Aram Kim

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.

Local gyrification index in patients with major depressive disorder and its association with tryptophan hydroxylase‐2 (TPH2) polymorphism

The tryptophan hydroxylase‐2 (TPH2) gene is considered a promising genetic candidate regarding its association with a predisposition to major depressive disorder (MDD). Local gyrification reflects the early neural development of cortical connectivity, and is regarded as a potential neural endophenotype in psychiatric disorders. They aimed to investigate the alterations in the cortical gyrification of the prefrontal cortex and anterior cingulate cortex and their association with the TPH2 rs4570625 polymorphism in patients with MDD. One hundred and thirteen patients with MDD and eighty‐six healthy controls underwent T1‐weighted structural magnetic resonance imaging and genotyping for TPH2 rs4570625. The local gyrification index of 22 cortical regions in the prefrontal cortex and anterior cingulate cortex was analyzed using the FreeSurfer. The patients with MDD showed significant hypergyria in the right rostral anterior cingulate cortex (P = 0.001), medial orbitofrontal cortex (P = 0.003), and frontal pole (P = 0.001). There was a significant genotype‐by‐diagnosis interaction for the local gyrification index in the right rostral anterior cingulate cortex (P = 0.003). Their study revealed significant hypergyria of the anterior cingulate cortex and prefrontal cortex and an interactive effect between the diagnosis of MDD and the genotype in the anterior cingulate cortex. This might be associated with the dysfunction of neural circuits mediating emotion processing, which could contribute to pathophysiology of MDD. Hum Brain Mapp 38:1299–1310, 2017.

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.

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.

Alterations in the brainstem volume of patients with major depressive disorder and their relationship with antidepressant treatment

BACKGROUND Morphologic changes of the brainstem in major depressive disorder (MDD) have rarely been reported in neuroimaging studies, even though, monoaminergic neurotransmitters are synthesized in several brainstem regions. We aimed to investigate volume changes in each region of the brainstem and their association with antidepressant use or the remission status of MDD. METHODS A total of 126 patients with MDD and 101 healthy controls underwent T1-weighted structural magnetic resonance imaging. We analyzed volumes of each brainstem region, including the medulla oblongata, pons, midbrain, and superior cerebellar peduncle, and the volume of the whole brainstem using the FreeSurfer. RESULTS The patients with MDD had significantly greater midbrain volumes (P=0.013) compared to healthy controls. In particular, drug-naïve patients with MDD had significantly greater brainstem volumes compared to healthy controls (P=0.007), while no significant findings were observed between the antidepressant treatment group and healthy controls. The remitted patient group had reduced pons (P=0.002) and midbrain (P=0.005) volumes compared to healthy controls, while the non-remitted MDD patient group had significantly greater midbrain volumes compared to the healthy controls (P=0.017). LIMITATIONS We could not distinguish gray versus white matter volumes changes in our analysis. CONCLUSIONS We observed that the midbrain is enlarged in patients with a current depressive episode, who are not undergoing antidepressant treatment. This volume then returns to normal after antidepressant treatment, and is even reduced, when the patient is in remission. Further studies are needed to confirm our observations.

The effects of 5-HTTLPR and BDNF Val66Met polymorphisms on neurostructural changes in major depressive disorder

The serotonin-transporter-linked polymorphic region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have been implicated in the pathophysiology of major depressive disorder (MDD). We aimed to investigate the effects of genetic variants of the 5-HTTLPR and BDNF Val66Met polymorphisms and their interactions with MDD on cortical volume and white matter integrity. Ninety-five patients with MDD and 65 healthy participants aged 20-65 years were recruited. The subjects were genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms and scanned with T1-weighted and diffusion tensor imaging. The gray matter volumes of 24 gyri in the prefrontal and anterior cingulate cortices and the fractional anisotropy values of nine white matter tracts in both hemispheres were determined. In the pooled sample of subjects from both groups, 5-HTTLPR L-allele carriers had significantly decreased cortical volume in the right anterior midcingulate gyrus compared to S-allele homozygotes. A significant effect of the interaction of the BDNF Val66Met polymorphism and MDD on the fractional anisotropy values of the right uncinate fasciculus was observed. Our results suggested that these genetic polymorphisms play important roles in the neurostructural changes of emotion-processing regions in subjects with MDD.

Interaction effects of oxytocin receptor gene polymorphism and depression on hippocampal volume

Many studies have revealed that the oxytocin receptor gene (OXTR) is associated with emotional salience and depression among females. Hippocampus is closely associated with the pathophysiology of major depressive disorder (MDD). However, little is known of the interaction effects of OXTR and MDD on hippocampal volume. We sought to investigate the interaction effects of OXTR (rs53576) allelic variants and MDD on hippocampal volumes which also including subfield volumes. The OXTR rs53576 genotype groups were categorized as minor G allele carriers and A allele homozygotes. A total of 47 female patients with depression and 30 healthy females were included in this study. There were significant interactions between OXTR allele type and diagnosis of MDD on the 7 hippocampal subfield volumes, such as left presubiculum, left subiculum, left molecular, right cornus ammonis 1, right granule cells in the molecular layer of the dentate gyrus, right molecular layer, and right subiculum. There were no differences in the hippocampal volumes between MDD vs healthy controls or OXTR A vs G alleles. Our results demonstrate the importance of the interactions between OXTR and MDD on hippocampal volume. Future studies with large sample size should expand those interactions in the whole brain volumes.

Differential effect of COMT gene methylation on the prefrontal connectivity in subjects with depression versus healthy subjects

&NA; Expression of the catechol‐O‐methyl transferase (COMT) gene mainly determines prefrontal dopaminergic availability. Deficient prefrontal dopaminergic activity leads to loss of interest, energy, and motivation, which are core symptoms of depression. Given the role of stress‐environmental interactions in major depressive disorder (MDD), we investigated the impact of COMT gene methylation status on prefrontal connectivity. We measured COMT gene methylation and polymorphisms (Val158Met) at the rs4468 locus in peripheral blood samples of healthy controls (n = 90) and patients with MDD (n = 90). We used diffusion tensor imaging to calculate the fractional anisotropy (FA) and radial diffusivity (RD) of the white matter tracts related to prefrontal cortex. Finally, we examined the effects of COMT gene methylation on the white matter connectivity in patients with MDD. The FA and RD values in the prefrontal white matter tracts of patients with MDD were positively and negatively associated with COMT gene methylation, respectively. In the control group, on the other hand, the association between white matter connectivity and COMT gene methylation showed opposite pattern to those of MDD. COMT gene methylation has a substantial effect on the prefrontal connectivity in patients with MDD. Moreover, COMT gene methylation and prefrontal connectivity showed opposite relationships in patients and controls. Thus, stress‐related alterations in dopaminergic neurotransmission have a differential effect on white matter connectivity according to the microenvironment in the brain. HighlightsCOMT gene methylation was lower in patients with depression than in healthy control individuals.The FA (and RD) of the white matter tracts of the PFC were lower (and higher) in patients than those in controls.The COMT gene methylation had opposite relationships with white matter connectivity in the two groups.

Vesicular monoamine transporter 1 gene polymorphism and white matter integrity in major depressive disorder

ABSTRACT The genetic variant of the vesicular monoamine transporter 1 gene (VMAT1) has been suggested to be associated with monoaminergic signaling and neural circuit activity related to emotion processing. We aimed to investigate microstructural changes in white matter tracts of patients with major depressive disorder (MDD), and examined the interaction effect between VMAT1 Thr136Ile (rs1390938) polymorphism and MDD on white matter integrity. Diffusion tensor imaging (DTI) and VMAT1 Thr136Ile (rs1390938) genotyping were performed on 103 patients diagnosed with MDD and 83 healthy control participants. DTI was used to investigate microstructural changes in white matter tracts in patients compared to healthy controls. The possible interaction effect between rs1390938 and MDD on white matter integrity was also assessed. Patients with MDD exhibited lower fractional anisotropy (FA) values of the forceps major (p < 0.001), forceps minor (p = 0.001), inferior longitudinal fasciculus (left: p = 0.001; right: p < 0.001), parietal endings of the superior longitudinal fasciculus (left: p < 0.001; right: p = 0.002), left temporal endings of the superior longitudinal fasciculus (p = 0.001), and right uncinate fasciculus (p = 0.001). Significant genotype‐by‐diagnosis interaction effects were observed on FA values of the right uncinate fasciculus (p = 0.001), with A‐allele carrier patients exhibiting lower FA values compared to G‐allele homozygous patients (p = 0.003). No significant differences in FA values were observed between genotype subgroups among healthy controls. Our results may contribute to the evidence indicating an association between the VMAT1 gene and structural brain alterations in depression. HIGHLIGHTSVMAT1 Thr136Ile (rs1390938) affects monoaminergic signaling and emotion processing.We investigated white matter integrity and its association with rs1390938 in MDD.MDD patients showed reduced FA in several white matter tracts.Genotype × diagnosis interaction effect was observed in FA of uncinate fasciculus.