Leaver, Amber M., Wade, Benjamin, Joshi, Shantanu, Woods, Roger P., Espinoza, Randall, Narr, Katherine L.
• Format: Article
• Language: English
• Subjects: Adult; Anhedonia - drug effects; Anhedonia - physiology; Antidepressants; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Antipsychotics; Benzodiazepines; Depressive Disorder, Major - diagnostic imaging; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - physiopathology; Drug abuse; Female; Females; fMRI; habenula; Habenula - diagnostic imaging; Habenula - drug effects; Habenula - physiopathology; Humans; Ketamine; Ketamine - administration & dosage; Ketamine - pharmacology; Magnetic Resonance Imaging; Male; Mental depression; Middle Aged; nucleus accumbens; Nucleus Accumbens - diagnostic imaging; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiopathology; Original; Psychotropic drugs; reward
• ISSN: 2162-3279; 2162-3279
• DOI: 10.1002/brb3.3511

Introduction Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks. Methods MDD participants (n = 58, mean age = 40.7 years, female = 28) received four ketamine infusions (0.5 mg/kg) 2−3 times weekly. Resting‐state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24 h post‐SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre‐to‐post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n = 55, mean age = 32.6, female = 31), and between HC assessed twice (n = 16) were conducted as follow‐up analyses. Results 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 mood ratings. 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. No differences were observed between HC at baseline or over time. Conclusion Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response. We investigated how ketamine treatment perturbs static and dynamic functional connectivity from reward circuitry in treatment resistant depression. We found that ketamine produces functional connectivity changes between the habenula and visual cortex, and changes in dynamic functional connectivity between the habenula, nucleus accumbens, visual cortex, and posterior cingulate cortex were associated with greater treatment response.