Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study

Abstract

Background: Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present after death. We conducted the first magnetic resonance imaging analysis of habenula volume in MDD and bipolar disorder (BD).

Methods: High-resolution images (resolution approximately .4 mm(3)) were acquired with a 3T scanner, and a pulse sequence was optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy control subjects (HC) were compared with both medicated (lithium/divalproex, n = 15) and unmedicated, depressed BD (n = 22) patients; unmedicated, depressed MDD patients (n = 28); and unmedicated MDD patients in remission (n = 32).

Results: The unmedicated BD patients displayed significantly smaller absolute (p < .01) and normalized (p < .05) habenula volumes than the HC subjects. In post hoc assessments analyzing men and women separately, the currently-depressed women with MDD had smaller absolute (p < .05) habenula volumes than the HC women. None of the other psychiatric groups differed significantly from the HC group.

Conclusions: We provide further evidence for the involvement of the habenula in affective illness but suggest that a reduction in volume might be more pronounced in unmedicated, depressed BD subjects and female currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress and in the suppression of dopamine cell activity after the absence of an expected reward. A reduction in habenula volume might thus have functional consequences that contribute to the risk for developing affective disease.

Figure 1

Coronal MRI sections showing the habenula and the local anatomical landmarks which enabled its segmentation. Because the habenular nuclei contain relatively dense white matter plexuses they can be collectively delimited from the gray matter of the adjacent thalamus dorsolaterally and of the limitans nucleus and pretectal area ventrolaterally (Mai et al. 2004). Moreover, in posterior planes the habenula is clearly evident as a pyramidal-shaped structure that bulges into the third ventricle along the ventromedial aspect of the thalamus, whereas in anterior planes it can be delimited ventrally and medially from the thalamus by the stria medullaris of thalamus (the white matter track that delimits the ventromedial aspect of the medial thalamus). In the image shown the habenular location shows sufficient asymmetry that the typical view of the posterior aspect is illustrated by the habenular nuclear complex located on the reader’s left, while the latter case is illustrated by the habenular complex on the reader’s right. Finally, the habenular nuclei are delimited ventrally by the white matter of the posterior commissure. The medial and lateral habenular nuclei could not be resolved specifically, so were combined within a single habenular volume-of-interest. The upper and lower panels consist of the identical image. The tracing of the habenula is shown in yellow in the lower panel.

Figure 2

Bar chart showing a comparison of absolute left and right habenula volume across the diagnostic groups. Absolute total habenula volumes (y-axis: scale = 0–40ml) are shown in the top panel, and absolute left and right habenula volumes (y-axis: scale 0–25ml) are shown in the bottom panel. Unmed.BD refers to the unmedicated BD sample, and Med.BD refers to the medicated BD sample. The standard error of the mean (SEM) is displayed on the top of each bar. The symbol, ** is indicative of a statistically significant (p<0.01) difference in habenula volume compared with the healthy control group.

Figure 3

Scatterplot of absolute left habenula volumes (y-axis) for the medicated BD, unmedicated BD, MDD, HC, and RD samples, respectively. The red horizontal bar shows the mean volume of each group.

Figure 4

Scatterplot of absolute right habenula volumes (y-axis) for the medicated BD, unmedicated BD, MDD, HC, and RD samples, respectively. The red horizontal bar shows the mean volume of each group.