Fronto-limbic disconnection in patients with multiple sclerosis and depression

Background: The biological mechanism of depression in multiple sclerosis (MS) is not well understood. Based on work in major depressive disorder, fronto-limbic disconnection might be important. Objective: To investigate structural and functional fronto-limbic changes in depressed MS (DMS) and non-depressed MS (nDMS) patients. Methods: In this retrospective study, 22 moderate-to-severe DMS patients (disease duration 8.2 +/- 7.7 years), 21 nDMS patients (disease duration 15.3 +/- 8.3 years), and 12 healthy controls underwent neuropsychological testing and magnetic resonance imaging (MRI; 1.5 T). Brain volumes (white matter (WM), gray matter, amygdala, hippocampus, thalamus), lesion load, fractional anisotropy (FA) of fronto-limbic tracts, and resting-state functional connectivity (FC) between limbic and frontal areas were measured and compared between groups. Regression analysis was performed to relate MRI measures to the severity of depression. Results: Compared to nDMS patients, DMS patients (shorter disease duration) had lower WM volume (p < 0.01), decreased FA of the uncinate fasciculus (p < 0.05), and lower FC between the amygdala and frontal regions (p < 0.05). Disease duration, FA of the uncinate fasciculus, and FC of the amygdala could explain 48% of variance in the severity of depression. No differences in cognition were found. Conclusion: DMS patients showed more pronounced (MS) damage, that is, structural and functional changes in temporo-frontal regions, compared to nDMS patients, suggestive of fronto-limbic disconnection.