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Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study.

ABSTRACT: 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 compared to the PTSD-MDD group. However, this cluster was no longer significantly different when PTSD patients that were using medication were excluded from analyses. Thus, resting state functional connectivity of the subgenual ACC can distinguish PTSD+MDD from PTSD-MDD, and this may therefore be used as a neurobiological marker for comorbid MDD in the presence of PTSD. As PTSD+MDD are more treatment resistant, these findings can also guide treatment development, for example by targeting the subgenual ACC network with treatment.

SUBMITTER: Kennis M

PROVIDER: S-EPMC4184309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have previously shown that in participants with major depressive disorder (MDD) trained to upregulate their amygdala hemodynamic response during positive autobiographical memory (AM) recall with real-time fMRI neurofeedback (rtfMRI-nf) training, depressive symptoms diminish. Here, we assessed the effect of rtfMRI-nf on amygdala functional connectivity during both positive AM recall and rest.The current manuscript consists of a secondary analysis on data from our published clinical trial of neurofeedback. Patients with MDD completed two rtfMRI-nf sessions (18 received amygdala rtfMRI-nf, 16 received control parietal rtfMRI-nf). One-week prior-to and following training participants also completed a resting-state fMRI scan. A GLM-based functional connectivity analysis was applied using a seed ROI in the left amygdala. We compared amygdala functional connectivity changes while recalling positive AMs from the baseline run to the final transfer run during rtfMRI-nf training, as well during rest from the baseline to the one-week follow-up visit. Finally, we assessed the correlation between change in depression scores and change in amygdala connectivity, as well as correlations between amygdala regulation success and connectivity changes.Following training, amygdala connectivity during positive AM recall increased with widespread regions in the frontal and limbic network. During rest, amygdala connectivity increased following training within the fronto-temporal-limbic network. During both task and resting-state analyses, amygdala-temporal pole connectivity decreased. We identified increased amygdala-precuneus and amygdala-inferior frontal gyrus connectivity during positive memory recall and increased amygdala-precuneus and amygdala-thalamus connectivity during rest as functional connectivity changes that explained significant variance in symptom improvement. Amygdala-precuneus connectivity changes also explain a significant amount of variance in neurofeedback regulation success.Neurofeedback training to increase amygdala hemodynamic activity during positive AM recall increased amygdala connectivity with regions involved in self-referential, salience, and reward processing. Results suggest future targets for neurofeedback interventions, particularly interventions involving the precuneus.

Project description:Altered resting-state functional connectivity in posttraumatic stress disorder (PTSD) suggests neuropathology of the disorder. While seed-based fMRI connectivity analysis is often used for the studies, such analysis requires defining a seed location a priori, which restricts search scope and could bias findings toward presupposed areas. Recently, a comprehensive exploratory voxel-wise connectivity analysis, the connectome-wide association approach, has been introduced using multivariate distance matrix regression (MDMR) for resting-state functional connectivity analysis. The current study performed a connectome-wide investigation of resting-state functional connectivity for war veterans with and without PTSD compared to non-trauma-exposed healthy controls using MDMR. Thirty-five male combat veterans with PTSD (unmedicated), 18 male combat veterans without PTSD (veterans control, VC), and 28 age-matched non-trauma-exposed healthy males (NC) participated in a resting-state fMRI scan. MDMR analysis was used to identify between-groups differences in regions with altered connectivity. The identified regions were used as a seed for post-hoc functional connectivity analysis. The analysis revealed that PTSD patients had hypoconnectivity between the left lateral prefrontal regions and the salience network regions as well as hypoconnectivity between the parahippocampal gyrus and the visual cortex areas. Connectivity between the ventromedial prefrontal cortex and the middle frontal gyrus and between the parahippocampal gyrus and the anterior insula were negatively correlated with PTSD symptom severity. VC subjects also had altered functional connectivity compared to NC, including increased connectivity between the posterior insula and several brain regions and decreased connectivity between the precuneus region and several other brain areas. The decreased connectivity between the lateral prefrontal regions and the salience network regions in PTSD was consistent with previous reports that indicated lowered emotion-regulation function in these regions. The decreased connectivity between the parahippocampal gyrus and visual cortex supported the dual representation theory of PTSD, which suggests dissociation between sensory and contextual memory representations in PTSD. The theory also supposes that the precuneus is a region that triggers retrieval of sensory memory of traumatic events. The decreased connectivity at the precuneus for VC might be associated with suppressing such a process.

Project description:Despite the heterogeneous symptom presentation and complex etiology of major depressive disorder (MDD), functional neuroimaging studies have shown with remarkable consistency that dysfunction in mesocorticolimbic brain systems are central to the disorder. Relatively less research has focused on the identification of biological markers of response to antidepressant treatment that would serve to improve the personalized delivery of empirically supported antidepressant interventions. In the present study, we investigated whether resting-state functional brain connectivity (rs-fcMRI) predicted response to Behavioral Activation Treatment for Depression, an empirically validated psychotherapy modality designed to increase engagement with rewarding stimuli and reduce avoidance behaviors. Twenty-three unmedicated outpatients with MDD and 20 matched nondepressed controls completed rs-fcMRI scans after which the MDD group received an average of 12 sessions of psychotherapy. The mean change in Beck Depression Inventory-II scores after psychotherapy was 12.04 points, a clinically meaningful response. Resting-state neuroimaging data were analyzed with a seed-based approach to investigate functional connectivity with four canonical resting-state networks: the default mode network, the dorsal attention network, the executive control network, and the salience network. At baseline, the MDD group was characterized by relative hyperconnectivity of multiple regions with precuneus, anterior insula, dorsal anterior cingulate cortex (dACC), and left dorsolateral prefrontal cortex seeds and by relative hypoconnectivity with intraparietal sulcus, anterior insula, and dACC seeds. Additionally, connectivity of the precuneus with the left middle temporal gyrus and connectivity of the dACC with the parahippocampal gyrus predicted the magnitude of pretreatment MDD symptoms. Hierarchical linear modeling revealed that response to psychotherapy in the MDD group was predicted by pretreatment connectivity of the right insula with the right middle temporal gyrus and the left intraparietal sulcus with the orbital frontal cortex. These results add to the nascent body of literature investigating pretreatment rs-fcMRI predictors of antidepressant treatment response and is the first study to examine rs-fcMRI predictors of response to psychotherapy.

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Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study.

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