Limitations and future directions
Although our findings are consistent with other clinical studies investigating altered WM in depressed adolescents, it should be noted that very liberal thresholds were used for the analyses and the inability to correct for multiple comparisons is an issue of concern. Although our statistical methodology and sample size were comparable to those of other studies of clinical populations using DTI (17, 63, 75), it is possible that the sample sizes used in many clinical studies are not large enough to produce adequate statistical power. In this way, it is difficult to adequately balance the concerns of committing a Type I error by not correcting while also avoiding a Type II error due to small sample sizes and reduced statistical power. Therefore, our findings are considered preliminary. Furthermore, the inclusion of patients with milder symptomatology may have weakened our ability to detect group differences.
Although small sample sizes may be a possible explanation for the relatively weak results in our and other clinical studies of adolescent depression, another possibility is that the adolescent brain is still malleable and the alterations in WM structure may not fully take hold until adulthood (11). Therefore, it is even more pressing to understand a neuroimmunological model of depression and the factors that may contribute to changes in WM before chronicity begins to take effect. For example, given past findings that depressed adolescents exhibit higher levels of circulating inflammatory cytokines (76), one possible explanation for the observed reduction in FA in adult MDD is that it may reflect effects of chronic low grade inflammation. Additionally, given our previous research on fronto-striatal functional connectivity in MDD, future studies should investigate altered WM microstructure using a targeted tractography approach. Finally, further research is needed to investigate this hypothesis and other models of the systemic consequences of depression. To this end, a better understanding of what FA, MD, AD, and RD illustrate in an adolescent population, as well as the factors that contribute to these diffusivity measures, is needed in the field.