Explicating the role of amygdala substructure alterations in the link between hypoleptinemia and rumination in anorexia nervosa.

Objective: The amygdaloid complex plays a pivotal role in emotion processing and has been associated with rumination transdiagnostically. In anorexia nervosa (AN), we previously observed differential reductions of amygdala nuclei volumes (rostral-medial cluster substantially affected) and, in another study, elevated food-/weight-related rumination. Both amygdala volumes and rumination frequency correlated with characteristically suppressed leptin levels in AN. Thus, we hypothesized that amygdala nuclei alterations might be associated with AN-related rumination and potentially mediate the leptin-rumination relationship in AN.

Methods: Rumination (food-/weight-related) was assessed using ecological momentary assessment for a 14-day period. We employed frequentist and Bayesian linear mixed effects models in females with AN (n = 51, 12-29 years, majority admitted to inpatient treatment) and age-matched healthy females (n = 51) to investigate associations between rostral-medial amygdala nuclei volume alterations (accessory basal, cortical, medial nuclei, corticoamygdaloid transitions) and rumination. We analyzed mediation effects using multi-level structural equation models.

Results: Reduced right accessory basal and cortical nuclei volumes predicted more frequent weight-related rumination in AN; both nuclei fully mediated the effect of leptin on weight-related rumination. In contrast, we found robust evidence for the absence of amygdala nuclei volume effects on rumination in healthy females.

Conclusion: This study provides first evidence for the relevance of specific amygdala substructure reductions regarding cognitive symptom severity in AN and points toward novel mechanistic insight into the relationship between hypoleptinemia and rumination, which might involve the amygdaloid complex. Our findings in AN may have important clinical value with respect to understanding the beneficial neuropsychiatric effects of leptin (treatment) in AN and potentially other psychiatric conditions such as depression.