Resting-state functional connectivity of the human habenula in healthy individuals: Associations with subclinical depression

Abstract

Introduction: The habenula (Hb) is postulated to play a critical role in reward and aversion processing across species, including humans, and has been increasingly implicated in depression. However, technical constraints have limited in vivo investigation of the human Hb, and its function remains poorly characterized. We sought to overcome these challenges by examining the whole-brain resting-state functional connectivity of the Hb and its possible relationship to depressive symptomatology using the high-resolution WU-Minn Human Connectome Project (HCP) dataset.

Methods: Anatomical and resting-state functional MRI data from 50 healthy subjects with low or high subclinical depression scores (n = 25 each) were analyzed. Using novel semi-automated segmentation and optimization techniques, we generated individual-specific Hb seeds and calculated whole-brain functional connectivity for the entire cohort and the contrast of high vs. low depression groups.

Results: In the entire cohort, the Hb exhibited significant connectivity with key brainstem structures (i.e., ventral tegmental area, substantia nigra, pons) as well as the anterior and posterior cingulate cortices, precuneus, thalamus, and sensorimotor cortex. Multiple regions showed differential Hb connectivity based on subclinical depression scores, including the amygdala, insula, and prefrontal, mid-cingulate, and entorhinal cortices.

Conclusions: Hb connectivity findings converged on areas associated with salience processing, sensorimotor systems, and the default mode network. We also detected substantial Hb-brainstem connectivity, consistent with prior histological and animal research. High and low subclinical depression groups exhibited differences in Hb connectivity with multiple regions previously linked to depression, suggesting the relationship between these structures as a potential target for future research and treatment. Hum Brain Mapp 37:2369-2384, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: depression; functional connectivity; habenula; high resolution; midbrain; resting state fMRI; seed optimization; substantia nigra; ventral tegmental area (VTA); whole brain.

Figure 1

Two representative results from our semi‐automatic habenula segmentation approach, subsequently used to generate functional connectivity seeds, with volumes one standard deviation below (A) and above (B) the mean. Habenulae are overlaid on subjects' MNI‐standardized 0.7mm isotropic resolution myelin maps. Central voxels (white) contain 100% habenula tissue; border voxels (red) contain partly Hb and partly surrounding tissue. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Regions with significantly (P_TFCE < 0.05, k ≥ 10) positive (red‐yellow) and negative (blue‐green) resting‐state functional connectivity with the bilateral habenula in 50 healthy subjects. ACC: Anterior Cingulate Cortex. Hb: Habenula. PCC: Posterior Cingulate Cortex. VTA: Ventral Tegmental Area.

Figure 3

(Top, Bottom) Consecutive axial views of positive bilateral habenula functional connectivity (P_TFCE < 0.05, k ≥ 10) with the midbrain (red‐yellow). Overlays (black) are derived from previously published, MNI‐standardized atlases [Jakab et al., 2012; Krauth et al., 2010; Murty et al., 2014], thresholded to exclude any voxels with <25% atlas probability. Slice orientations follow neurological convention. (Right) Sagittal view showing the location of the axial slices (green) on an MNI template brain. RN: Red Nucleus. SN: Substantia Nigra. VTA: Ventral Tegmental Area.

Figure 4

(Top) Regions where habenula functional connectivity was greater (red‐yellow) and lower (blue‐green) in healthy subjects with high relative to low subclinical depression scores (n = 25 each) at the uncorrected P < 0.001, k ≥ 10 level, represented by corresponding t values. (Bottom) Bar plots showing mean z‐transformed correlation coefficients of the habenula (Hb), dorsomedial thalamic nuclei (DM), and centromedian thalamic nuclei (CM) seeds with the displayed clusters for the low (blue) and high (red) subclinical depression groups. Error bars indicate 95% confidence intervals. dmPFC: Dorsomedial Prefrontal Cortex. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

(Left) Location and shape of the dorsomedial (blue) and centromedian (green) thalamic nuclei control seeds, which are based on the group‐mean of all subjects' individual habenula seeds (red). (Center, Right) Functional connectivity patterns (binarized at P_TFCE < 0.05, k ≥ 10) for the habenula and thalamic control seeds. Colors are additive in overlapping areas. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]