Depression is associated with dimensional and categorical effects on white matter pathways

Abstract

Background: Diffusion tensor imaging (DTI) studies report reduced fractional anisotropy (FA) in major depressive disorder (MDD). However, whether FA covaries with key depressive symptoms, such as anhedonia, is unclear.

Methods: Magnetic resonance imaging data were acquired from 38 unmedicated adults with MDD and 52 healthy controls. DTI metrics were extracted from regions of interest that have consistently shown reduced FA in MDD. Analyses focused first on identifying group differences, and then determining whether reduced FA in depressed adults was related to individual differences in anhedonia and depressive severity. To establish specificity to depression, these analyses controlled for symptoms of anxiety.

Results: Relative to controls, depressed adults showed reduced FA in the genu of the corpus callosum, the anterior limb of the internal capsule (ALIC), the cingulum bundle near the anterior cingulate cortex, and the uncinate fasciculus (UF). In the depressed group, anhedonia negatively correlated with FA in the genu, cingulum, and UF, but positively correlated with radial diffusivity (RD)-a metric previously linked to demyelination-in the genu and ALIC. Depressive severity positively correlated with RD in the ALIC. These relationships remained significant after accounting for anxiety.

Conclusion: Anhedonia was positively correlated with reduced FA and increased RD in white matter pathways that connect regions critical for value coding, representing stimulus-reward associations, and guiding value-based action selection. Thus, a cardinal symptom of MDD-anhedonia-was lawfully related to abnormalities in reward network connectivity.

Keywords: anhedonia; anxiety; corpus callosum; depression; white matter.

Figure 1

FA, RD, AD, and MD were extracted from ROIs in (from left to right) the cingulum of the hippocampus (cyan), uncinate fasciculus (blue), median forebrain bundle (white), corpus callosum (yellow), anterior limb of the internal capsule (ALIC; red), anterior corona radiata (purple), and cingulum of the anterior cingulate cortex (ACC; green). The ROI for the median forebrain bundle appears rectangular in this plane but was actually a 3-mm sphere.

Figure 2

FA was reduced in the MDD group relative to the control group in four of seven ROIs: the genu of corpus callus, the anterior limb of the internal capsule (ALIC), the cingulum bundle near the ACC, and the uncinate fasciculus. The group difference in the cingulum remained significant after removal of the extreme outlier in the control group. Boxes show quartiles (center line indicates the median), with whiskers extending to 1.5 times the interquartile range.

Figure 3

Individual differences in anhedonia are related to variation in FA in the genu of the corpus callosum, the cingulum bundle near the ACC, and the uncinate fasciculus.

Figure 4

Individual differences in anhedonia are related to variation in RD in the genu of the corpus callosum (left) and the anterior limb of the internal capsule (ALIC) (middle); individual differences in depressive severity are also related to variation in RD in the ALIC (right).