Altered Volume and Functional Connectivity of the Habenula in Schizophrenia

Abstract

The pathogenesis of schizophrenia (SCH) is associated with the dysfunction of monoamine neurotransmitters, the synthesis and release of which are mainly regulated by a key structure, the habenular (Hb) nucleus. However, little is known regarding whether SCH is associated with structural or functional alterations in the Hb. In this study, we combined structural and resting-state functional magnetic resonance imaging to investigate the changes in volume and functional connectivity of the Hb in 15 patients with SCH vs. 16 age- and gender-matched healthy controls (HCs). Morphologically, the absolute volume of the bilateral Hb was significantly lower in the SCH patients than in the HCs. Functionally, the bilateral Hb showed significantly enhanced functional connectivity with the left medial prefrontal cortex (mPFC) in the SCH patients. Additionally, the SCH patients exhibited increased functional connectivity of the left Hb with the left lingual gyrus and right inferior frontal gyrus (IFG). A further exploratory analysis revealed that the SCH patients showed increased functional connectivity between the right Hb and several subcortical regions related to dopaminergic pathways, including the left ventral striatum, caudate and putamen. Finally, the increased functional connectivity of the right Hb with the mPFC was positively correlated with the Brief Psychiatric Rating Scale (BPRS) scores in the patients. Together, these results suggest that the altered volume and functional connectivity of the Hb may be involved in the pathogenesis of SCH and thus that the Hb may serve as a potential target in developing new therapeutic strategies in SCH.

Imaging Habenula Volume in Schizophrenia and Bipolar Disorder

“…To our knowledge, there are only two prior neuroimaging studies of the Hb in the clinical populations considered here. Zhang et al ( 52 ) compared the volume, manually segmented using a geometric method, and resting state connectivity of the Hb of 15 patients with SCZ and 16 healthy individuals. They reported bilateral Hb volume reductions with large effect size ( d = −0.84 on the left and d = −0.72 on the right) that did not correlate with the patients' total BPRS scores.…”

“…The study sample ( n = 140) was powered at α = 0.05 and β = 0.20 for an effect size of 0.5 for each case-control comparison. This effect size was chosen as it is large enough to be considered meaningful ( 65 ) while remaining conservative despite the reported effect sizes of approximately 0.7 in the two previous positive studies ( 52 , 53 ). The normality of distribution of the continuous variables of interest was tested using one-sample Kolmogorov–Smirnov test.…”

“…A single post-mortem study of the Hb in patients with Major Depressive Disorder (MDD; n = 6), BD ( n = 8) and SCZ ( n = 17) found that volume reduction in the Hb was associated with affective disorders ( 49 ). This association was contradicted in subsequent in-vivo imaging studies that were unable to find case-control differences in the Hb volume in patients with MDD ( 50 , 51 ) but reported a significant reduction in patients with SCZ ( 52 ). A further study suggested that Hb volume reductions may be restricted to unmedicated BD patients and to depressed women with MDD ( 53 ).…”

Altered habenula resting state functional connectivity in deprived veteran tobacco smokers: A pilot study

“…Furthermore, Peng et al (2018) found that structural connectivity of the lingual gyrus differentiated heavy smokers from light smokers and controls: Heavy smokers had significantly greater white matter atrophy of the lingual gyrus. Although no previous research has found aberrant habenula-lingual connectivity in smokers, habenula-lingual abnormalities in individuals with schizophrenia (Zhang et al, 2017) and high "negative connectivity" between the habenula and lingual gyrus in both healthy controls and psychiatric patients have been reported (Curtis et al, 2017;Ely et al, 2016).…”

Three-Dimensional Analysis of Mouse Habenula Subnuclei Reveals Reduced Volume and Gene Expression in the Lipopolysaccharide-mediated Depression Model

“…Jacinto et al also found that rats exposed to chronic, unpredictable stress had reduced volumes of MHb and LHb in both hemispheres and had lower number of cells in their right MHb and bilateral LHb areas [11]. However, functional magnetic resonance imaging (fMRI) studies have failed to identify significant differences for major depressive disorder (MDD) and healthy control groups [12][13][14]; meanwhile, analysis of schizophrenia patients showed atrophy of their Hb volume compared with controls [15]. Such differences might be due to the insufficient resolution of the imaging methods used and/or inaccurate measurement of the volumes post tissue processing and 3D reconstitution of the volumes.…”