Ho Kyoung Yoon

Demonstration of decreased gray matter concentration in the midbrain encompassing the dorsal raphe nucleus and the limbic subcortical regions in major depressive disorder: An optimized voxel-based morphometry study

BACKGROUND Previous neuroimaging studies in patients with major depressive disorder (MDD) have reported changes in several brain areas, such as the medial and dorsolateral orbital cortex, amygdala, hippocampus, and basal ganglia. However, the results of these studies are inconsistent, and relatively few studies have been conducted using voxel-based morphometry (VBM) to detect gray matter concentration (GMC) abnormalities in patients with MDD. METHODS We examined 47 MDD patients and 51 healthy controls to investigate structural abnormalities using a 1.5 T magnetic resonance imaging system, which was normalized to a customized T1 template and segmented with optimized VBM. Analysis of covariance with age and gender as covariates was adopted for the VBM statistics; the level of statistical significance was set at P<0.05 for the corrected false discovery rate. RESULTS Decreased GMC was found in MDD patients in the bilateral amygdalae, hippocampi, fusiform gyri, lingual gyri, insular gyri, middle-superior temporal gyri, thalami, cingulate gyri, the central lobule of the cerebellum, and the midbrain encompassing the dorsal raphe nuclei (DRN). LIMITATIONS Half of our study subjects were taking antidepressants. This may have been a potential confounding factor if any of the medications affected cortical volume. CONCLUSIONS The results suggest that the GMC of several regions associated with emotion regulation was lower in MDD patients. In particular, we found decreased GMC in the DRN. These findings may provide a better understanding of the anatomical properties of the neural mechanisms underlying the etiology of MDD.

TPH2 -703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression

BACKGROUND Serotonergic system-related genes can be good candidate genes for both major depressive disorder (MDD) and suicidal behavior. In this study, we aimed to investigate the association of serotonin 2A receptor gene -1438A/G SNP (HTR2A -1438A/G), tryptophan hydroxylase 2 gene -703G/T SNP (TPH2 -703G/T) and serotonin 1A receptor C-1019G (HTR1A C-1019G) with suicidal behavior. METHODS One hundred and eighty one suicidal depressed patients and 143 non-suicidal depressed patients who met DSM-IV criteria for major depressive disorder were recruited from patients who were admitted to Korea University Ansan Hospital. One hundred seventy six normal controls were healthy volunteers who were recruited by local advertisement. Patients and normal controls were genotyped for HTR2A -1438A/G, TPH2 -703G/T and 5-HT1A C-1019G. The suicidal depressed patients were evaluated by the lethality of individual suicide attempts using Weisman and Wordens risk-rescue rating (RRR) and the Lethality Suicide Attempt Rating Scale-updated (LSARS-II). In order to assess the severity of depressive symptoms of patients, Hamiltons Depression Rating Scale (HDRS) was administered. Genotype and allele frequencies were compared between groups by chi(2) statistics. Association of genotype of the candidate genes with the lethality of suicidal behavior was examined with ANOVA by comparing the mean scores of LSARS and RRR according to the genotype. RESULTS There were statistically significant differences in the genotype distributions and allele frequencies of TPH2 -703G/T between the suicidal depressive group and the normal control group. The homozygous allele G (G/G genotype) frequency was significantly higher in suicidal depressed patients than in controls. However, no differences in either genotype distribution or in allele frequencies of HTR2A -1438A/G and HTR1A C-1019G were observed between the suicidal depressed patients, the non-suicidal depressed patients, and the normal controls. There were no differences in the lethality of suicidal behavior in suicidal depressed patients according to the genotypes of three polymorphisms. CONCLUSION Our results suggest that TPH2 -703G/T SNP may have an important effect on susceptibility to suicidal behavior. Furthermore, an increased frequency of G allele of TPH2 SNP may be associated with elevated suicidal behavior itself rather than with the diagnosis of major depression and may increase risk of suicidality, independent of diagnosis.

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.

The association between serotonin-related gene polymorphisms and panic disorder

Dysfunction of the serotonergic system has been hypothesized to play an important role in panic disorder. We investigated the 5-HT2A receptor (5HTR2A) and tryptophan hydroxylase (TPH) genes for an association with panic disorder (PD). Patients with PD (n=107) and control subjects (n=161) were genotyped for 5HTR2A 1438A/G, 5HTR2A 102T/C, and TPH218 A/C. The severity of their symptoms was measured using the Spielberger State-Trait Anxiety Inventory (STAI), Panic Disorder Severity Scale (PDSS), Anxiety Sensitivity Index (ASI), Acute Panic Inventory (API), and Hamiltons Rating Scale for Depression (HAMD). There were no significant differences in the genotype distributions or allelic frequencies in the three serotonergic polymorphisms between PD patients and normal controls. However, we found a significant difference in symptom severity among the genotypes of both the 5HTR2A 1438A/G and 102T/C polymorphisms. Although there were no significant differences in the genotype and allele distributions, we found a significant association between panic symptom severity and the serotonin 2A receptor gene. This result suggests that 5HTR2A 1438A/G and 102T/C polymorphic regions can be associated with the phenotype or the pathogenesis of panic disorder.

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.

Role of cytokines in atypical depression

Background: Atypical depression (AD) is considered a biologically and psychologically distinct subtype of depression. AD, contrary to melancholic depression (MD), may have different alteration in cytokine activity. Aims: We aimed to investigate the differences of cytokine activity between AD patients and MD patients. Among psychiatric patients visited to the Psychiatry Department, Korea University Medical Center, 105 patients with major depression who met the Diagnostic and Statistical Manual (DSM-IV) criteria based on clinical interviews using a Structured Clinical Interview for DSM-IV were recruited. Among 105 patients, 35 patients had atypical feature. We measured in vitro cytokines (interleukins) IL-2, IL-4, IL-6 and tumor necrosis factor-α (TNF-α). Results: Decreased IL-4 and increased IL-2 was observed in AD patients. IL-6 and TNF-α level of AD patients showed no difference from the controls. Conclusions: Contrary to MD, AD has reversed vegetative symptoms, i.e. hypersomnia and hyperphagia. It is assumed that the phenotype difference between AD and MD might be related to Th1 cytokines (IL-2) and Th2 cytokines (IL-4) and not related to monocytic cytokines (IL-6, and TNF-α).

High insulin-like growth factor-1 in patients with bipolar I disorder: A trait marker?

OBJECTIVES Neurotrophic factors exert substantial effects on the central nervous system. The present study investigates the roles of insulin-like growth factor-1 (IGF-1), β-nerve growth factor (β-NGF), and brain-derived neurotrophic factor (BDNF) in bipolar disorder. METHODS Baseline levels of culture-stimulated IGF-1, β-NGF, and BDNF were compared in 116 patients with bipolar I disorder and 123 healthy controls. Neurotrophic factors were also compared in patients before and after 6 weeks of pharmacotherapy. A multivariate logistic regression analysis was used to investigate the influence of the neurotrophic factors analyzed in quartile form, in relation to confounding variables, such as age, sex, and body mass index. RESULTS IGF-1 was significantly higher in patients (mean=514.57, SD=259.78) than in healthy controls (mean=316.82, SD=270.00, p<0.0001) at baseline. Furthermore, higher levels of IGF-1 substantially increased the risk for bipolar I disorder. IGF-1 level was not significantly changed at 6-weeks (mean=506.41, SD=313.66). No changes in BDNF or β-NGF-1 levels were found following the 6-week treatment period. IGF-1 and β-NGF were negatively correlated in healthy controls, but not in patients. Severity of manic symptoms was not associated with any of the neurotrophic factors. LIMITATIONS We did not measure cortisol, growth hormone, or IGF-1 receptors. This study is cross-sectional in design. CONCLUSIONS Elevated IGF-1 levels may be a trait marker for bipolar disorder. Further studies are needed to thoroughly investigate the role of IGF-1 in relation to other neuroendocrine factors and biological markers for bipolar disorder.

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.

Effects of Korean Red Ginseng on Cognitive and Motor Function: A Double-blind, Randomized, Placebo-controlled Trial

Ginseng has a long history of use for health enhancement, and there is some evidence from animal studies that it has a beneficial effect on cognitive performance. The purpose of this study was to investigate the effect of Korean red ginseng on cognitive performance in humans. A total of 15 healthy young males with no psychiatric or cognitive problems were selected based on an interview with a board-certified psychiatrist. The subjects were randomly assigned to receive a daily dose of 4,500 mg red ginseng or placebo for a 2-week trial. There were 8 subjects in the red ginseng group and 7 subjects in the placebo group. All of the subjects were analyzed with the Vienna test system and a P300 event-related potential (ERP) test. There were no significant differences in the Vienna test system scores between the red ginseng group and the placebo group. In the event-related potential test, the C3 latency of the red ginseng group tended to decrease during the study period (p=0.005). After 2 wk, significant decreases were observed in the P300 latencies at Cz (p=0.008), C3 (p=0.005), C4 (p=0.002), and C mean (p=0.003) in the red ginseng group. Our results suggest that the decreased latency in ERP is associated with improved cognitive function. Further studies with a higher dosage of ginseng, a larger sample size, and a longer follow-up period are necessary to confirm the clinical efficacy of Korean red ginseng.

Exposure to dim artificial light at night increases REM sleep and awakenings in humans

ABSTRACT Exposure to artificial light at night (ALAN) has become increasing common, especially in developed countries. We investigated the effect of dALAN exposure during sleep in healthy young male subjects. A total of 30 healthy young male volunteers from 21 to 29 years old were recruited for the study. They were randomly divided into two groups depending on light intensity (Group A: 5 lux and Group B: 10 lux). After a quality control process, 23 healthy subjects were included in the study (Group A: 11 subjects, Group B: 12 subjects). Subjects underwent an NPSG session with no light (Night 1) followed by an NPSG session randomly assigned to two different dim light conditions (5 or 10 lux, dom λ: 501.4 nm) for a whole night (Night 2). We found significant sleep structural differences between Nights 1 and 2, but no difference between Groups A and B. Exposure to dALAN during sleep was significantly associated with increased wake time after sleep onset (WASO; F = 7.273, p = 0.014), increased Stage N1 (F = 4.524, p = 0.045), decreased Stage N2 (F = 9.49, p = 0.006), increased Stage R (F = 6.698, p = 0.017) and non-significantly decreased REM density (F = 4.102, p = 0.056). We found that dALAN during sleep affects sleep structure. Exposure to dALAN during sleep increases the frequency of arousals, amount of shallow sleep and amount of REM sleep. This suggests adverse effects of dALAN during sleep on sleep quality and suggests the need to avoid exposure to dALAN during sleep.