Reduced Integrity of the Uncinate Fasciculus and Cingulum in Depression: A Stem-by-stem Analysis

Introduction: The subgenual cingulate gyrus (Brodmann's Area 25: BA25) is hypermetabolic in depression and has been targeted successfully with deep brain stimulation. Two of the white matter tracts that play a role in treatment response are the uncinate fasciculus (UF) and the cingulum bundle. The UF has three prefrontal stems, the most medial of which extends from BA25 (which deals with mood regulation) and the most lateral of which extends from the dorso-lateral prefrontal cortex (concerned with executive function). The cingulum bundle has numerous fibers connecting the lobes of the cerebrum, with the longest fibers extending from BA25 to the amygdala. We hypothesize that there is reduced integrity in the UF, specific to the medial prefrontal stems, as well as in the subgenual and amygdaloid fibers of the cingulum bundle. Our secondary hypothesis is that these changes are present from the early stages of depression.

Objective: Compare the white matter integrity of stems of the UF and components of the cingulum bundle in first-onset depressed, recurrent/chronic depressed, and non-depressed control subjects.

Methods: Depressed patients (n = 103, first-onset = 57, chronic = 46) and non-depressed control subjects (n = 74) underwent MRI with 32-directional DTI sequences. The uncinate fasciculi and cingulum bundles were seeded, and the fractional anisotropy (FA) measured in each of the three prefrontal stems and the body of the UF, as well as the subgenual, body, and amygdaloid fiber components of the cingulum bundle. FA measurements were compared between groups using ANOVA testing with post-hoc Tukey analysis.

Results: There were significant reductions in FA in the subgenual and polar stems of the UF bilaterally, as well as the subgenual and amygdaloid fibers of the cingulum bundle, in depressed patients compared with controls (p < 0.001). There was no significant difference seen in the lateral UF stem or the main body of the cingulum. No significant difference was demonstrated in any of the tracts between first-onset and chronic depression patients.

Conclusion: Depressed patients have reduced white matter integrity in the subgenual and polar stems of the uncinate fasciculi but not the lateral stems, as well as in the subgenual and amygdaloid cingulum fibers. These changes are present from the first-onset of the disease.