Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus

Abstract

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks--the cognitive control network, default mode network, and affective network--were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks--decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation--could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect "hot wiring" networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.

Conflict of interest statement

Conflict of interest statement: Y.I.S. has served on the advisory board and speakers’ bureau of Eli Lilly, Inc. M.A.M. serves as a consultant for Avid Radiopharmaceuticals. Y.I.S. is independent of any commercial provider, had full access to all of the data in this study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. No author named on the title page of this study has any financial interest in the results of the study or any other conflict of interest relevant to the subject matter of this manuscript.

Figures

Fig. 1.

Seed regions and targets. Each of the three solid circles corresponds to a seed region in the DLPFC, part of the CCN (yellow); precuneus, part of the DMN (pink); and subgenual and pregenual cingulate cortex, the affective division of the ACC (16) (turquoise). The correspondingly colored open circles represent regions with significantly increased connectivity with the respective seed regions.

Fig. 2.

Comparison of connectivity maps for depressed and control subjects across three networks. Connectivity of the CCN for control participants (A), depressed participants (B), and between-group differences (C); connectivity of DMN for controls (D), depressed participants (E), and between-group differences (F); and connectivity of the AN for controls (G), depressed participants (H), and between-group differences (I). Networks were identified by seed regions placed in the DLPFC (A–C), precuneus (D–F), and subgenual ACC (G–I). In each network, the dorsal nexus is seen at z = 30. The color bar indicates that images were thresholded at z = 2.58, P < 0.01.

Fig. 3.

A 3D image of the dorsal nexus. (A) Left (−24, 35, 28). (B) Right (18, 34, 29). The nexus was created from a conjunction analysis of the overlap of the areas of significantly increased connectivity among the three networks arising from seeds placed in the DLPFC, precuneus, and subgenual ACC. The individual connectivity maps for these seed regions are shown in Fig. 2. The nexus is comprised primarily of medial BA9, a portion of the ACC (BA32), and a small portion of medial BA8.

Fig. 4.

Connectivity map from the dorsal nexus to all of the voxels in the brain. Pictured are lateral and medial surface connectivity of the left hemisphere for both control (A and B) and depressed (C and D) participants. Dramatically higher connectivity for depressed participants is evident.

Fig. 5.

Comparison of depressed and control participants for mean resting-state connectivity between the dorsal nexus and the combined three seed regions in the DLPFC, precuneus, and subgenual ACC. Images were thresholded at z = 2.58, P < 0.01, as shown in Figure 4.