The topography of infratentorial lesions in depression and anxiety in multiple sclerosis

Background: Depression and anxiety are highly prevalent in multiple sclerosis and significantly impact patient outcomes. However, their link to specific areas of demyelination remains unclear. Objectives: This study examines the association between infratentorial lesions and depression or anxiety, focusing on three regions of interest: raphe nuclei, locus coeruleus, and cerebellar lobule VIIA. Methods: Patients were recruited from the cognitive neuroimmunology clinic at the Royal Melbourne Hospital. Participants were categorised as belonging to the groups ‘depression’/‘no depression’ and ‘anxiety’/‘no anxiety’ based on SPECTRA Indices of Psychopathology. MRI scans were examined for lesion presence in regions of interest. Association analyses were performed using multivariable logistic regression, adjusting for demographics, clinical parameters, and therapy. Results: Of 73 patients, 21 (29%) had clinically relevant depressive symptoms, and 18 (25%) had anxiety. Depression was significantly associated with lesions in the raphe nuclei (47.6% vs. 17.3%, OR 10.5, 95%CI 1.9–57.5, p=0.007) and locus coeruleus (38.1% vs. 15.4%, OR 20.5, 95%CI 2.3–184, p=0.007). Anxiety showed a potential association with locus coeruleus lesions (38.9% vs. 16.4%, OR 8.62, 95%CI 0.9–79.2, p=0.057). Conclusions: Depression in multiple sclerosis is associated with lesions within serotoninergic and noradrenergic brainstem nuclei. No definitive anatomical substrate for anxiety was identified. These findings suggest that inflammatory structural changes may underlie mood disorders in multiple sclerosis, potentially serving as early imaging markers of susceptibility to depression.