Eunsoo Won

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.

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.

Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition

Abstract Objective: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. Results: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

Impact of lingual gyrus volume on antidepressant response and neurocognitive functions in Major Depressive Disorder: a voxel-based morphometry study.

BACKGROUND Voxel-based morphometry (VBM) has demonstrated structural brain changes between patients with Major Depressive Disorder (MDD) and healthy individuals. The initial response to antidepressants is crucial to predict prognosis in the treatment of MDD. The aim of the present study was to investigate gray matter abnormalities predicting antidepressant responsiveness and the relationships between volumetric differences and clinical/cognitive traits in MDD patients. METHODS Fifty MDD patients who received 8 week period antidepressant treatment and 29 healthy controls participated in this study. VBM was applied to assess structural changes between MDD groups and control group. Neuropsychological tests were conducted on all participants. RESULTS Both treatment responsive and non-responsive patients showed a significant volume reduction of the left insular, but only non-responsive patients had decreased volume in the right superior frontal gyrus compared to healthy controls. The comparison between treatment responsive and non-responsive patient groups demonstrated a significant difference in gray matter volume in the lingual gyrus. The larger volume of lingual gryus predicted early antidepressant response, which was attributable to better performance in neuropsychological tests. LIMITATION This study included a small sample size and the patients received various antidepressants and benzodiazepines. CONCLUSION Our findings suggest that the patients who responded poorly to antidepressants were morphologically and cognitively impaired, whereas the treatment responsive patients showed less structural changes and relatively preserved cognitive functions. The lingual gyrus may be a possible candidate region to predict antidepressant responsiveness and maintained cognition in MDD.

Imaging genetics studies on monoaminergic genes in major depressive disorder.

Although depression is the leading cause of disability worldwide, current understanding of the neurobiology of depression has failed to be translated into clinical practice. Major depressive disorder (MDD) pathogenesis is considered to be significantly influenced by multiple risk genes, however genetic effects are not simply expressed at a behavioral level. Therefore the concept of endophenotype has been applied in psychiatric genetics. Imaging genetics applies anatomical or functional imaging technologies as phenotypic assays to evaluate genetic variation and their impact on behavior. This paper attempts to provide a comprehensive review of available imaging genetics studies, including reports on genetic variants that have most frequently been linked to MDD, such as the monoaminergic genes (serotonin transporter gene, monoamine oxidase A gene, tryptophan hydroxylase-2 gene, serotonin receptor 1A gene and catechol-O-methyl transferase gene), with regard to key structures involved in emotion processing, such as the hippocampus, amygdala, anterior cingulate cortex and orbitofrontal cortex.

Brain-derived neurotrophic factor promoter methylation and cortical thickness in recurrent major depressive disorder.

Recent studies have reported that methylation of the brain-derived neurotrophic factor (BDNF) gene promoter is associated with major depressive disorder (MDD). This study aimed to investigate the association between cortical thickness and methylation of BDNF promoters as well as serum BDNF levels in MDD. The participants consisted of 65 patients with recurrent MDD and 65 age- and gender-matched healthy controls. Methylation of BDNF promoters and cortical thickness were compared between the groups. The right medial orbitofrontal, right lingual, right lateral occipital, left lateral orbitofrontal, left pars triangularis, and left lingual cortices were thinner in patients with MDD than in healthy controls. Among the MDD group, right pericalcarine, right medical orbitofrontal, right rostral middle frontal, right postcentral, right inferior temporal, right cuneus, right precuneus, left frontal pole, left superior frontal, left superior temporal, left rostral middle frontal and left lingual cortices had inverse correlations with methylation of BDNF promoters. Higher levels of BDNF promoter methylation may be closely associated with the reduced cortical thickness among patients with MDD. Serum BDNF levels were significantly lower in MDD, and showed an inverse relationship with BDNF methylation only in healthy controls. Particularly the prefrontal and occipital cortices seem to indicate key regions in which BDNF methylation has a significant effect on structure.

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.

The influence of stress on neuroinflammation and alterations in brain structure and function in major depressive disorder

&NA; Major depressive disorder (MDD) is a condition which has often been associated with chronic stress. The sympathetic nervous system is continuously activated without the normal counteraction of the parasympathetic nervous system under the influence of chronic stress. As a result, epinephrine and norepinephrine levels are increased, and acetylcholine levels are decreased, which in turn can increase the levels of pro‐inflammatory cytokines. Peripheral inflammatory responses can access the brain, with neuroinflammation contributing to the increase in neurotoxic kynurenine pathway metabolites such as 3‐hydroxykynurenine, 3‐hydroxyanthranilic acid and quinolinic acid, and decrease in neuroprotective metabolites such as kynurenic acid. Pro‐inflammatory cytokines can also exert direct neurotoxic effects on specific brain regions. Previous imaging studies have reported associations between pro‐inflammatory states and alterations in brain regions involved in emotional regulation, including the hippocampus, amygdala and anterior cingulate cortex. Alterations in structure and function of such brain areas due to the neurotoxic effects of increased inflammation may be associated with the pathophysiology of depression. This review focuses the influence of stress on neuroinflammation which may cause alterations in brain structure and function in MDD. HighlightsChronic stress can lead to increases in pro‐inflammatory cytokine levels.Inflammation leads to alterations in the ratio of kynurenine pathway metabolites.Pro‐inflammatory cytokines and kynurenine pathway metabolites can be neurotoxic.Neurotoxicity causes changes in the hippocampus, amygdala, and cingulate cortex.Alterations in brain regions are associated with the pathophysiology of depression.

Hippocampal subfield analysis in medication-naïve female patients with major depressive disorder

BACKGROUND Hippocampal volume loss is known as the best-replicated finding of structural brain imaging studies on major depressive disorder (MDD). Several evidences suggest localized mechanisms of hippocampal neuroplasticity lead the brain imaging studies on the hippocampus and MDD to perform analyses in the subfield level. The aim of this study was to investigate the differences in total and subfield hippocampal volumes, between medication-naïve female MDD patients and healthy controls, through automated segmentation and volumetric methods. METHODS Twenty medication-naïve female patients diagnosed with MDD and 21 age-matched healthy controls, underwent T1-weighted structural magnetic resonance scanning. Total volumes of both hippocampi and subfield regions were calculated by the automated procedure for volumetric measures implemented in FreeSurfer and automated segmentation method by Van Leemput et al. RESULTS We observed patients to have significantly smaller volumes of the left hippocampus, subiculum, cornu ammonis 2-3, cornu ammonis 4-dentate gyrus, and right subiculum compared to healthy controls. There were no significant predictors for these subfield region volumes among the illness burden-related parameters including duration of illness, number of depressive episodes, severity of depressive symptoms and memory performances. LIMITATIONS Our findings relied on the data of only female participants. CONCLUSIONS We found significant volume reductions in several hippocampal subfield regions in medication-naïve female MDD patients. Our results are consistent with neurobiological evidences on hippocampal neuroplasticity in MDD, and replicate previous findings that suggest morphologic changes of hippocampal subfields in MDD patients.

Stress, the Autonomic Nervous System, and the Immune-kynurenine Pathway in the Etiology of Depression.

The autonomic nervous system is one of the major neural pathways activated by stress. In situations that are often associated with chronic stress, such as major depressive disorder, the sympathetic nervous system can be continuously activated without the normal counteraction of the parasympathetic nervous system. As a result, the immune system can be activated with increased levels of pro-inflammatory cytokines. These inflammatory conditions have been repeatedly observed in depression. In the search for the mechanism by which the immune system might contribute to depression, the enhanced activity of indoleamine 2,3-dioxygenase by pro-inflammatory cytokines has been suggested to play an important role. Indoleamine 2,3-dioxygenase is the first enzyme in the kynurenine pathway that converts tryptophan to kynurenine. Elevated activity of this enzyme can cause imbalances in downstream kynurenine metabolites. This imbalance can induce neurotoxic changes in the brain and create a vulnerable glial-neuronal network, which may render the brain susceptible to depression. This review focuses on the interaction between stress, the autonomic nervous system and the immune system which can cause imbalances in the kynurenine pathway, which may ultimately lead to major depressive disorder.