Depression severity and WM integrity
Our use of an approach that accounts for a range of depression severity in our sample revealed a pattern of reduced WM integrity as depression severity increased. Specifically, we found reduced integrity in the genu of the corpus callosum, a region that connects prefrontal and orbitofrontal cortices. Many studies have documented altered diffusivity in the genu (16) as well as reduced volume (6, 43–45). Given that the prefrontal and orbitofrontal cortices are involved in critical processes, including decision-making, attention, reward processing, and the evaluation and regulation of emotion (46–48), an interruption in communication between these areas has implications for depression and mood disorders.
Additionally, we found decreased integrity in the sagittal stratum with increasing severity, not only in this analysis, but also in the dimensional analyses within the MDD population. The sagittal stratum is a complex fiber bundle connecting the occipital cortex to the rest of the brain, and includes fibers from many major tracts including the ILF and IFOF (49). The ILF and IFOF both connect the occipital cortex to temporal limbic structures (i.e., amygdala, hippocampus) and the PFC, although the IFOF connects directly to the OFC and the ILF does so indirectly through the uncinate fasciculus (50). Therefore, both tracts are involved in connecting visual information with areas involved in emotional memories, judgments, and behaviors. A meta-analysis of diffusion studies of patients with MDD found WM alterations in both the ILF and IFOF (16). Additionally, alterations in WM have been found in the IFOF for depressed adolescents (17), adolescents with a familial risk for depression (18), and adults with MDD (51).
We also observed reduced integrity with increasing severity in bilateral clusters in the ATR near the pallidum. The ATR connects thalamic nuclei with the PFC through the anterior limb of the internal capsule. Reduced WM integrity has been reported in the ATR in several studies of depressed adults (16). Furthermore, given the role of the thalamus in motivation and goal pursuit (52, 53), altered connectivity within this circuit could contribute to the motivational deficits associated with depression.
Additionally, increased illness severity was associated with reduced integrity in the corticospinal tract near the postcentral gyrus. The corticospinal tract transmits motor impulses from the motor and premotor cortices to the spinal cord. Although this was an unexpected finding, motor disturbances and retardation are a relevant clinical symptom of depression (54). In this way, altered diffusivity may be related to the observed slowing and impairment of motor functions. Finally, we again found decreased integrity with increasing severity in the previously described anterior cingulum near the precuneus, which is consistent with the findings from our group analysis. Overall, our analysis with varied levels of depression severity was more robust than the categorical comparison and revealed a more extensive network of reduced WM integrity.