Interoceptive training impacts the neural circuit of the anterior insula cortex.

Interoception is the perception of afferent information that arises from anywhere and everywhere within the body. Recently, interoceptive accuracy could be enhanced by cognitive training. Given that the anterior insula cortex (AIC) is a key node of interoception, we hypothesized that resting functional connectivity (RSFC) from AIC was involved in an effect of interoceptive training. To address this issue, we conducted a longitudinal intervention study using interoceptive training and obtained RSFC using fMRI before and after the intervention. A heartbeat perception task evaluated interoceptive accuracy. Twenty-two healthy volunteers (15 females, age 19.9 ± 2.0 years) participated. After the intervention, interoceptive accuracy was enhanced, and anxiety levels and somatic symptoms were reduced. Also, RSFC from AIC to the dorsolateral prefrontal cortex (DLPFC), superior marginal gyrus (SMG), anterior cingulate cortex (ACC), and brain stem, including nucleus tractus solitarius (NTS) were enhanced, and those from AIC to the visual cortex (VC) were decreased according to enhanced interoceptive accuracy. The neural circuit of AIC, ACC, and NTS is involved in the bottom-up process of interoception. The neural circuit of AIC, DLPFC, and SMG is involved in the top-down process of interoception, which was thought to represent the cognitive control of emotion. The findings provided a better understanding of neural underpinnings of the effect of interoceptive training on somatic symptoms and anxiety levels by enhancing both bottom-up and top-down processes of interoception, which has a potential contribution to the structure of psychotherapies based on the neural mechanism of psychosomatics.

Individualized peer support needs assessment for families with eating disorders.

BACKGROUND: Peer support among family members is important in cases of mental illness, but there has been limited practice or research on individual peer support specific to families taking care of patients with eating disorders (EDs). To conduct peer support activities, it is necessary to clarify the needs of families. OBJECTIVES: The objective of this study are to identify the needs for group and individual peer support and the characteristics of family members with EDs who are willing to receive and provide individual peer support. METHOD: A cross-sectional questionnaire survey was conducted for family members with EDs recruited via the Internet. The questionnaires included demographic information on respondents and their patients, questions about the need for family peer support, interest in offering peer support, and social resources. All participants were given the General Health Questionnaire (GHQ-12), the Zarit Caregiver Burden Interview (J-ZBI_8), and the Anorectic Behavior Observation Scale (ABOS). RESULTS: Out of 314 respondents, 87.3% believed that a group peer support system was necessary, whereas 56.7% believed that an individual peer support system was necessary. As to whether they want to use individual peer support, 70 (22.4%) stated "Extremely YES" and 99 (31.7%) stated "Moderately YES." Family members who were willing to receive individual peer support used more social resources and had higher scores on the GHQ and J-ZBI_8. Regarding the provision of peer support, 38 (12.2%) responded "very interested and willing to provide it if possible" and 87 (27.9%) responded "interested and willing to study." Those with a high willingness to provide peer support used more social resources and had lower ABOS scores; however, 38 respondents (45.7%) exceeded the GHQ mental health screening cutoff (3/4). CONCLUSION: Family members with ED had a strong need for family peer support Those willing to receive individual peer support suffered from poor mental health and high burden of care. Family members willing to provide peer support tended to have patients whose EDs symptoms had already improved, but their own mental health was not necessarily good. Training for potential peer supporters is needed to implement peer support.

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.

Effects of interoceptive training on decision making, anxiety, and somatic symptoms.

BACKGROUND: Interoception is the perception of afferent information that arises from any point within the body. Individual differences in interoception have been associated with affective processing and decision-making processing. The somatic marker hypothesis summarizes the potential effects of interoception on decision-making processes. According to this theory, individuals with interoceptive dysfunction exhibit disadvantageous decision making. Recently, enhancement of interoceptive accuracy, an element of interoception assessed by objective decision-making tasks, has been demonstrated using biofeedback. Garfinkle et al. developed an interoceptive training task, modified from the heartbeat perception task, which enhanced interoceptive accuracy and reduced anxiety symptoms. The purpose of this study was to determine the effects of interoceptive training on decision-making processes. Based on improvements in interoceptive accuracy, we hypothesized that decision-making scores would change in a manner indicative of increased rationality. METHODS: This longitudinal interventional study was performed with interoceptive training. Before and after the intervention, interoceptive accuracy and rationality of decision-making processes were assessed using a heartbeat perception task and rational decision-making tasks, respectively. Fourteen healthy volunteers (nine women; mean age, 21.9 ± 4.5 years) participated. The analysis included data from 12 participants. To detect individual differences in the effects of interoceptive accuracy on rationality of decision making, correlation analysis was conducted on change ratios of the indices of interoceptive accuracy and rationality of decision making. RESULTS: Interoceptive training resulted in significant enhancement of interoceptive accuracy scores and significant reductions in somatic symptom and state anxiety scores. In contrast, interoceptive training did not cause significant changes in decision-making indices. There was a significant positive correlation between change ratios of indices of interoceptive accuracy and rationality of decision making. CONCLUSIONS: The results suggested a causal relation between interoception and rationality of decision making. These findings will enhance the understanding of mechanisms underlying alterations of decision-making related to psychotherapy by focusing on interoception. TRIAL REGISTRATION: Trial registration number: UMIN000037548.

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.

Total Synthesis and Structural Elucidation of Two Unusual Non-Methylene-Interrupted Fatty Acids in Ovaries of the Limpet Cellana toreuma.

In our previous study, unusual odd-numbered dienoic acids with a terminal olefin were found as minor components in ovaries of the Japanese limpet Cellana toreuma, and the synthetic interests have been focused onto their structural confirmation and the inspection into their potential biological activity. Here, we describe an efficient and stereoselective total synthesis of two new unusual dienoic acids, 19:2∆7,18 and 21:2∆7,20, through a common pathway involving the strategic combination of alkyne-zipper reaction and Lindlar hydrogenation for the construction of their unique carbon chains. In our synthetic study, 2-propyn-1-ol was at first subjected to alkylation and alkyne-zipper reaction to form the two fragments, and the subsequent carbon chain elongation was achieved by the usual coupling reaction to obtain the C-19 and C-21 products bearing an internal acetylenic group. Then, the internal acetylenic group of these products was subjected to Lindlar hydrogenation to form a Z-alkenyl moiety, and the subsequent deprotection of the products was carried out under an acidic condition without isomerization of the internal Z-alkenyl group. Total synthesis of target fatty acids, 19:2∆7,18 and 21:2∆7,20, was finally accomplished by two-step oxidation of the resulting alcohols into carboxylic acids in a highly chemoselective manner, and the structures of these unusual natural fatty acids were finally elucidated by identifying the GC-MS spectra of the methyl esters of authentic and synthetic fatty acids.

Small eye phenotypes observed in a human tau gene transgenic rat.

We developed a rat line showing small eye from transgenic rats that were obtained by microinjection of a DNA segment containing the human (h)tau cDNA (GenBank: BC000558: 31-677,774-1180) expressed under control of CAG promoter, which is related to Alzheimer disease, into the pronuclei rat embryos. The rat line was established by selective brother-sister mating of rats showing small eyes. Of 11 offspring in the 11th generation, there were eight animals with microphthalmia and the transgene. The remaining three rats without transgene did not show the small eyes phenotype. The globes of affected rats were 1.2 mm in length compared with normal globes (3.5 mm), and all other ocular structures were normal. The expression of hTau protein was evident immunohistochemically in the ciliary body, extraocular muscle, lens epithelium, and pigment epithelium. Cytogenetic analysis suggested that the chromosome location of the transgene was chromosome 1 (1p12). This region may include genes related to lens development, such as Cat5.

Current status of chromosomal abnormalities in mouse embryonic stem cell lines used in Japan.

We performed chromosomal analysis on 540 mouse embryonic stem (ES) cell lines obtained during 2001 to 2004 from 20 institutions in Japan. Overall, 66.5% of the ES cell lines showed normal chromosomal numbers, but 15.9%, 9.1%, and 2.8% showed modal chromosomal numbers of 41, 42, and 39, respectively. When we karyotyped 88 ES cell lines selected arbitrarily from the 540 lines, 53 (60.2%) showed normal diploid karyotypes; the sex chromosome constitution of 52 lines was XY, with the remaining 1 being XX. Among 35 ES cell lines showing abnormal karyotypes, trisomy of chromosome 8 (41, XY, +8) was dominant (51.4%), 14.3% had trisomy 8 with loss of one sex chromosome (40, XO, +8), and 11.4% had trisomy 8 together with trisomy 11 (42, XY, +8, +11). Karyotypic abnormalities including trisomy 8 and trisomy 11 occurred in 88.6% and 17.1% of ES cell lines, respectively. The XO sex chromosome constitution was observed in 25.7% of all abnormal ES cell lines. Of the 88 selected ES cell lines, 60 lines were established from strain 129 animals, 17 from F1 progeny of C57BL/6J x CBA (called TT2 in this study), and 11 from C57BL/6J mice. Normal diploid karyotypes were observed in 58.3% of lines derived from 129, 58.8% of those from TT2, and 72.7% of C57BL/6J. The relatively high incidence of abnormalities in chromosomal number and karyotype in ES cell lines used in Japan suggests the importance of chromosomal analysis of ES cells for successful establishment of new animal models through germline transmission.

Effect of endotoxin on doxorubicin transport across blood-brain barrier and P-glycoprotein function in mice.

The aim of this study was to investigate whether Klebsiella pneumoniae endotoxin modifies transport of doxorubicin, a P-glycoprotein substrate, across the blood-brain barrier and P-glycoprotein function in mice. Doxorubicin (30 mg/kg) was administered into the tail vein or fluorescein isothiocyanate-labeled dextran (FD-4) was infused (20 microg/min) into the right jugular vein of mice intravenously injected with endotoxin (10 mg/kg) 6 or 24 h earlier. Blood and brain samples were collected 4 h after injection of doxorubicin or 1 h after infusion of FD-4. We examined using Western blotting the influence of endotoxin on the expression of P-glycoprotein in brains obtained 6, 12 and 24 h after injection. Endotoxin did not change the plasma and brain concentrations and brain-to-plasma concentration ratio (K(p) value) of FD-4. No histopathological changes in brain capillaries were observed. These results suggest that endotoxin does not cause damage to brain capillaries. Plasma and brain concentrations of doxorubicin in mice treated 6 h earlier with endotoxin were significantly higher than those in control and mice treated 24 h earlier. However, endotoxin did not significantly change the K(p) value of doxorubicin. The protein level of P-glycoprotein was significantly, but slightly down-regulated 6 h after endotoxin treatment. However, the levels remained almost unchanged after 12 and 24 h. The present results suggest that Klebsiella pneumoniae endotoxin has no effect on the brain capillary integrity and doxorubicin transport across the blood-brain barrier in mice. It is likely that P-glycoprotein function might be sufficient to transport doxorubicin in spite of decreased levels of P-glycoprotein in the brain.

Preimplantation development of somatic cell cloned embryos in the common marmoset (Callithrix jacchus).

The somatic cell nuclear transfer technique has been applied to various mammals to produce cloned animals; however, a standardized method is not applicable to all species. We aimed here to develop optimum procedures for somatic cell cloning in nonhuman primates, using common marmosets. First, we confirmed that parthenogenetic activation of in vitro matured oocytes was successfully induced by electrical stimulation (three cycles of 150 V/mm, 50 microsec x 2, 20 min intervals), and this condition was applied to the egg activation procedure in the subsequent experiments. Next, nuclear transfer to recipient enucleated oocytes was performed 1 h before, immediately after, or 1 h after egg activation treatment. The highest developmental rate was observed when nuclear transfer was performed 1 h before activation, but none of the cloned embryos developed beyond the eight-cell stage. To investigate the causes of the low developmental potential of cloned embryos, a study was performed to determine whether the presence of metaphase II (MII) chromosome in recipient ooplasm has an effect on developmental potential. As a result, only tetraploid cloned embryos produced by transferring a donor cell into a recipient bearing the MII chromosome developed into blastocysts (66.7%). In contrast, neither parthenogenetic embryos nor cloned embryos (whether diploid or tetraploid) produced using enucleated oocytes developed past the eight-cell stage. These results suggest that MII chromosome, or cytoplasm proximal to the MII chromosome, plays a major role in the development of cloned embryos in common marmosets.

Establishment of novel embryonic stem cell lines derived from the common marmoset (Callithrix jacchus).

The successful establishment of human embryonic stem cell (hESC) lines has inaugurated a new era in regenerative medicine by facilitating the transplantation of differentiated ESCs to specific organs. However, problems with the safety and efficacy of hESC therapy in vivo remain to be resolved. Preclinical studies using animal model systems, including nonhuman primates, are essential to evaluate the safety and efficacy of hESC therapies. Previously, we demonstrated that common marmosets are suitable laboratory animal models for preclinical studies of hematopoietic stem cell therapies. As this animal model is also applicable to preclinical trials of ESC therapies, we have established novel common marmoset ESC (CMESC) lines. To obtain marmoset embryos, we developed a new embryo collection system, in which blastocysts can be obtained every 3 weeks from each marmoset pair. The inner cell mass was isolated by immunosurgery and plated on a mouse embryonic feeder layer. Some of the CMESC lines were cultured continuously for more than 1 year. These CMESC lines showed alkaline phosphatase activity and expressed stage-specific embryonic antigen (SSEA)-3, SSEA-4, TRA-1-60, and TRA-1-81. On the other hand, SSEA-1 was not detected. Furthermore, our novel CMESCs are pluripotent, as evidenced by in vivo teratoma formation in immunodeficient mice and in vitro differentiation experiments. Our established CMESC lines and the common marmoset provide an excellent experimental model system for understanding differentiation mechanisms, as well as the development of regenerative therapies using hESCs.