Harumi Oshita

Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

Background Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. Methods To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). Results A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. Conclusion These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic–pituitary–adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

Genetic association of the transcription of neuroplasticity-related genes and variation in stress-coping style.

Stress coping has been defined as the cognitive and behavioral efforts made to conquer, endure, or decrease external and internal demands and the conflicts between them. It has two main elements: the control or modification of the person–environment relationship causing the stress (i.e., problem‐focused coping) and/or regulation of stressful feelings (i.e., emotion‐focused coping). Research suggests that the expressions of brain‐derived neurotrophic factor (BDNF) and neurotrophic tyrosine kinase receptor type 2 (NTRK2) play important roles in brain adaptation to investigate stress. To clarify the genetic basis of stress coping, we investigated the association of stress‐coping strategies and social adaptation with single‐nucleotide polymorphisms (SNPs) involved in neural plasticity, anxiety, and depression.

FKBP5 is associated with amygdala volume in the human brain and mood state: A voxel-based morphometry (VBM) study

Abstract The present study was to investigate the effects of 6 FK506 binding protein 51 (FKBP5) single nucleotide polymorphisms (SNPs) on brain structure using voxel-based morphometry (VBM) and the psychological tests to psychological stress. We genotyped 112 healthy controls with respect to 6 SNPs (rs) of FKBP5. We examined the Beck Depression Inventory and the State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory and the Profile of Mood States (POMS) to evaluate mood. The right amygdala was larger in subjects with the minor allele (C) of rs3800373 and rs992105 and the minor allele (T) of rs1360780. The right middle orbitofrontal region in those with the minor allele (C) of rs3800373 and the right inferior orbitofrontal region in those with the minor allele (T) of rs9470080 was larger. Both the amygdala volumes were associated significantly with FKBP5 SNPs. We found significant relationships between factors in POMS and the right and left amygdala and left insula. Our results suggest that FKBP5 SNPs are associated with the alternations of volumes in right amygdala and the right middle and inferior orbitofrontal region. Genetic variants of FKBP5 may be associated with depressive and anxiety state via differential effects on amygdala and orbitofrontal region.

Gender determines cortisol and alpha-amylase responses to acute physical and psychosocial stress in patients with borderline personality disorder

Borderline personality disorder (BPD) is characterized by affective instability, unstable relationships, and identity disturbance. We measured salivary alpha-amylase (sAA) and salivary cortisol levels in all participants during exposure to the Trier Social Stress Test (TSST) and an electric stimulation stress. Seventy-two BPD patients were compared with 377 age- and gender- matched controls. The State and Trait versions of the Spielberger Anxiety Inventory test (STAI-S and STAI-T, respectively), the Profile of Mood State (POMS) tests, and the Beck Depression Inventory (BDI), the Depression and Anxiety Cognition Scale (DACS) were administered to participants before electrical stimulation. Following TSST exposure, salivary cortisol levels significantly decreased in female patients and significantly increased in male patients compared with controls. POMS tension-anxiety, depression-dejection, anger-hostility, fatigue, and confusion scores were significantly increased in BPD patients compared with controls. In contrast, vigor scores were significantly decreased in BPD patients relative to controls. Furthermore, STAI-T and STAI-S anxiety scores and BDI scores were significantly increased in BPD patient compared with controls. DACS scores were significantly increased in BPD patient compared with controls. Different stressors (e.g., psychological or physical) induced different responses in the HPA and SAM systems in female or male BPD patients.

Genetic association of the oxytocin receptor genes with panic, major depressive disorder, and social anxiety disorder

Oxytocin (OXT) is secreted into the brain through the pituitary gland. It stimulates neurons expressing oxytocin receptors (OXTR) and controls multiple physiologic and reproductive functions. OXT plays a role in the modification of stress response and stress-related behaviors (Arletti and Bertolini, 1987). OXT also plays an important role in anxiety and social interaction. Serum OXT level is related to parent–child bonding behavior, romantic feelings, and trust (Feldman et al., 2007). The individuals with the A allele (AG/AA) showed lower empathy and higher stress reactivity compared with the individuals who were homozygous for the G allele (GG) in humans (Rodrigues et al., 2009). The girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety (Thompson et al., 2011). The objective of this study was to investigate the relationship between polymorphisms of OXTR rs2254298 and rs53576 and panic disorder, social anxiety disorder, and major depressive disorder risk through a case–control study of 1257 Japanese participants. The patient and the control group comprised 643 controls and 210 panic disorder, 117 social anxiety disorder, 287 major depressive disorder patients diagnosed according to the criteria of Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) (the MiniInternational Neuropsychiatric Interview). This study was approved by the Ethics Committee for Genome Research of the Oita University Faculty of Medicine. All participants provided written informed consent. The proportion of AA, AG, and GG of rs2254298 in panic disorder, social anxiety disorder, and major depressive disorder healthy individuals was 8.7, 30.1, 61.2%; 14.5, 38.5, 47.0%; 15.4, 39.0, 45.6%; and 11.3, 39.8, 48.9%, respectively. The proportion of AA, AG, and GG of rs53576 was 41.3, 44.6, 14.1%; 43.6, 42.7, 13.7%; 42.0, 51.4, 6.6%; and 43.5, 48.0, 8.5%, respectively. The frequencies of the genotypes did not fit the Hardy– Weinberg equilibrium. The presence of the AA+AG genotype of rs2254298 in panic disorder had a protective effect compared with the GG genotype [odds ratio (OR)=1.6 (1.2–2.3), P=0.002]. The presence of the AA+AG genotype of rs53576 in panic disorder had a protective effect compared with the GG genotype [OR=1.8 (1.1–2.8), P=0.02]. The presence of the AA+AG genotype of rs53576 was associated with increased major depressive disorder risk compared with the GG genotype [OR=0.3 (0.2–0.4), P<0.0001]. However, there was no association between rs2254298 and major depressive disorder [OR=0.9 (0.7–1.2), P=0.36]. There was no association between OXTR rs2254298 and rs53576, and social anxiety disorder [OR=0.9 (0.6–1.4), P=0.71; OR=0.8 (0.4–1.3), P=0.34]. Some reports showed that there was a positive association between the GG genotype of OXTR rs53576 and major depressive disorder (Costa et al., 2009). However, there are no reports on the association between OXTR genotype and social anxiety disorder. Some reports showed that there was a significant relationship between OXTR and panic disorder (Johnson et al., 2010). Our data suggest that G carriers of the OXTR thus might have been more vulnerable to panic and major depressive disorder.

Near-Infrared Spectroscopy during the Verbal Fluency Task before and after Treatment with Image Exposure and SSRI Therapy in Patients with Obsessive-Compulsive Disorder

Drug therapy with selective serotonin reuptake inhibitors (SSRIs) has been used as a treatment for obsessive-compulsive disorder (OCD). In the present case report, exposure therapy was used in addition to escitalopram (20 mg) to treat a 28-year-old female patient with OCD for 6 months. Her obsessive-compulsive symptoms comprised thoughts of words such as rape, crematorium, neck hanging, unhappy, death, die, and kill and images such as a shelf of gods, a shrine, a Buddhist altar, the sun, the sky, and the faces of her parents, siblings, and relatives. As exposure therapy, she was asked to view the images associated with these symptoms three times a day along with drug therapy. With the combination of drug and exposure therapies, her obsessive-compulsive symptoms improved within 6 months, with no interference in her daily life. Multichannel near-infrared spectroscopy (NIRS) showed improvement of brain function in the temporal and frontal lobes after treatment. These results suggest that NIRS can be used as an indicator of brain function improvement in patients with OCD.

Different functioning of prefrontal cortex predicts treatment response after a selective serotonin reuptake inhibitor treatment in patients with major depression

BACKGROUND Major depressive disorder (MDD) is often resistant to treatment with usual approaches. Patients with MDD have shown hypofunction of the frontotemporal cortex in verbal fluency test (VFT)-related near-infrared spectroscopy (NIRS). METHODS We examined whether the reactions to drug treatment in treatment-naive patients with MDD could be predicted by NIRS outcomes at the initial investigation. All subjects underwent psychological testing to determine levels of anxiety and depression. VFT was used to examine the functioning of the frontotemporal lobes. We administered selective serotonin reuptake inhibitors (SSRIs) for 12 weeks. Subjects included 28 patients with MDD with response to SSRIs (Response group), 19 with no response (Non-Response group), and 63 age-, sex-, and education years-matched healthy controls (HC). RESULTS We found in the frontotemporal region that hemodynamic responses were significantly smaller in patients with Response and Non-Response groups than in HC before treatment. We also found in the medial frontal region that hemodynamic responses were significantly larger in patients with Response groups than in patients with Non-Response group before treatment. Patients with MDD scored significantly higher anxiety and depressive states than those in HC on several measures. The Response and Non-Response groups also had higher scores in future denial, threat prediction, self-denial, past denial, and interpersonal threat sections of Anxiety Cognition Scale (DACS). According to the stepwise regression analysis, one variable was determined as independent predictors of response: confusion (Post-POMS). LIMITATIONS The number of patients and healthy controls was relatively small, and we will increase the number of participants in future studies. NIRS has reduced spatial resolution, which confuses the identification of the measurement position when using NIRS alone. CONCLUSION Cognitive vulnerabilities are associated with predictors of SSRI treatment response. Different hemodynamic activities in the frontotemporal cortex predict response to SSRI treatment in MDD.

Hyperfunction of left lateral prefrontal cortex and automatic thoughts in social anxiety disorder: A near-infrared spectroscopy study

BACKGROUND Patients with social anxiety disorder (SAD) experience unusual fear in normal social situations. The verbal fluency task (VFT) was administered while subjects were undergoing near-infrared spectroscopy (NIRS) scanning. The purpose of VFT was to examine the functions of the frontal and temporal lobes. METHODS Subjects included 145 drug-naïve patients with SAD and 152 healthy controls (HCs). All subjects underwent psychological testing to determine levels of anxiety and depression and to evaluate cognition. RESULTS The scores of patients with SAD indicated significantly higher anxiety and depressive states than those in HCs on several measures: Leibowitz Social Anxiety Scale (LSAS), Profile of Mood States (POMS), Spielberger Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Social Adaptation Self-evaluation Scale (SASS). The patients with SAD also had higher scores on the future denial, threat prediction, self-denial, past denial, and interpersonal threat sections of the Depression and Anxiety Cognition Scale (DACS). NIRS scanning revealed hyperactivity in the left frontal cortex of patients with SAD. Threat prediction scores on DACS were negatively correlated with oxy-Hb responses in the right frontal cortex. LIMITATIONS Further studies with a larger sample size are required to verify our findings. CONCLUSIONS The results of this study demonstrate the different mechanisms of the right and left frontal cortex in situations of social anxiety disorder.

Sex determines cortisol and alpha-amylase responses to acute physical and psychosocial stress in patients with avoidant personality disorder

Avoidant personality disorder (AVPD) has excessive and pervasive anxiety and discomfort in social situations. The aims of this study were to explore the relationship between AVPD and physical and psychological stress and psychological tests.

Reduced white matter integrity in borderline personality disorder: A diffusion tensor imaging study

BACKGROUND Borderline personality disorder (BPD) has a pervasive pattern of instability in interpersonal relationships, self-image, and emotions. BPD may be linked to an abnormal brain anatomy, but little is known about possible impairments of the white matter microstructure in BPD or their relationship with impulsivity or risky behaviors. The aims of the present study were to explore the relationship between BPD and diffusion tensor imaging (DTI) parameters and psychological tests. METHODS We evaluated 35 un-medicated BPD patients in a medication-free state and 50 healthy controls (HCs). We performed DTI tractography in BPD patients and HCs. The Childhood Trauma Questionnaire (CTQ), Profile of Mood State (POMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Social Adaptation Self-Evaluation Scale (SASS), and Depression and Anxiety Cognition Scale (DACS) were administered to BPD patients and HCs. RESULTS A tract-based spatial statistics (TBSS) revealed that the BPD group had three clusters with a significantly lower axial diffusivity (AD) than the HC group: one located mainly in the cingulum and the other mainly in the inferior front-occipital fasciculus and inferior longitudinal fasciculus. Regarding the AD values, one cluster correlated negatively and significantly with POMS (Depression) and it was located in the cingulum, while another cluster correlated positively and significantly with DACS (Future Denial) and it was located in the inferior front-occipital fasciculus (IFOF). LIMITATIONS The small sample size of this study prevents us from forming any definitive conclusions, meaning that more studies are needed to confirm our findings. We are unable to generalize our findings to include other ethnic groups. CONCLUSIONS Our results suggested that hypo-metabolism in a front-limbic network dysfunction is characterized by the cingulum and a front-occipital network dysfunction characterized by the occipital lobe, while an occipital-temporal network dysfunction characterized by the inferior longitudinal fasciculus.