Irritability and WM integrity
As predicted, we found decreased integrity as irritability increased in a tract near the amygdala (i.e., sagittal stratum including the ILF and IFOF). However, increased irritability was correlated with decreased integrity in tracts primarily connecting to prefrontal and occipital cortices. We also found clusters in the previously discussed IFOF, although one was in the lingual gyrus while the other was in the middle frontal gyrus. The lingual gyrus has been implicated in processing emotional faces (59), which is typically altered in MDD (60). Altered cerebral blood flow and resting state connectivity have been demonstrated in the lingual gyrus in adults with MDD (61, 62). Additionally, decreased integrity in WM has previously been found around the middle frontal gyrus (63), an area broadly involved in a variety of higher-level cognitive processes (64) which are often compromised in MDD.
Reduced integrity related to elevated irritability was also found in the ACR, which connects the striatum to the ACC. Reduced integrity has previously been demonstrated in the ACR in pediatric bipolar patients (65), and dysfunctional activity in the ACC is typically considered a hallmark of depression (37, 42, 66–70). Furthermore, altered intrinsic functional connectivity (i.e., resting state) between the striatum and ACC has been documented for depressed adolescents (8). Finally, a cluster in the SLF in the IT gyrus was found. The SLF is a major bidirectional association tract connecting large parts of the frontal cortex with the parietal, temporal, and occipital lobes. Less restricted diffusion in the SLF has been previously demonstrated for depressed adolescents (17), adolescents with a genetic risk for depression (18), and adults with MDD (71).