Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study [version 1; peer review: 1 approved, 1 approved with reservations]

Posttraumatic stress disorder (PTSD) is an anxiety disorder that is often diagnosed with comorbid depressive disorder. Therefore, neuroimaging studies investigating PTSD typically include both patients with and without comorbid depression. Differences in activity of the anterior cingulate cortex (ACC) and insula have been shown to differentiate PTSD patients with and without major depressive disorder (MDD). Whether or not comorbid MDD affects resting state functional connectivity of PTSD patients has not been investigated to our knowledge. Here, resting state functional connectivity of PTSD patients with (PTSD+MDD; n=27) and without (PTSD-MDD; n=23) comorbid MDD was investigated. The subgenual ACC and insula were investigated as seed regions. Connectivity between the subgenual ACC and perigenual parts of the ACC was increased in PTSD+MDD versus PTSD-MDD. Reduced functional connectivity of the subgenual ACC with the thalamus was found in the PTSD+MDD group versus the PTSD-MDD group. These results remained significant after controlling for PTSD severity. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus compared to the PTSD-MDD group. However, this cluster was no longer significantly different when controlling for PTSD severity. Thus, resting state functional connectivity of the subgenual ACC may distinguish PTSD+MDD from PTSD-MDD. As PTSD patients with comorbid MDD are more treatment resistant, this result may be important for treatment development. The paper shows convincing (to the technical non-specialist) differences in resting state functional connectivity between PTSD patients with or without comorbid major depression MDD. There are clear effects on connectivity of the subgenual anterior cingulate cortex with the left ACC (increased with MDD) and with the thalamus (decreased with MDD). The interpretations are hampered by the design, which ideally would be a 2 X 2, i.e. +/- MDD and +/- PTSD. Therefore sentences like 'we found that connectivity . is more reduced in PTSD +MDD than in PTSD-MDD' cannot be made. The authors determined that effects on connectivity of insula and hippocampus are related to symptom this should probably be in figure 3 somehow, as this may end up being used as a graphic summary of the data. I whether the the use a factor affected connectivity, it may interact with the condition. Second the authors, at correlation between connectivity - and symptom severity in the PTSD-MDD, group in a post hoc correlation. A similar effect is specifically for the PTSD+MDD group. unclear the authors look at the in all correlations can be performed and seem more appropriate here. Finally, we have also added figures of the correlations with CAPS symptom clusters. Competing Interests: No competing interests were disclosed. Thank you for the opportunity to review this interesting study on the impact of disorder comorbidity on resting state functional MRI. This is an important and under-studied area of research. I have a number of comments that may help to improve the manuscript. Abstract: The abstract is disappointing, dense and requires development. At present it is mostly comprised of statements relating to the findings obtained, rather than providing an interpretation of findings. Are all the findings reported key to the bottom-lines of the article? The authors need to add a brief interpretation after each of the KEY findings. What is the take home message; what are the bottom-lines? While the findings may indeed be “ important for treatment development ”, it is unclear how. Please elaborate.