Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study [version 2; peer review: 2 approved]

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, which may reflect the presence of depressive specific symptoms such as rumination. Functional connectivity of the subgenual ACC with the thalamus was reduced, potentially related to more severe deficits in executive functioning in the PTSD+MDD group versus the PTSD-MDD group. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus I appreciate the authors detailed responses to my earlier comments. The reiterated manuscript makes a solid and welcome contribution to the literature. Well done! 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 PTSD symptom severity - this should probably be in figure somehow, as this may end up being used as a graphic summary of the data. I missed whether the authors looked at the use of a factor affected connectivity, as it may interact with the condition. Second the authors, at correlation between connectivity severity in the PTSD-MDD, group in a post hoc correlation. A similar effect is specifically for the PTSD+MDD group. unclear the authors did not at the in all Competing competing 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. Abstract and introduction: We have attempted to make the abstract clearer, and added more context in both the abstract and introduction. We also acknowledge that the amygdala could have been another interesting seed to investigate PTSD with and without comorbid MDD. However, since the two previous neuroimaging studies that investigated PTSD and MDD with task paradigms reported alterations in the insula (Lanius et al. , 2007; Whalley et al. , 2009) while differences in the amygdala between PTSD and MDD patients were only reported by Whalley et al. (2009). Therefore, we argued that the insula is an appropriate candidate to investigate here.