Thalamocortical functional connectivity in patients with insomnia using resting-state fMRI.

BACKGROUND: Insomnia is a common disorder that affects a vast number of patients; the hyperarousal theory of insomnia postulates that patients with insomnia are physiologically activated not only at nighttime but also during the daytime. We aimed to investigate the differences in the resting-state functional connectivity (RSFC) of the thalamus with cortical areas between patients with insomnia disorder and healthy controls. METHODS: All participants completed clinical questionnaires and underwent portable polysomnography and resting-state fMRI. RESULTS: Patients in the insomnia group (n = 50) showed increased RSFC between the thalamus and right medial superior frontal area, bilateral middle temporal areas, left rectus and right parahippocampal areas compared with controls (n = 42) after controlling for age, sex and education level. Among the pairs that showed increased connectivity, several functional connections were negatively correlated with sleep efficiency, measured by polysomnography.Limitations: We used a small sample size. CONCLUSION: We consider these results on increased thalamocortical hyperactivity in brain areas related to sensory functions as providing evidence for the hyperarousal theory of insomnia.

Associations between Melatonin, Neuroinflammation, and Brain Alterations in Depression.

Pro-inflammatory systemic conditions that can cause neuroinflammation and subsequent alterations in brain regions involved in emotional regulation have been suggested as an underlying mechanism for the pathophysiology of major depressive disorder (MDD). A prominent feature of MDD is disruption of circadian rhythms, of which melatonin is considered a key moderator, and alterations in the melatonin system have been implicated in MDD. Melatonin is involved in immune system regulation and has been shown to possess anti-inflammatory properties in inflammatory conditions, through both immunological and non-immunological actions. Melatonin has been suggested as a highly cytoprotective and neuroprotective substance and shown to stimulate all stages of neuroplasticity in animal models. The ability of melatonin to suppress inflammatory responses through immunological and non-immunological actions, thus influencing neuroinflammation and neurotoxicity, along with subsequent alterations in brain regions that are implicated in depression, can be demonstrated by the antidepressant-like effects of melatonin. Further studies that investigate the associations between melatonin, immune markers, and alterations in the brain structure and function in patients with depression could identify potential MDD biomarkers.

Neuroinflammation-Associated Alterations of the Brain as Potential Neural Biomarkers in Anxiety Disorders.

Stress-induced changes in the immune system, which lead to neuroinflammation and consequent brain alterations, have been suggested as possible neurobiological substrates of anxiety disorders, with previous literature predominantly focusing on panic disorder, agoraphobia, and generalized anxiety disorder, among the anxiety disorders. Anxiety disorders have frequently been associated with chronic stress, with chronically stressful situations being reported to precipitate the onset of anxiety disorders. Also, chronic stress has been reported to lead to hypothalamic-pituitary-adrenal axis and autonomic nervous system disruption, which may in turn induce systemic proinflammatory conditions. Preliminary evidence suggests anxiety disorders are also associated with increased inflammation. Systemic inflammation can access the brain, and enhance pro-inflammatory cytokine levels that have been shown to precipitate direct and indirect neurotoxic effects. Prefrontal and limbic structures are widely reported to be influenced by neuroinflammatory conditions. In concordance with these findings, various imaging studies on panic disorder, agoraphobia, and generalized anxiety disorder have reported alterations in structure, function, and connectivity of prefrontal and limbic structures. Further research is needed on the use of inflammatory markers and brain imaging in the early diagnosis of anxiety disorders, along with the possible efficacy of anti-inflammatory interventions on the prevention and treatment of anxiety disorders.

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. © 2016 Wiley Periodicals, Inc.

An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms.

Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be the treatment of choice for acute manic, mixed and depressive episodes of BD, along with long-term prophylaxis. Lithium's specific mechanism of action in mood regulation is progressively being clarified, such as the direct inhibition on glycogen synthase kinase 3ß, and its various effects on neurotrophic factors, neurotransmitters, oxidative metabolism, apoptosis, second messenger systems, and biological systems are also being revealed. Furthermore, lithium has been proposed to exert its treatment effects through mechanisms associated with neuronal plasticity. In this review, we have overviewed the clinical aspects of lithium use for BD, and have focused on the neuroprotective and neurotrophic effects of lithium.

Regional cortical thinning of the orbitofrontal cortex in medication-naïve female patients with major depressive disorder is not associated with MAOA-uVNTR polymorphism.

BACKGROUND: Orbitofrontal cortex alterations have been suggested to underlie the impaired mood regulation in depression. MAOA-uVNTR (monoamine oxidase A-upstream variable number of tandem repeats) polymorphism has been reported to be associated with major depressive disorder by various studies. The influence of MAOA-uVNTR genotype on function and structure of the orbitofrontal cortex has previously been reported. In this study, we investigated the difference in orbitofrontal cortex thickness between medication-naïve female patients with major depressive disorder and healthy controls, and the influence of MAOA-uVNTR genotype on orbitofrontal cortex thickness in depression. METHODS: Thirty-one patients with major depressive disorder and 43 healthy controls were included. All participants were subjected to T1-weighted structural magnetic resonance imaging and genotyped for MAOA-uVNTR polymorphism. An automated procedure of FreeSurfer was used to analyze difference in orbitofrontal cortex thickness. RESULTS: Patients showed a significantly thinner left orbitofrontal cortex (F(1,71) = 7.941, p = 0.006) and right orbitofrontal cortex (F(1,71) = 17.447, p < 0.001). For the orbitofrontal cortex sub-region analysis, patients showed a significantly thinner left medial orbitofrontal cortex (F(1,71) = 8.117, p = 0.006), right medial orbitofrontal cortex (F(1,71) = 21.795, p < 0.001) and right lateral orbitofrontal cortex (F(1,71) = 9.932, p = 0.002) compared to healthy controls. No significant interaction of diagnosis and MAOA-uVNTR genotype on orbitofrontal cortex thickness was revealed. CONCLUSIONS: Our results suggest that structural alterations of the orbitofrontal cortex may be associated with the pathophysiology of major depressive disorder. Future studies with larger sample sizes are needed to detect a possible association between MAOA-uVNTR genotype and orbitofrontal cortex thickness in depression.

Escitalopram efficacy in depression: a cross-ethnicity examination of the serotonin transporter promoter polymorphism.

Current evidence suggests that polymorphism in the serotonin transporter gene (5-HTTLPR) predicts antidepressant efficacy in whites but less so in Asians. However, it is not clear whether this effect can be observed for specific types of antidepressant drugs. White (n = 47) and Korean (n = 118) participants with major depressive disorder were treated with escitalopram and assessed over 8 weeks. Among those with the l/l but not l/s or s/s genotypes, whites had greater depression score reductions, response rates, and remission rates compared with Koreans. Our results suggest that 5-HTTLPR predicts escitalopram efficacy in an ethnicity-dependent manner.

Serotonin-related polymorphisms in TPH1 and HTR5A genes are not associated with escitalopram treatment response in Korean patients with major depression.

BACKGROUND/AIMS: The genetic variations in serotonin-related genes may be associated with antidepressant treatment response in major depressive disorder (MDD). The tryptophan hydroxylase-1 (TPH1) gene and serotonin 5A receptor (HTR5A) gene are known to be involved in serotonin biosynthesis and signal transduction, respectively. The purpose of this study was to investigate a possible interaction between the TPH1 gene and the HTR5A gene in the treatment outcome of escitalopram in MDD. METHODS: In total, 245 patients diagnosed with MDD were recruited, and their symptoms were evaluated using the 17-item Hamilton Depression Rating scale (HAMD-17). The association between the TPH1 218A/C and HTR5A 12A/T polymorphisms and the clinical outcomes (remission, response and changes in HAMD-17 score) was investigated after 2, 4 and 8 weeks of escitalopram treatment using multiple logistic regression or multiple linear regression analysis. RESULTS: No significant associations of TPH1 or HTR5A gene polymorphisms were observed with either response rate or remission rate at 2, 4 and 8 weeks after escitalopram treatment. In addition, the gene-gene interaction between TPH1 and HTR5A genes was not associated with the treatment outcome. CONCLUSIONS: Our results suggest that TPH1 218A/C and HTR5A 12A/T polymorphisms cannot predict treatment response in major depression.

Evidence-based, pharmacological treatment guideline for depression in Korea, revised edition.

This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition'. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.

Association between serotonin transporter-linked polymorphic region and escitalopram antidepressant treatment response in Korean patients with major depressive disorder.

OBJECTIVE: Various studies have shown that short (s)/long (l) polymorphisms of the serotonin transporter-linked polymorphic region (5-HTTLPR) might predict treatment outcome to selective serotonin reuptake inhibitors. The purpose of this study was to evaluate the association between 5-HTTLPR and clinical response to escitalopram treatment in Korean subjects with major depressive disorder. METHODS: One hundred and fifteen Korean patients diagnosed with major depressive disorder were evaluated during 8 weeks of escitalopram treatment at a dose of 5-20 mg/day. Patients were genotyped for 5-HTTLPR using polymerase chain reaction. Clinical symptoms were evaluated by the 21-item Hamilton Depression Rating (HAMD-21) scale during the 8 weeks of treatment. RESULTS: Therapeutic response to antidepressant escitalopram was better in s allele carriers (ss, sl) than in l allele homozygotes (ll) at 8 weeks of treatment (OR = 6.24, p = 0.026). The proportion of s allele carriers in responders was higher than that in non-responders (96.6 vs. 85.7%). The percentile decline in HAMD-21 in s allele carriers (59.86 ± 3.23%) was larger than that in HAMD-21 in l allele homozygotes (43.13 ± 11.49%; p = 0.029). However, 5-HTTLPR genotypes were not significantly associated with remission (p > 0.05). CONCLUSIONS: Our results show that treatment response to escitalopram at 8 weeks was moderated by 5-HTTLPR, with better response rates for s allele carriers than for l allele homozygotes. Although the role of 5-HTTLPR as a definite predictor of selective serotonin reuptake inhibitor treatment response cannot be confirmed from current results, they do suggest a trend for better response in s allele carriers.

Association between work-family conflict and depressive symptoms in female workers: An exploration of potential moderators.

Work-family conflict (WFC), an inter-role conflict between work and family, negatively affects mental health. Using a nationally representative systematic sample, this study aimed to investigate the association between WFC, depressive symptoms, and potential moderators in the association of adult female workers. Data of 4714 female workers (aged ≥19 years) were obtained cross-sectionally from the 2018 nationwide Korean Longitudinal Survey of Women and Families (KLoWF). WFC was assessed using a 7-item questionnaire, based on which scores were classified into high (>75th percentile score) and low (≤75th percentile score) levels of WFC. Significant depressive symptoms were defined as a score of ≥10 on the 10-item version of the Center for Epidemiologic Studies for Depression Scale. Female workers with high WFC levels were more likely to have depressive symptoms than those with low WFC levels (odds ratio = 2.29, 95% confidence interval = 1.91-2.74). In stratified analyses, high WFC levels were associated with the highest odds of depressive symptoms in the following groups: young adults (19-39 years), those with a college degree or above or with high income, never-married individuals, those with a family size of three or a single child, nonstandard workers, and pink-collar workers. This study replicated and extended previous findings on the association between WFC and depressive symptoms. The association was moderated by age, education and income levels, marital status, family size, number of children, and job conditions.

Gender discrimination in workplace and depressive symptoms in female employees in South Korea.

BACKGROUND: Workplace gender discrimination (WGD) may have long-term negative impacts on female workers' mental health. We aimed to investigate the association between WGD and the prevalence of depressive symptoms using a nationally representative sample of female employees in South Korea. METHODS: Data of 3190 adult female employees were obtained from the 2018 nationwide Korean Longitudinal Survey of Women and Families. Women's perception of WGD was assessed using a 6-item questionnaire. Respondents were classified into high, medium, and low levels of WGD according to the 25th and 75th percentile scores. A score of ≥10 on the 10-item version of the Center for Epidemiologic Studies for Depression Scale was defined as having significant depressive symptoms. RESULTS: A high level of WGD was significantly associated with a higher odds ratio (OR) for depressive symptoms compared to the low level (OR = 1.87, 95% confidence interval = 1.45-2.41). In the subgroup analyses, high WGD levels were associated with the highest OR for depressive symptoms in the following subgroups: younger age (19-39 years), those with a college degree, non-standard workers, pink collar workers, those with a workplace size of 10-29 employees, those with high levels of job autonomy, or low levels of emotional labor. LIMITATIONS: Causal interpretation is limited owing to the study's cross-sectional design. CONCLUSIONS: A high level of perceived WGD was associated with depressive symptoms among female employees. Certain groups of female employees may be particularly vulnerable to the detrimental effects of WGD on depression.

Association between Uncinate Fasciculus Integrity and Agoraphobia Symptoms in Female Patients with Panic Disorder.

OBJECTIVE: Although neural correlates of sub-clinical agoraphobia (AG) symptoms have been previously suggested, only a few studies evaluating structural changes of the brain have been conducted in agoraphobic patients with panic disorder (PD). We investigated and compared white matter (WM) micro-structural alterations between PD patients with AG (PD ＋ AG) and those without AG (PD - AG). METHODS: Our study included 56 female PD patients, of which 25 were diagnosed with AG and 31 were diagnosed without AG. Diffusion tensor imaging was performed to investigate micro-structural changes in the WM tracts related to fronto-temporo-occipital areas (uncinate fasciculus, cingulum bundle, inferior longitudinal/fronto-occipital fasciculus, fornix column and body, and fornix/stria terminalis). All participants were subjected to the Anxiety Sensitivity Inventory-Revised (ASI-R), Beck Depression Inventory-II (BDI-II), and Albany Panic and Phobia questionnaires. RESULTS: The fractional anisotropy values of the right uncinate fasciculus in PD ＋ AG were significantly lower than that of PD - AG and showed significant correlations with BDI-II and ASI-R total scores. Mean diffusivity and radial diffusivity values of the right uncinate fasciculus were significantly higher in PD ＋ AG as compared to PD - AG. CONCLUSION: Our findings suggest that the uncinate fasciculus may be associated with AG symptoms in PD, possibly through demyelination. Our findings may contribute to the neurobiological evidence regarding the association between AG and WM structural changes in PD.

Higher Rightward Laterality of the Hippocampal Tail and Its Association with Early Trauma in Panic Disorder.

OBJECTIVE: Early trauma (ET) is widely recognized as a contributing factor to the development of panic disorder (PD) in patients. However, there is a dearth of research on the specific volumes of hippocampal subregions and their laterality with respect to ET and PD. METHODS: A total of 30 subjects with PD and 30 age- and sex-matched healthy controls (HCs) were included in this study. All the subjects were evaluated by 3T-magnetic resonance imaging. FreeSurfer version 6.0 was used for volumetric analysis of the hippocampal subregions and their laterality. A shortened version of the Early Trauma Inventory Self Report (ETISR) as well as Anxiety Sensitivity Inventory-Revised (ASI-R), and Panic Disorder Severity Scale were utilized for analysis. RESULTS: Multivariate analysis of variance showed that the volume of the right hippocampal tail and laterality indices (LIs) of the hippocampal body and tail were significantly larger in subjects with PD relative to HCs. The significance of the observations remained unchanged after multivariate analysis of covariance, controlling for age, sex, years of education, medication, depressive symptoms, and intracranial volume as covariates. The LIs of the hippocampal tails that showed a significant correlation to ETISR emotional and physical subscales were also associated with ASI-R for cardiovascular symptoms in PD. CONCLUSION: Our study displayed an increased rightward lateralization of the hippocampal tails in subjects with PD compared with HCs. This alteration in the brain, which was associated with early emotional and physical trauma, would negatively affect anxiety sensitivity to cardiovascular symptoms in subjects with PD.

A review on inflammatory cytokine-induced alterations of the brain as potential neural biomarkers in post-traumatic stress disorder.

The heterogeneity of post-traumatic stress disorder (PTSD) symptoms indicates that multiple neurobiological mechanisms underlie the pathophysiology of the condition. However, no generally accepted PTSD biomarkers in clinical practice currently exist. The sequential responses to recurrent and chronic stress by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) system are considered to play a significant role in the onset and progression of PTSD. Decreased activity of the HPA axis and parasympathetic nervous system, along with increased activity of the sympathetic nervous system, have been observed in PTSD, which may lead to increased levels of proinflammatory cytokines. Such heightened activity of the immune system may cause alterations in the structure and function of brain regions-for example, the amygdala, hippocampus, medial prefrontal cortex, anterior cingulate cortex, and insula-through changes in levels of serotonin and kynurenine pathway metabolites, and direct neurotoxic effects of cytokines. Although chronic inflammation-induced alterations in brain regions critical in controlling emotional behavior and fear regulation may represent a strong candidate biomarker of PTSD, future studies are necessary to further elucidate inflammation-associated neural biomarkers of PTSD. Continued research on therapeutic methods that involve the normalization of the HPA axis, ANS, and immune system is expected to contribute to the development of novel ways to treat PTSD.

Hippocampal subfield volumes in major depressive disorder and bipolar disorder.

BACKGROUND: The hippocampus is not a uniform structure, but rather consists of multiple, functionally specialized subfields. Few studies have explored hippocampal subfield volume difference in the same sample of major depressive disorder (MDD) and bipolar disorder (BD) cases. We aimed to investigate the difference of hippocampal subfield volume between patents with MDD and BD and healthy controls (HCs). METHODS: A total of 102 MDD and 55 BD patients and 135 HCs were recruited and underwent T1-weighted image. Hippocampal subfield volume was calculated by automated segmentation and volumetric procedures developed by Iglesias et al. and implemented in FreeSurfer. Volume differences between the groups were analyzed using the analysis of covariance and controlling for age, sex, and total intracranial cavity volume. RESULTS: Patients with MDD had significantly reduced volumes in the bilateral cornu ammonis 1 (CA1), CA4, the granule cell layer (GCL), molecular layer (ML), whole hippocampus, the left CA2/3, and right presubiclum and subiculum. Patients with BD had significantly reduced volumes in the right CA1, GCL, and the whole hippocampus as compared to HCs. No significant volume differences were observed between the MDD and BD groups. Illness duration was negatively correlated with volumes of the left CA1, CA4, ML, presubiculum, subiculum, and the whole hippocampus in patients with BD. CONCLUSION: We observed hippocampal subfield volume reductions in both MDD and BD, a finding which more prominent in MDD. The inverse correlation between BD illness duration and hippocampal subfield volume may evidence the neuroprogressive nature of BD.

Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders.

BACKGROUND: Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. METHODS: We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). RESULTS: We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. LIMITATION: The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. CONCLUSION: This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.

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.

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.

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

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.