Reduced global functional connectivity of the medial prefrontal cortex in major depressive disorder

Abstract

Background Major depressive disorder is a disabling neuropsychiatric condition that is associated with disrupted functional connectivity across brain networks. The precise nature of altered connectivity, however, remains incompletely understood. The current study was designed to examine the coherence of large-scale connectivity in depression using a recently developed technique termed global brain connectivity. Methods A total of 82 subjects, including medication-free patients with major depression (n=57) and healthy volunteers (n=25) underwent functional magnetic resonance imaging with resting data acquisition for functional connectivity analysis. Global brain connectivity was computed as the mean of each voxel’s time series correlation with every other voxel and compared between study groups. Relationships between global connectivity and depressive symptom severity measured using the Montgomery-Åsberg Depression Rating Scale were examined by means of linear correlation. Results Relative to the healthy group, patients with depression evidenced reduced global connectivity bilaterally within multiple regions of medial and lateral prefrontal cortex. The largest between-group difference was observed within the right subgenual anterior cingulate cortex, extending into ventromedial prefrontal cortex bilaterally (Hedges’ g = −1.48, p<0.000001). Within the depressed group, patients with the lowest connectivity evidenced the highest symptom severity within ventromedial prefrontal cortex (r = −0.47, p=0.0005). Conclusions Patients with major depressive evidenced abnormal large-scale functional coherence in the brain that was centered within the subgenual cingulate cortex, and medial prefrontal cortex more broadly. These data extend prior studies of connectivity in depression and demonstrate that functional disconnection of the medial prefrontal cortex is a key pathological feature of the disorder.

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

“…In addition, patients with a history of more severe treatment failures had higher levels of vPFC GBCr. Along with previous reports (16, 35), the current study findings associate vPFC GBCr increases with TRD as defined by failure to respond to adequate trials of monoaminergic drugs and traditional antidepressants. Intriguingly, subjects with more prominent baseline vPFC GBCr abnormalities showed an enhanced response to ketamine, but poor response to placebo.…”

“…Comparable to our previous reports, baseline severity of depression was not associated with the level of GBCr abnormalities (16, 35). Our current working model of depression (46, 47), which accounts for the latter finding, is that MDD patients could be stratified into two groups: Glutamate-Based Depression (GBD) and non-GBD.…”

“…Depressive features and chronic stress in animal models reduce prefrontal glutamate synaptic density and strength, abnormalities that are reversed by ketamine treatment (40). Consistent with this model, we have recently demonstrated widespread GBCr reduction in the dorsomedial, frontolateral, and ventral PFC in patients with MDD (35). In treatment-resistant depression (TRD), we found comparable GBCr reduction in dorsomedial and frontolateral, but not ventral (Limbic network; vPFC), PFC in patients at baseline (16).…”

“…In addition, previous reports associated this brain area with TRD and ketamine infusion (16, 35, 42). Therefore, we conducted a follow-up region of interest (ROI) analysis examining the average GBCr in the vPFC (Fig.…”

Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

“…The clinical evidence supporting this hypothesis is limited currently, but it is being actively studied. In depression, reductions in cortical functional connectivity as measured by functional MRI appear to be ameliorated within 24 h by a single dose of ketamine, in conjunction with clinical improvement [115•, 116]. Similar studies are underway in PTSD patients.…”