Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

Rare CRHR2 and GRM8 variants identified as candidate factors associated with eating disorders in Japanese patients by whole exome sequencing.

Eating disorders (EDs) are a type of psychiatric disorder characterized by pathological eating and related behavior and considered to be highly heritable. The purpose of this study was to explore rare variants expected to display biological functions associated with the etiology of EDs. We performed whole exome sequencing (WES) of affected sib-pairs corresponding to disease subtype through their lifetime and their parents. From those results, rare single nucleotide variants (SNVs) concordant with sib-pairs were extracted and estimated to be most deleterious in the examined families. Two non-synonymous SNVs located on corticotropin-releasing hormone receptor 2 (CRHR2) and glutamate metabotropic receptor 8 (GRM8) were identified as candidate disease susceptibility factors. The SNV of CRHR2 was included within the cholesterol binding motif of the transmembrane helix region, while the SNV of GRM8 was found to contribute to hydrogen bonds for an α-helix structure. CRHR2 plays important roles in the serotoninergic system of dorsal raphe nuclei, which is involved with feeding and stress-coping behavior, whereas GRM8 modulates glutamatergic neurotransmission. Moreover, GRM8 modulates glutamatergic neurotransmission, and is also considered to have effects on dopaminergic and adrenergic neurotransmission. Thus, identification of rare and deleterious variants in this study is expected to increase understanding and treatment of affected individuals. Further investigation regarding the biological function of these variants may provide an opportunity to elucidate the pathogenesis of EDs.

Pilot study of the relation between various dynamics of avatar experience and perceptual characteristics.

In recent years, due to the prevalence of virtual reality (VR) and human-computer interaction (HCI) research, along with the expectation that understanding the process of establishing sense of ownership, sense of agency, and limb heaviness (in this study, limb heaviness is replaced with comfort level) will contribute to the development of various medical rehabilitation, various studies have been actively conducted in these fields. Previous studies have indicated that each perceptual characteristics decrease in response to positive delay. However, it is still unclear how each perceptual characteristic changes in response to negative delay. Therefore, the purpose of this study was to deduce how changes occur in the perceptual characteristics when certain settings are manipulated using the avatar developed in this study. This study conducted experiments using an avatar system developed for this research that uses electromyography as the interface. Two separate experiments involved twelve participants: a preliminary experiment and a main experiment. As observed in the previous study, it was confirmed that each perceptual characteristics decreased for positive delay. In addition, the range of the preliminary experiment was insufficient for the purpose of this study, which was to confirm the perceptual characteristics for negative delay, thus confirming the validity of conducting this experiment. Meanwhile, the main experiment showed that the sense of ownership, sense of agency, and comfort level decreased gradually as delay time decreased, (i.e., this event is prior to action with intention, which could not be examined in the previous study). This suggests that control by the brain-machine interface is difficult to use when it is too fast. In addition, the distribution of the most strongly perceived settings in human perceptual characteristics was wider in regions with larger delays, suggesting this may lead to the evaluation of an internal model believed to exist in the human cerebellum. The avatar developed for this study may have the potential to create a new experimental paradigm for perceptual characteristics.

Physio-avatar EB: aftereffects in error learning with EMG manipulation of first-person avatar experience.

Introduction: Many studies have investigated the manipulation of a virtual upper arm using electromyogram (EMG); however, these studies primarily used a machine learning model or trigger control for this purpose. Furthermore, most of them could only display the constant motion of the virtual arm because the motion to be displayed was selected by pattern recognition or trigger control. In addition, these studies did not examine changes in the electromyographic signals after experiencing the virtual arm. By contrast, we propose a real-time, continuous, learning-free avatar that manipulates the virtual arm with electromyogram signals or physio-avatar EMG biofeedback (EB). The goal of the physio-avatar EB system is to induce physiological changes through experiential interactions. Methods: We explored the possibility of changing motor control strategies by applying the system to healthy individuals as a case study. An intervention method that provided an experience of a body different from one's own was conducted on seven participants using a time-invariant calculation algorithm to determine the joint angles of the avatar. Control strategies for an indicator of the equilibrium point in the baseline and adaptation phases were determined to evaluate the physio-avatar EB intervention effect. The similarity of these BL and adaptation control strategies compared to those used during the washout period was assessed using the coefficient of determination. The accuracy and reliability of the virtual reality (VR) system were evaluated by comparison with existing studies and the required specs. Results and Discussion: Changes in motor control strategies due to the physio-avatar EB system were observed in four experiments, where the participants gradually returned to their pre-intervention control strategies. This result can be attributed to the aftereffects caused by error learning. This implies that the developed system influenced their motor control strategies. The number of EMG acquisition bits was 16 bits, and the sampling rate was 1,000 Hz. The refresh rate of the head-mounted display was 90 Hz, and its resolution was 1440 × 1600 for a single eye. Additionally, the simulation frame rate was 30 FPS. These values were adequate compared to existing studies and required specs. The essential contribution of this study is the development of an avatar that is controlled by a different method than has been used in previous studies and the demonstration of changes in a subject's muscle activity after they experience an avatar. In the future, the clinical efficacy of the proposed system will be evaluated with actual patients.

A multi-center, randomized, parallel-group study to compare the efficacy of enhanced cognitive behavior therapy (CBT-E) with treatment as usual (TAU) for anorexia nervosa: study protocol.

BACKGROUND: The superiority of Enhanced Cognitive Behavior Therapy (CBT-E) with regard to weight gain and improvement of psychopathology of eating disorders for patients with anorexia nervosa (AN) over other psychotherapies and treatment as usual (TAU) has not been demonstrated in randomized controlled trials (RCTs). However, a previous RCT showed that patients with AN whose baseline body mass index (BMI) was less than 17.5 kg/m2 gained more weight when treated with CBT-E than with other psychotherapies. The aim of the study is to compare the efficacy of CBT-E and TAU for patients with AN. It was hypothesized that CBT-E would be superior to TAU, at least in terms of weight gain, as most patients with AN are likely to have a BMI lower than 17.5 kg/m2. METHODS/DESIGN: A randomized parallel-group multicenter trial will be conducted in three teaching hospitals in Japan between January 2023 and March 2026. Patients with DSM-5 AN, aged 16 years and older, with a BMI equal to or above 14.0 and below 18.5 will be eligible to participate. 56 patients will be randomly and evenly assigned to two intervention groups (CBT-E and TAU). Those assigned to CBT-E will be offered 25-40 sessions in accordance with their initial BMI. Patients assigned to TAU will have at least one session every 2 weeks, with the number of sessions and treatment period not fixed in advance. The primary outcome is BMI at 40 weeks after treatment initiation. The secondary outcomes are the results from the Japanese version of the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment questionnaire to measure eating disorder psychopathology and psychological impairment. The follow-up assessment will be performed 6 months after the 40-week assessment. DISCUSSION: This multi-center randomized controlled study will probably evaluate the efficacy of CBT-E compared with TAU for patients with more severe AN than in previous studies since Japanese patients are likely to have a lower BMI than those in Western countries. While it may be difficult to generalize the results of a study conducted in Japan, it would be valuable to clarify the efficacy of CBT-E as a treatment package. TRIAL REGISTRATION: UMIN, UMIN000048847. Registered 12 Sep 2022.

Economic costs for outpatient treatment of eating disorders in Japan.

BACKGROUND: Few studies have examined the economic costs of outpatient care for eating disorders in Japan. This study aimed to clarify the reimbursement for outpatient treatment of eating disorders and compare the costs between the departments of Psychosomatic Medicine and Psychiatry in Japan. METHOD: A multicenter, prospective, observational study of patients with an eating disorder was conducted in the Psychosomatic Medicine departments of three centers and the Psychiatry departments of another three centers in Japan. We analyzed medical reimbursement for an outpatient revisit, time of clinical interviews, and the treatment outcome measured by the Eating Disorder Examination Questionnaire (EDE-Q) global scores and body mass index (BMI) at 3 months. Multivariate linear regression models were performed to adjust for covariates. RESULTS: This study included 188 patients in the Psychosomatic Medicine departments and 68 in the Psychiatry departments. The average reimbursement cost for an outpatient revisit was 4670 yen. Even after controlling for covariates, the Psychosomatic Medicine departments had lower reimbursement points per minute of interviews than the Psychiatry departments (coefficient = - 23.86; 95% confidence interval = - 32.09 to - 15.63; P < 0.001). In contrast, EDE-Q global scores and BMI at 3 months were not significantly different between these departments. CONCLUSIONS: This study clarifies the economic costs of treating outpatients with eating disorders in Japan. The medical reimbursement points per interview minute were lower in Psychosomatic Medicine departments than in Psychiatry departments, while there were no apparent differences in the treatment outcomes. Addressing this issue is necessary to provide an adequate healthcare system for patients with eating disorders in Japan.

This study examined the cost of outpatient care for eating disorders in Japan, comparing treatment costs between the Psychosomatic Medicine and Psychiatry departments. The actual cost of outpatient care for eating disorders in Japan was clarified. The results indicate that Psychosomatic Medicine departments have lower reimbursement points per interview time compared to the Psychiatry departments, but there were no noticeable differences in treatment outcomes between the two. This highlights the need to address this cost difference to improve the healthcare system for patients with eating disorders in Japan.

No association of brain-derived neurotrophic factor Val66Met polymorphism with anorexia nervosa in Japanese.

The Met66 allele of the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has been reported to be associated with anorexia nervosa (AN), and also lower minimum body mass index (BMI) and higher harm avoidance in AN. We genotyped the Val66Met polymorphism (rs6265) in 689 AN cases and 573 control subjects. There were no significant differences in the genotype or allele frequencies of the Val66Met between AN and control subjects (allele wise, odds ratio = 0.920, 95% CI 0.785-1.079, P = 0.305). No difference was found in minimum BMIs related to Val66Met in AN (one-way ANOVA, P > 0.05). Harm avoidance scores on the Temperament and Character Inventory were lower in the Met66 allele carriers (P = 0.0074) contrary to the previous report. Thus we were unable to replicate the previous findings that the Met66 allele of the BDNF is associated with AN and that the minimum BMI is lower or the harm avoidance score is higher in AN patients with the Met66 allele.

Validity and reliability of the Japanese versions of cognitive and behavioral scales for irritable bowel syndrome.

BACKGROUND: The Cognitive Scale for Functional Bowel Disorders (CS-FBD) and Irritable Bowel Syndrome-Behavioral Responses Questionnaire (IBS-BRQ) are a useful measures to assess cognitive-behavioral aspects in individuals with IBS. This study aimed to confirm the reliability and validity of the Japanese versions of the CS-FBD (CS-FBD-J) and IBS-BRQ (IBS-BRQ-J). METHODS: Participants comprised 192 students and 22 outpatients diagnosed with irritable bowel syndrome (IBS). There were 76 students who met the diagnostic criteria for IBS and two students who received treatment for IBS. Participants completed questionnaires containing the CS-FBD-J, IBS Severity Index (IBS-SI), Visceral Sensitivity Index (VSI), 24-item Dysfunctional Attitudes Scale (DAS-24), Hospital Anxiety and Depression Scale (HADS), and Social Adaptation Self-evaluation Scale (SASS). RESULTS: Our exploratory factor analysis revealed that the CS-FBD-J had a unidimensional factor structure and that the factor loadings for two of the 25 items were less than 0.4. The IBS-BRQ-J had a two-factor structure, and the factor loadings for eight of the 26 items were less than 0.4. The confirmatory factor analysis for the 18-item version of IBS-BRQ-J showed that the model fit indices were not sufficient. The CS-FBD-J and IBS-BRQ-J had significant, moderate correlations with the IBS-SI and VSI in the IBS and control groups. Correlation between the DAS-24 and the CS-FBD-J was not significant. The CS-FBD-J and IBS-BRQ-J were significantly correlated to the HADS and SASS (IBS-BRQ-J) only in the IBS group. The scores of CS-FBD-J and IBS-BRQ-J showed significant group differences between the IBS patient group, non-patient IBS group, and control group. The internal consistencies of the CS-FBD-J and IBS-BRQ-J were high. The item-total correlation analysis for the CS-FBD-J and IBS-BRQ-J showed that the correlations between each item and the total score were significant. CONCLUSION: This study confirmed the reliability and validity of the 23-item version of the CS-FBS-J and the 18-item version of the IBS-BRQ-J with the deletion of items with low factor loadings. Regarding the IBS-BRQ-J, two factor structures were confirmed (factor 1: behavior obsessed with abdominal symptoms, factor 2: avoidance of abdominal symptoms and associated difficulties) although the model fit of the structure needs further study.

Functional polymorphism in the GPR55 gene is associated with anorexia nervosa.

Endocannabinoids, anandamide, and 2-arachidonoyl glycerol are involved in food intake and appetite. Although anandamide is now thought to be a ligand for vanilloid receptor, receptors that are targets of anandamide could play a similar role in eating behaviors and related disorders. This study therefore focused on the receptor, which is called G-protein-coupled receptor 55 (GPR55) that had recently been reported to have binding affinity for endocannabinoids. Functional analysis of the sole missense polymorphism, rs3749073 (Gly195Val) in the GPR55 gene was performed by detecting the phosphorylation level of extracellular signal-regulated kinase (ERK) in Chinese-Hamster-Ovary (CHO) cells engineered to express human GPR55. Val195 type GPR55 appeared to induce less phosphorylated ERK than Gly195 type GPR55 when CHO cells were treated with anandamide and lysophosphatidylinositol (LPI). An association between the functional Gly195Val polymorphism and anorexia nervosa was tested in a female Japanese population comprising 235 patients and 1244 controls. The Val195 allele and homozygote of the Val195 allele were more abundant in the group of patients diagnosed with anorexia nervosa (P = 0.023, Odds ratio = 1.31 (95% Cl = 1.03-1.37), P = 0.0048, OR = 2.41 (95% Cl = 1.34-4.34), respectively). In conclusion, the low-functioning Val195 allele of GPR55 appears to be a risk factor for anorexia nervosa.

Microstructure and Properties of SUS304 Stainless Steel Joints Brazed with Electrodeposited Ni-Cr-P Alloy Coatings.

In this study, an amorphous Ni-13.4Cr-11.6P (mass%) alloy coating with a thickness of 30 µm was deposited on the surface of SUS304 stainless steel as a brazing filler metal to conduct brazing. The differential thermal analysis measurements indicate that the electrodeposited Ni-13.4Cr-11.6P alloy has a melting point of approximately 892 °C, which is almost consistent with that of the commercial BNi-7 filler metal. The microstructure, shear strength, and fracture mode of the brazed joint were investigated using an electron probe X-ray microanalyzer, a scanning electron microscope, an optical microscope, and a universal testing machine. The results showed that the brazed filler metal is filled between the SUS304 stainless steel plates without any flaws in the brazed seam. The P-containing phases, i.e., the Cr-P rich phase and the (Ni,Fe)3P phase, were formed in the brazed seam. The shear strength of the brazed joint obtained in this study is 59.0 MPa. The fracture occurs in the brazed filler zone, where the brittle P-containing phases are present. Galvanic current measurement results showed that the brazed Ni-13.4Cr-11.6P alloy coating has a better corrosion resistance than that of the brazed Ni-11P alloy coating, which can be attributed to the formation of a large amount of Ni-Fe solid solution and Cr-P rich phase in the top layer of the brazed Ni-13.4Cr-11.6P alloy coating.

Correction: Liu et al. Microstructure and Properties of SUS304 Stainless Steel Joints Brazed with Electrodeposited Ni-Cr-P Alloy Coatings. Materials 2021, 14, 4216.

Error in Figure/Table [...].

Hybrid Cognitive Behavioral Therapy With Interoceptive Exposure for Irritable Bowel Syndrome: A Feasibility Study.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, which severely impairs the quality of life of patients. Treatment of refractory IBS patients is needed, but it is not yet widely available. Therefore, we previously developed a Japanese version of cognitive behavioral therapy with interoceptive exposure (CBT-IE) involving 10 face-to-face sessions to treat refractory IBS patients. To disseminate this treatment of IBS in places where therapists are limited, we further developed a hybrid CBT-IE program with complementary video materials that include psychoeducation and homework instructions so that patients can prepare for face-to-face sessions in advance at home and the session time can be shortened, thereby reducing the burden on both patient and therapist. In this study, we conducted a trial to evaluate the feasibility, efficacy, and safety of the hybrid CBT-IE program for Japanese IBS patients. The study was a single-arm, open-label pilot clinical trial. A total of 16 IBS patients were included in the study and 14 patients completed the intervention, which consisted of 10 weekly individual hybrid CBT-IE sessions. We performed an intention to treat analysis. The primary outcome measure for the efficacy of the intervention was a decrease in the severity of IBS symptoms. The feasibility and safety of the intervention were examined by the dropout rate and recording of adverse events, respectively. The dropout rate of the hybrid CBT-IE was comparable to that of our previous CBT-IE with only face-to-face sessions and no adverse events were recorded. The severity of IBS symptoms within-group was significantly decreased from the baseline to mid-treatment [Hedges' g = -0.98 (-1.54, -0.41)], post-treatment [Hedges' g = -1.48 (-2.09, -0.88)], 3-month follow-up [Hedges' g = -1.78 (-2.41, -1.14)], and 6-month follow-up [Hedges' g = -1.76 (-2.39, -1.13)]. Our results suggest that the hybrid CBT-IE is effective and could be conducted safely. To confirm the effectiveness of the hybrid CBT-IE, it is necessary to conduct a multicenter, parallel-design randomized control trial. Clinical Trial Registration: [https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041376], identifier [UMIN000036327].

Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive-behavioural therapy for eating disorders.

INTRODUCTION: Anorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality ratio of bulimia nervosa is 1.49; however, it is characterised by suicidality resulting in a shorter time to death. While there is no current validated drug treatment for eating disorders in Japan, cognitive-behavioural therapy (CBT) is a well-established and commonly used treatment. CBT is also recommended in the Japanese Guidelines for the Treatment of Eating Disorders (2012) and has been covered by insurance since 2018. However, the neural mechanisms responsible for the effect of CBT have not been elucidated, and the use of biomarkers such as neuroimaging data would be beneficial. METHODS AND ANALYSIS: The Eating Disorder Neuroimaging Initiative is a multisite prospective cohort study. We will longitudinally collect data from 72 patients with eating disorders (anorexia nervosa and bulimia nervosa) and 70 controls. Data will be collected at baseline, after 21-41 sessions of CBT and 12 months later. We will assess longitudinal changes in neural circuit function, clinical data, gene expression and psychological measures by therapeutic intervention and analyse the relationship among them using machine learning methods. ETHICS AND DISSEMINATION: The study was approved by The Ethical Committee of the National Center of Neurology and Psychiatry (A2019-072). We will obtain written informed consent from all patients who participate in the study after they had been fully informed about the study protocol. All imaging, demographic and clinical data are shared between the participating sites and will be made publicly available in 2024. TRIAL REGISTRATION NUMBER: UMIN000039841.

Urocortin 1: A putative excitatory neurotransmitter in the enteric nervous system.

BACKGROUND: Urocortin 1 (Ucn1), a stress-related peptide, is a member of the corticotropin-releasing factor (CRF) family and acts as a CRF1 receptor agonist. Ucn1 and CRF1 receptor immunoreactivity are present in the enteric nervous system (ENS), and Ucn1 elicits contraction of colonic muscle strips. Considering these findings, we have hypothesized that Ucn1 acts as an excitatory neurotransmitter in the ENS. The present study was conducted to determine whether exogenously applied Ucn1 causes contractions, whether it participates in neurally mediated contraction, and whether it is released from the ENS of the rat colon. METHODS: Isometric tension of the rat colonic muscle strips (middle to distal colon) in a longitudinal direction was measured. The effects of Ucn1 on phasic contractions were examined in the absence and presence of antalarmin (CRF1 receptor antagonist), tetrodotoxin (TTX), and atropine. The effects of antalarmin on electrical field stimulation (EFS)-induced contractions were examined in the absence and presence of atropine. Ucn1 peptide in the bath solution was measured after EFS using an EIA kit. KEY RESULTS: Ucn1 caused a significant and dose-dependent increase in phasic contractions. These effects were completely inhibited by antalarmin, TTX, and atropine. EFS-induced contractions were inhibited by antalarmin. Atropine markedly reduced EFS-induced contractions, and antalarmin did not decrease these contractions further. EFS elicited a significant increase in the concentration of Ucn1 in the bath solution, and this increase was completely inhibited by TTX. CONCLUSIONS AND INFERENCES: These results suggest that Ucn1 acts as an excitatory neurotransmitter in the ENS enhancing the cholinergic neurotransmission.

Effectiveness of enhanced cognitive behavior therapy for bulimia nervosa in Japan: a randomized controlled trial protocol.

BACKGROUND: The effectiveness of psychotherapeutic interventions for eating disorders (EDs) is widely studied in Europe, North America, and Australia/New Zealand. However, few controlled studies and no randomized controlled trials (RCTs) have been conducted in Japan despite the relatively high prevalence of EDs in the Japanese population. The aim of this study is to evaluate the effect of enhanced cognitive behavior therapy (CBT-E), an evidence-supported ED-focused form of cognitive behavior therapy (CBT), for the treatment of bulimia nervosa (BN) in Japan. METHODS/DESIGN: This multicenter RCT will compare CBT-E with treatment as usual (TAU), which is widely used in Japan. A group of 140 adult outpatients with a Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnosis of BN, ≥18 years of age, a body mass index (BMI) > 17.5 and < 40 kg/m2 will be randomly assigned to CBT-E or TAU. Participants will be stratified by intervention site and BN severity. CBT-E participants will receive 20 sessions of focused form CBT-E for 20 weeks. Those in the TAU group will receive routine treatment provided by specialists. Assessment will be performed in a blinded manner prior to the start of treatment, after 6 weeks of treatment, at the end of treatment (20 weeks), and at follow-up at 40 and 80 weeks after the start of treatment. The primary outcome is the remission of BN, defined by the absence, in the previous 4 weeks, of symptoms required to meet the DSM-5 criteria for a diagnosis of BN. Secondary outcomes include the levels of ED psychopathology and impairment due to the ED, anxiety, depression, family function, and satisfaction with treatment. DISCUSSION: This will be the first RCT conducted in Japan to compare CBT-E and TAU for the treatment of BN. If CBT-E is found to be more effective than TAU, then the evidence would support its wider use for patients with BN in Japan. Because it is possible to train therapists who do not possess extensive specialist experience, wider use is also likely to be practically feasible. In addition, demonstrating the effectiveness of CBT-E in Japan would demonstrate that it could be successfully extended to additional world cultures and regions. TRIAL REGISTRATION: UMIN, UMIN000031625. Registered 7 Mar 2018.

Identification of novel candidate loci for anorexia nervosa at 1q41 and 11q22 in Japanese by a genome-wide association analysis with microsatellite markers.

The Japanese Genetic Research Group for Eating Disorders (JGRED) is a multisite collaborative study group that was organized for the systematic recruitment of patients with an eating disorder for the purpose of genetic study in Japan. We conducted a genome-wide case-control association study using 23 465 highly polymorphic microsatellite (MS) markers to identify genomic loci related to anorexia nervosa (AN). Pooled DNA typing in two screening stages, followed by individual typing of 320 AN cases and 341 controls, allowed us to identify 10 MS markers to be associated with AN. To narrow down genomic regions responsible for the association of these MS markers, we further conducted a single-nucleotide polymorphism (SNP) association analysis for 7 of the 10 loci in 331 AN cases and 872 controls, which include the 320 AN cases and the 341 controls genotyped in the MS screening, respectively. Two loci, namely 1q41 and 11q22, remained significantly associated with AN in the SNP-based fine mapping, indicating the success in narrowing down susceptibility regions for AN. Neither of these loci showed a positive evidence of association with bulimia nervosa. The most significant association was observed at SNP rs2048332 (allelic P-value=0.00023) located at 3'-downstream of the SPATA17 gene on the 1q41 locus. The association analysis for MS-SNP haplotypes detected a statistically significant association (permutation P-value=0.00003) of the A-4-G-T haplotype that comprised four SNP/MS markers (rs6590474-D11S0268i-rs737582-rs7947224) on the 11q22 locus with AN. This linkage disequilibrium block spanning a 20.2-kb interval contains exon 9 of the CNTN5 gene encoding contactin 5.

Cognitive behavioral therapy with interoceptive exposure and complementary video materials for irritable bowel syndrome (IBS): protocol for a multicenter randomized controlled trial in Japan.

BACKGROUND: There is growing evidence of the treatment efficacy of cognitive behavioral therapy (CBT) for irritable bowel syndrome (IBS). CBT is recommended by several practice guidelines for patients with IBS if lifestyle advice or pharmacotherapy has been ineffective. Manual-based CBT using interoceptive exposure (IE), which focuses on the anxiety response to abdominal symptoms, has been reported to be more effective than other types of CBT. One flaw of CBT use in general practice is that it is time and effort consuming for therapists. Therefore, we developed a set of complementary video materials that include psycho-education and homework instructions for CBT patients, reducing time spent in face-to-face sessions while maintaining treatment effects. The purpose of this study is to examine the effects of CBT-IE with complementary video materials (CBT-IE-w/vid) in a multicenter randomized controlled trial (RCT). METHODS: This study will be a multicenter, parallel-design RCT. Participants diagnosed with IBS according to the Rome IV diagnostic criteria will be randomized to either the treatment as usual (TAU) group or the CBT-IE-w/vid + TAU group. CBT-IE-w/vid consists of 10 sessions (approximately 30 min face-to-face therapy + viewing a video prior to each session). Patients in the CBT-IE-w/vid group will be instructed to pre- view 3- to 13-min videos at home prior to each face-to-face therapy visit at a hospital. The primary outcome is the severity of IBS symptoms. All participants will be assessed at baseline, mid-treatment, post-treatment, and follow-up (3 months after post assessment). The sample will include 60 participants in each group. DISCUSSION: To our knowledge, this study will be the first RCT of manual-based CBT for IBS in Japan. By using psycho-educational video materials, the time and cost of therapy will be reduced. Manual based CBTs for IBS have not been widely adopted in Japan to date. If our CBT-IE-w/vid program is confirmed to be more effective than TAU, it will facilitate dissemination of cost-effective manual-based CBT in clinical settings. TRIAL REGISTRATION: The trial was registered to the University Hospital Medical Information Network Clinical Trial Registry: UMIN, No. UMIN000030620 (Date of registration: December 28, 2017).

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Neural correlates of body comparison and weight estimation in weight-recovered anorexia nervosa: a functional magnetic resonance imaging study.

BACKGROUND: The neural mechanisms underlying body dissatisfaction and emotional problems evoked by social comparisons in patients with anorexia nervosa (AN) are currently unclear. Here, we elucidate patterns of brain activation among recovered patients with AN (recAN) during body comparison and weight estimation with functional magnetic resonance imaging (fMRI). METHODS: We used fMRI to examine 12 patients with recAN and 13 healthy controls while they performed body comparison and weight estimation tasks with images of underweight, healthy weight, and overweight female bodies. In the body comparison task, participants rated their anxiety levels while comparing their own body with the presented image. In the weight estimation task, participants estimated the weight of the body in the presented image. We used between-group region of interest (ROI) analyses of the blood oxygen level dependent (BOLD) signal to analyze differences in brain activation patterns between the groups. In addition, to investigate activation outside predetermined ROIs, we performed an exploratory whole-brain analysis to identify group differences. RESULTS: We found that, compared to healthy controls, patients with recAN exhibited significantly greater activation in the pregenual anterior cingulate cortex (pgACC) when comparing their own bodies with images of underweight female bodies. In addition, we found that, compared with healthy controls, patients with recAN exhibited significantly smaller activation in the middle temporal gyrus corresponding to the extrastriate body area (EBA) when comparing their own bodies, irrespective of weight, during self-other comparisons of body shape. CONCLUSIONS: Our findings from a group of patients with recAN suggest that the pathology of AN may lie in an inability to regulate negative affect in response to body images via pgACC activation during body comparisons. The findings also suggest that altered body image processing in the brain persists even after recovery from AN.

Correction to: Purging behaviors relate to impaired subjective sleep quality in female patients with anorexia nervosa: a prospective observational study.

[This corrects the article DOI: 10.1186/s13030-017-0107-7.].