Chuan-Chia Chang

Sex-specific association between nerve growth factor polymorphism and cardiac vagal modulation.

Objective Substantial research has shown that anxiety disorders are associated with decreased cardiac vagal tone, which is a known risk factor for cardiac vulnerability. A functional nerve growth factor (NGF) polymorphism (rs6330, c.104C > T, p.Ala35Val) has been associated with anxiety such that in males but not females, T-allele carriers exhibit higher levels of trait anxiety. Here we investigate whether the nonsynonymous NGF variant has an effect on cardiac autonomic control. Methods From 705 adults initially screened for medical and psychiatric illnesses, a final cohort of 580 healthy Han Chinese (352 men, 228 women; mean [standard deviation] age = 34.46 [8.45] years) was included in the NGF genotyping (C/C: 428% [73.8%] and T-allele carriers: 152% [26.2%]). Short-term heart rate variability was used to assess cardiac autonomic function. Results There were significant genotype-by-sex interaction effects (p < .05) on high-frequency power (HF) and root mean square of successive heartbeat interval differences (RMSSD), both indices of cardiac vagal control. Even after adjusting for possible confounders, men with any T allele showed lower HF and RMSSD compared with men with the C/C genotype. Women, however, showed an opposite but nonsignificant pattern. Conclusions The studied NGF polymorphism modulates autonomic outflow to the heart in a sex-dependent manner. The findings support the view that male T-allele carriers are at increased susceptibility for anxiety by association with low vagal activity and suggest a potential sex-specific genetic link between the highly comorbid anxiety disorders and cardiovascular diseases.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way

The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation.

Amelioration of pathological yawning after tracheostomy in a patient with locked-in syndrome.

A 66-year-old female with a past history of hypertension, who initially presented with four limbs weakness for a duration of 3 h, poor visual acuity, ataxia and slurred speech at ER and progressed to drowsiness, tetraplegia with episodes of unjustified excessive and repetitive yawning and acute respiratory failure within few hours. On admission, the patient was drowsy and showed a positive doll s eye sign and positive gag reflex. Her uvula and tongue deviated to the left and weakness of facial muscle caused drooling. The right upper and lower extremity strength were rated 3+/5 and 2+/5 separately. The left upper and lower extremity strength were rated 2+/5 and 0+/5 respectively. Deep tendon reflexes were enhanced and bilateral Babinski signs were present. A brain magnetic resonance imaging (MRI) scan showed an infarct in most parts of the pons and another small lesion in right medial occipital lobe appearing as increased signal intensity on DWI with corresponding low ADC. MRI showed total occlusion of the middle and distal thirds of basilar artery. Besides, the left posterior cerebral artery arose from the left internal carotid artery with focal stenosis at its proximal portion and there was an aneurysm about 3 mm in size located at the anterior communicating artery (Fig. 1). The patient developed acute respiratory failure and progress to flaccid tetraplegia several hours after admission. The frequency of excessive yawning persisted despite adequate sleep at night. An endotracheal tube was inserted as a prerequisite of subsequent ventilatory support. Several days later, she still had limitations

Association study of the norepinephrine transporter gene polymorphisms and bipolar disorder in Han Chinese population

Many studies have indicated that the norepinephrine transporter (NET) may play an important role in the mechanisms underlying affective disorders. Thus, the genes of the NET (SLC6A2) are good candidates for research on bipolar disorder (BPD). This study examined whether the NET gene is a susceptibility factor for the BPD in Han Chinese. A promoter −182 T/C polymorphism (rs 2242446) and the exonic polymorphism 1287 G/A (rs 5569) of the NET gene were analysed using a polymerase chain reaction (PCR)-based method in 261 BPD patients and 245 unrelated, age- and gender-matched controls. Furthermore, to reduce the clinical heterogeneity, we also carried out analysis in clinical subgroups of bipolar patients defined according to type I and type II BPD, presence or absence of family history of major affective disorders and the age at onset of BPD. No significant difference was found between either bipolar patients or its more homogeneous subgroups and healthy controls in the genotype and allele frequencies for the investigated NET polymorphisms. Our results suggest that the investigated polymorphisms of NET are not major risk factors responsible for predisposition to BPD or its clinical subtypes in Han Chinese. However, replication studies with larger different ethnic samples are needed.

Effects of REM sleep deprivation on sensorimotor gating and startle habituation in rats: Role of social isolation in early development

The present study examined the role of rapid eye movement (REM) sleep on sensorimotor gating function in a developmentally rodent model of schizophrenic-spectrum disorders. Startle magnitude, prepulse inhibition (PPI) and startle habituation in an acoustic startle test were measured after 72-h of REM sleep deprivation (REMSD) in 14-week-old rats that were reared in one of the following conditions: control social interaction, 2-week isolation, and continuous isolation, since weaning. The results showed that REMSD significantly inhibited rats PPI in socially controlled rats, and rats in two isolation groups appeared less sensitive to REMSD. After REMSD, startle habituation was significantly reduced in continuous-isolated rats but not in 2-week-isolated rats. These data indicate that REM sleep is essential for PPI; REMSD inhibits startle habituation in rats with continuous social isolation. In addition, social interaction, in early life or for the whole life, functions differently to the sensorimotor gating.

Serotonin 2A receptor (5-HT2A) gene promoter variant interacts with chronic perceived stress to modulate resting parasympathetic activity in humans

Decreased resting vagal (parasympathetic) tone is implicated in the development of stress-related disorders, including anxiety and depression. Chronic stress elevates the expression of serotonin 2A receptors (5-HT2A), while activation of 5-HT2A leads to inhibition of parasympathetic synaptic transmission. The T allele of the promoter variant, rs6311 (C>T), of the 5-HT2A gene has been shown to increase the 5-HT2A expression in vitro and to be associated with anxiety and depressive disorders. We thus hypothesized that the 5-HT2A functional polymorphism may influence resting vagal activity among persons with chronically high levels of perceived stress. A total of 1138 well-defined healthy, medication-free Han Chinese were included for 5-HT2A genotyping. The Perceived Stress Scale (PSS) was used to measure the level of perceived stress during the last month and participants were divided into low and high PSS groups. Resting-state heart rate variability (HRV) was used to assess autonomic function. No significant between-genotype difference was found in any HRV variable in the low PSS group (n=610). However, in the high PSS group (n=528), high frequency power and root mean square of successive heartbeat interval differences (both HRV indices of parasympathetic activity) were significantly reduced in T/T genotype carriers compared to C/C homozygotes. Our findings are the first to show that individuals homozygous for the high-expressing 5-HT2A (T) allele exhibit diminished resting vagal tone-an index of stress vulnerability-when experiencing chronically elevated levels of perceived stress. The present results may advance our understanding of the genetic mechanism underlying individual differences in susceptibility to stress.

Functional Ser205Leu polymorphism of the nerve growth factor receptor (NGFR) gene is associated with vagal autonomic dysregulation in humans.

Evidence indicates that reduced cardiac vagal (parasympathetic) tone, a robust cardiovascular risk factor, is a trait vulnerability marker of major depressive disorder (MDD). The Ser205/Ser205 genotype of the functional polymorphism (Ser205Leu) of the nerve growth factor receptor (NGFR), also called p75 neurotrophin receptor (p75NTR), gene is reported to increase the risk of MDD. Here, we hypothesized that the NGFR Ser205Leu polymorphism may have an effect on vagal control. A sample of 810 healthy, drug-free, unrelated Han Chinese (413 males, 397 females; mean age 35.17u2009±u20098.53 years) was included in the NGFR genotyping. Short-term heart rate variability (HRV) was used to assess vagus-mediated autonomic function. Potential HRV covariates, such as mood/anxiety status and serum metabolic parameters, were assessed. Homozygotes of the Ser205 allele had significantly lower high frequency power and root mean square of successive heartbeat interval differences, both HRV indices of vagal modulation, compared to Leu205 allele carriers. Even after adjusting for relevant confounders, these associations remained significant. Further stratification by sex revealed that the associations were observed only in males. Our results implicate that decreased parasympathetic activity is associated with the NGFR Ser205/Ser205 genotype in a gender-specific manner, suggesting a potential role of NGFR polymorphism in modulating cardiac autonomic function.

Association of neuropeptide Y promoter polymorphism (rs16147) with perceived stress and cardiac vagal outflow in humans.

Neuropeptide Y (NPY) is involved in resilience to stress, and higher vagal (parasympathetic) activity has been associated with greater stress resilience. Thus, we examined whether rs16147, a functional promoter polymorphism (C>T) of the NPY gene, could influence vagal tone during chronic high stress levels. NPY genotyping, chronic psychological stress level measurement (using the Perceived Stress Scale [PSS]), cardiac autonomic function assessment (using short-term heart rate variability [HRV]) were performed in 1123 healthy, drug-free Han Chinese participants who were divided into low- and high-PSS groups. In the high-PSS group (nu2009=u2009522), the root mean square of successive heartbeat interval differences and high frequency power (both HRV indices of parasympathetic activity) were significantly increased in T/T homozygotes compared to C/C homozygotes. However, no significant between-genotype difference was found in any HRV variable in the low-PSS group (nu2009=u2009601). Our results are the first to demonstrate that functional NPY variation alters chronic stress-related vagal control, suggesting a potential parasympathetic role for NPY gene in stress regulation.

Gender-specific association between serotonin transporter polymorphisms (5-HTTLPR and rs25531) and neuroticism, anxiety and depression in well-defined healthy Han Chinese

BACKGROUNDnA tri-allelic serotonin transporter promoter polymorphism (5-HTTLPR/rs25531) more effectively determines the levels of transcriptional efficacy than that with the bi-allelic 5-HTTLPR polymorphism in vitro. Both are reportedly associated with personality traits of negative emotionality, but with conflicting findings. One explanation for this is that a gender difference may play a role in genetic contribution. Here, we hypothesized that the tri-allelic genotype of the serotonin transporter is more closely linked to neuroticism, an anxiety- and depression-related trait, than the bi-allelic variation, particularly in a gender-dependent way.nnnMETHODSnThe genotypes of the 5-HTTLPR and rs25531 loci were determined in 1139 well-defined physically and mentally healthy Han Chinese (550 men, 589 women; mean age 38.3±10.3 years). All participants completed the neuroticism measure of the short-form Maudsley Personality Inventory (MPI). The levels of anxiety and depression were assessed by the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory (BDI), respectively.nnnRESULTSnA significant tri-allelic genotype-by-gender interaction effect was found in the MPI-neuroticism measure. SS homozygotes were associated with higher neuroticism than L allele carriers in men. Also, both the BAI and BDI scores were higher in the SS homozygotic men. In the bi-allelic analyses, however, there was only an association between SS genotype and MPI-neuroticism in men.nnnLIMITATIONSnSub-analyses by gender-stratification may reduce the statistical power.nnnCONCLUSIONSnOur findings confirm that gender differences exist in the genetic contributions of the serotonin transporter in human neuroticism, and anxiety/depression. Our data provide further support for rs25531, strengthening the effects of 5-HTTLPR.

Increased Risk of Psychiatric Disorders in Allergic Diseases: A Nationwide, Population-Based, Cohort Study

Background/objective Allergic diseases, such as bronchial asthma, allergic rhinitis, atopic dermatitis, and psychiatric disorders, are major health issues. There have been reports that allergic diseases were associated with depression or anxiety disorders. This study aimed to investigate the association between these allergic diseases and the risk of developing overall psychiatric disorders in patients from Taiwan. Methods This cohort study used the database of the Taiwan National Health Insurance Program. A total of 186,588 enrolled patients, with 46,647 study subjects who had suffered from allergic diseases, and 139,941 controls matched for sex and age, from the Longitudinal Health Insurance Dataset of 2000–2015, were selected from a sub-dataset of the National Health Insurance Research Database. Fine and Gray’s competing risk model analysis was used to explore the hazard ratio (HR), and 95% confidence interval, for the risk of allergic diseases being associated with the risk of developing psychiatric disorders during the 15u2009years of follow-up. Results Of the study subjects, 5,038 (10.8%) developed psychiatric disorders when compared to 9,376 (6.7%) in the control group, with significant difference (pu2009<u20090.001). Fine and Gray’s competing risk model analysis revealed that the adjusted HR was 1.659 (95% CIu2009=u20091.602–1.717, pu2009<u20090.001). In this study, we found that the groups of atopic dermatitis alone and the allergic rhinitisu2009+u2009atopic dermatitis were associated with a lower risk of psychiatric disorders, but all the other four groups, such as bronchial asthma alone, allergic rhinitis alone, bronchial asthmau2009+u2009allergic rhinitis, bronchial asthmau2009+u2009atopic dermatitis, and the combination of all these three allergic diseases, were associated with a higher risk of psychiatric disorders. Conclusion Allergic diseases are therefore associated with a 1.66-fold increased hazard of psychiatric disorders in Taiwan.