Sunyoung Choi

Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder.

Background DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls. Methods We compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed. Results In total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2–3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas. Conclusions Lower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non-psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation.

Cortical thickness, cortical and subcortical volume, and white matter integrity in patients with their first episode of major depression.

BACKGROUND The uncertainty over the true morphological changes in brains with major depressive disorder (MDD) underlines the necessity of comprehensive studies with multimodal structural brain imaging analyses. This study aimed to evaluate the differences in cortical thickness, cortical and subcortical volume, and white matter integrity between first episode, medication-naïve MDD patients and healthy controls. METHODS Subjects with their first episode of MDD whose illness duration had not exceeded 6 months (n=20) were enrolled in this study and were compared to age-, sex-, and education level-matched healthy controls (n=22). All participants were subjected to T1-weighted structural magnetic resonance imaging (MRI). We used an automated procedure of FreeSurfer and Tract-based spatial statistics (TBSS) to analyze differences in cortical thickness, cortical and subcortical volume, and white matter integrity between two groups. RESULTS The patients with first episode MDD exhibited significantly reduced cortical volume in the caudal anterior cingulate gyrus (P<0.0015) compared to healthy controls. We also observed altered white matter integrity in the body of the corpus callosum (P<0.01), reduced cortical volume of the caudal middle frontal gyrus and medial orbitofrontal gyrus, and enlarged hippocampal volume in the first episode MDD patients. LIMITATIONS We relied on a relatively small sample size and cortical volume reduction in several brain regions was not replicated in the analysis of cortical thickness. CONCLUSIONS Using multimodal imaging analyses on medication-naïve first episode MDD patients, we demonstrated fundamental structural alteration of brain gray and white matter, such as reduced cortical volume of the caudal ACC and white matter integrity in the body of the corpus callosum.

Association of brain-derived neurotrophic factor DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression

Considerable evidence suggests a crucial role for the epigenetic regulation of brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD). However, the relationship between BDNF DNA methylation and white matter (WM) integrity in MDD has not yet been investigated. In the current study, we examined the association between the DNA methylation status of the BDNF promoter region and WM integrity in MDD. Sixty patients with MDD and 53 healthy controls underwent T1-weighted structural magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), to assess their WM integrity. BDNF DNA methylation at 4 CpG sites of the promoter region was also measured. As compared to healthy controls, the MDD group demonstrated reduced fractional anisotropy (FA) in the bilateral anterior and posterior corona radiata (ACR and PCR), genu of the corpus callosum, and the bilateral posterior thalamic radiations. We observed a significant inverse correlation between the DNA methylation of the BDNF promoter region and the FA of the right ACR in MDD patients. Our findings demonstrate a relationship between methylation of the BDNF promoter region and the integrity of the ACR, a key structural component of the emotional and cognitive control network involved in the pathophysiology of MDD. This correlation suggests that BDNF DNA methylation may contribute to structural WM changes in MDD patients.

Effect of the COMT val158met polymorphism on white matter connectivity in patients with major depressive disorder.

Cortico-limbic network dysfunction and genetic polymorphism are considered to be associated with major depressive disorder (MDD). Using diffusion tensor imaging (DTI), we investigated the relationship between catechol-O-methyltransferase (COMT) gene polymorphisms and white matter tract integrity in patients with MDD. Eighty-six patients with MDD and 62 healthy controls participated in this study. DTI and genotyping for the COMT val158met gene (rs4680) polymorphism were conducted to determine the impact of COMT polymorphisms on white matter changes in patients with MDD. Voxel-wise statistical analyses of fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). FAs of the MDD patient group were significantly decreased in bilateral frontal forceps minor, bilateral anterior cingulum, genu of corpus callosum, left posterior cingulum, right superior longitudinal fasciculus, and right posterior thalamic radiation compared with those of healthy controls. In the MDD patient group, mean FA in subjects with the GG allele was significantly decreased in left inferior longitudinal fasciculus, bilateral middle temporal gyrus, right frontal gyrus, and right cingulum bundle area compared with subjects with the AA/AG allele. These findings suggest cortico-limbic network dysfunction in MDD. Specifically, further FA reduction was evident in MDD patients with the valine homozygote group of the COMT gene. MDD may be associated with dysfunctional white matter changes, and the valine homozygote of COMT gene may contribute to further abnormalities in these pathological changes.

Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder

Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearsons correlation: r=−0.493, P=0.003) and axial diffusivity (CpG3, Pearsons correlation: r=−0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD.

Effects of a Polymorphism of the Neuronal Amino Acid Transporter SLC6A15 Gene on Structural Integrity of White Matter Tracts in Major Depressive Disorder

Background The SLC6A15 gene has been identified as a novel candidate gene for major depressive disorder (MDD). It is presumed to be involved in the pathophysiology of MDD through regulation of glutamate transmission in the brain. However, the involvement of this gene in microstructural changes in white matter (WM) tracts remains unclear. We aimed to investigate the influence of a polymorphism of this gene (rs1545853) on the structural integrity of WM tracts in the cortico-limbic network. Methods Eighty-six patients with MDD and 64 healthy controls underwent T1-weighted structural magnetic resonance imaging, including diffusion tensor imaging (DTI), and genotype analysis. We selected the genu of the corpus callosum, the uncinate fasciculus, cingulum, and fornix as regions of interest, and extracted fractional anisotropy (FA) values using the FMRIB Diffusion Toolbox software. Results FA values for the left parahippocampal cingulum (PHC) was significantly reduced in the patients with MDD compared to healthy control participants (p = 0.004). We also found that MDD patients with the A allele showed reduced FA values for the left PHC than did healthy controls with the A allele (p = 0.012). There was no significant difference in the FA value of left PHC for the comparison between the G homozygotes of MDD and healthy control group. Conclusions We observed an association between the risk allele of the SLC6A15 gene rs1545843 and the WM integrity of the PHC in MDD patients, which is known to play an important role in the neural circuit involved in emotion processing.

The association between substance P and white matter integrity in medication-naive patients with major depressive disorder

Substance P (SP) has been implicated in major depressive disorder (MDD), with SP antagonists being studied as potential antidepressants. Although impaired neural plasticity is considered a key mechanism in MDD pathophysiology, the association between SP and brain structural changes in depression has not been investigated. We investigated the correlations between SP levels and white matter (WM) integrity in 42 medication-naive patients with MDD and 57 healthy controls (HCs). Plasma levels of SP were determined, and diffusion tensor imaging (DTI) was performed to investigate microstructural changes in WM tracts. In patients, negative correlations between SP levels and fractional anisotropy (FA) values of the forceps minor of the corpus callosum, and positive correlations between SP levels and radial diffusivity (RD) and mean diffusivity (MD) values of the right corticospinal tract (CST) were observed, with no significant correlations in HCs. Linear regression analyses showed SP levels to significantly predict FA values of the forceps minor, and RD and MD values of the right CST in patients, but not in HCs. We consider our findings to contribute to the neurobiological evidence on the association between SP and brain structural changes in depression, which may be related with the pathophysiology and treatment of MDD.

Influence of BclI C/G (rs41423247) on hippocampal shape and white matter integrity of the parahippocampal cingulum in major depressive disorder

We investigated the interactive effects of BclI C/G (rs41423247) allelic variants and the diagnosis of major depressive disorder (MDD) on hippocampal shape and integrity of the left parahippocampal subdivision of the cingulum. Fifty-two patients with MDD and 52 healthy controls (HCs) underwent T1-weighted structural magnetic resonance imaging and BclI C/G (rs41423247) genotyping. We analyzed hippocampal shape using the FIRST module of FSL and analyzed white matter (WM) integrity using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). Significant alterations in left hippocampal shape and decreased fractional anisotropy (FA) values of the left parahippocampal cingulum were observed in MDD patients, compared to HCs. In addition, MDD patients of the BclI minor (G-) allele carrier group showed significant alterations in left hippocampal shape and decreased FA values of the left parahippocampal cingulum compared to BclI minor (G-) allele carrier HCs. No significant differences between diagnostic subgroups of the C/C homozygotes were observed. Our study provides evidence for alterations in hippocampal shape and decreased integrity of the WM region associated with the hippocampus in MDD, and for the possible influence of BclI C/G polymorphism (rs41423247) on hippocampal shape and integrity of the parahippocampal subdivision of the cingulum in depression.

Structural characteristics of the brain reward circuit regions in patients with bipolar I disorder: A voxel-based morphometric study

Bipolar I disorder (BD-I) is often misdiagnosed, leading to inadequate treatment and significant disability along with reduced quality of life. Recent neural models suggest that the reward circuitry is affected in bipolar disorder. The purpose of the present study was to identify structural abnormalities in the brain reward-processing neural circuitry among patients with BD-I. 21 patients with BD-I and 21 healthy controls (HC) participated in this study. Structural magnetic resonance imaging was performed. Region-of-interest (ROI) voxel-based morphometry analysis was applied to assess the presence of structural changes between the BD-I patient group and the control group. The results of the reward circuitry ROI analysis revealed lower gray matter volumes in the left ventromedial prefrontal cortex (VMPFC), left dorsomedial prefrontal cortex (DMPFC), and left ventrolateral prefrontal cortex (VLPFC) in patients with BD-I compared to HC. Our results suggest that abnormalities in the brain reward-processing neural circuitry, especially those in the left VMPFC, left DMPFC, and left VLPFC, may play an important role in the pathophysiology of BD-I.

TESC gene-regulating genetic variant (rs7294919) affects hippocampal subfield volumes and parahippocampal cingulum white matter integrity in major depressive disorder

Two recent genome-wide association studies have suggested that rs7294919 is associated with changes in hippocampal volume. rs7294919 regulates the transcriptional products of the TESC gene, which is involved in neuronal proliferation and differentiation. We investigated the interactive effect of rs7294919 and major depressive disorder (MDD) on the volume of the hippocampal subfields and the integrity of the parahippocampal cingulum (PHC). We also investigated the correlation of these structural changes with the DNA methylation status of rs7294919. A total of 105 patients with MDD and 85 healthy control subjects underwent T1-weighted structural magnetic resonance imaging and diffusion tensor imaging. The rs7294919 was genotyped and its DNA methylation status was assessed in all the participants. We analyzed the hippocampal subfield volumes and PHC integrity using FreeSurfer and the Tracts Constrained by Underlying Anatomy (TRACULA) respectively. Significant interactive effects of rs7294919 and MDD were observed in the volumes of the dentate gyrus and CA4. The patients with MDD had increased methylation in two of the three CpG loci of rs7294919, and the methylation of CpG3 was significantly correlated with right PHC integrity in the MDD group. Our results provide neurobiological evidence for the association of rs7294919 with brain structural changes in MDD.