Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus

Abstract

Background: Positron emission tomography (PET) studies of major depression have revealed resting-state abnormalities in the prefrontal and cingulate cortices. Recently, fMRI has been adapted to examine connectivity within a specific resting-state neural network--the default-mode network--that includes medial prefrontal and anterior cingulate cortices. The goal of this study was to examine resting-state, default-mode network functional connectivity in subjects with major depression and in healthy controls.

Methods: Twenty-eight subjects with major depression and 20 healthy controls underwent 5-min fMRI scans while resting quietly. Independent component analysis was used to isolate the default-mode network in each subject. Group maps of the default-mode network were compared. A within-group analysis was performed in the depressed group to explore effects of depression refractoriness on functional connectivity.

Results: Resting-state subgenual cingulate and thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects. Within the depressed group, the length of the current depressive episode correlated positively with functional connectivity in the subgenual cingulate.

Conclusions: This is the first study to explore default-mode functional connectivity in major depression. The findings provide cross-modality confirmation of PET studies demonstrating increased thalamic and subgenual cingulate activity in major depression. Further, the within-subject connectivity analysis employed here brings these previously isolated regions of hypermetabolism into the context of a disordered neural network. The correlation between refractoriness and subgenual cingulate functional connectivity within the network suggests that a quantitative, resting-state fMRI measure could be used to guide therapy in individual subjects.

Figure 1. Automated selection of the default-mode component

Each subject's default-mode component is selected from among their 25 components based on the two-step process outlined above (shown here with only 3 components). Each component consists of a spatial map (colored axial images) and its corresponding timeseries shown beneath it. The color scale indicates the degree to which a given voxel's timeseries is correlated with the overall timeseries of that component (with yellow-red colors indicating a positive correlation and blue colors indicating a negative correlation). Firstly, because resting-state neural networks are driven by low-frequency oscillations, all high-frequency components (component 1 in this example) are removed using a frequency filter. The remaining low-frequency components are scored based on their spatial goodness-of-fit to a standard template of the default-mode network derived from a separate dataset (template not shown). The component with the highest goodness-of-fit score (component 3 here) is then entered into the group analyses. Note that all voxels of the selected component have z-scores, not just those voxels that fall within the regions defined by the standard template.

Figure 2. Increased default-mode network functional connectivity in subjects with major depression

Axial images of group default-mode functional connectivity in depressed subjects (A) and in healthy controls (B). The contrast map in (C) demonstrates clusters in the subgenual cingulate, thalamus, and precuneus where resting-state functional connectivity was greater in depressed subjects versus controls. T-score bars are shown at right. Note that while the color scale range begins at 1, the minimum t-value for the analyses were 3.42 for the depressed group map (A), 3.58 for the control group map (B), and 2.41 for the depressed versus control contrast map (C). Numbers at the bottom left of the images refer to the z-coordinates (and for the sagittal image the x-coordinates) in the standard space of the Montreal Neurological Institute (MNI) template. The left side of the image corresponds to the left side of the brain.

Figure 3. Subgenual cingulate functional connectivity in the default-mode network correlates with duration of the current depressive episode

A sagittal image (A) shows the subgenual cingulate cluster whose resting-state functional connectivity correlated with the duration of the current depressive episode across 24 depressed subjects. The same finding is represented graphically (B) in a scattergram of duration in weeks against the mean z-score within the subgenual cluster shown in (A). The pearson correlation coefficient was 0.49 (Fisher's r to z, p = 0.014). Red circles indicate the 8 depressed subjects who were unmedicated.

Figure 4. Both groups show adequate T2* signal in the region of the subgenual cingulate

The region of the subgenual cingulate is often prone to loss of T2* signal due to susceptibility artifact. Here it is shown that the scanning parameters used in this study allowed for adequate signal detection in this region that does not appear to differ between the groups. The mean T2* images from the 20 healthy controls (left panel) and the 28 depressed subjects (right panel) are shown with the crosshairs on the subgenual cluster (middle panel) that showed greater functional connectivity in depressed subjects.