Hemodynamic responses in prefrontal cortex and personality characteristics in patients with bulimic disorders: a near-infrared spectroscopy study.

PURPOSE: This study sought to identify the prefrontal cortex hemodynamic response that is dependent on cognitive performance in patients with bulimic disorders (BD), and investigate its association with personality characteristics. METHODS: Nineteen female patients with BD and 23 healthy women were recruited. Their personality characteristics related to eating disorders were examined using a self-reporting questionnaire, namely the eating disorder inventory-2 (EDI-2). Cerebral blood flow response in the prefrontal cortex during the digit span backward task (DSBT) was measured using near-infrared spectroscopy (NIRS). Change in oxygenated hemoglobin concentration (ΔoxyHb), obtained using NIRS, were used as an index of brain activity. Further, the relationship between prefrontal cortical activity and personality characteristics was investigated in patients with BD. RESULTS: The cognitive performance of patients with BD was significantly lower in the DSBT compared with healthy subjects. There was no difference between the groups in ΔoxyHb during the task. Task scores of patients with BD correlated with asceticism and perfectionism. Moreover, the asceticism score was negatively correlated with ΔoxyHb of the bilateral prefrontal cortex in patients with BD. CONCLUSION: The results suggest that cognitive performance and brain activity induced during DSBT might be affected by asceticism in BD patients. LEVEL OF EVIDENCE: III, case-control study.

Paternal methyl donor deficient diets during development affect male offspring behavior and memory-related gene expression in mice.

It has become increasingly evident that the methylation of DNA, known as an epigenetic marker, affects behavior in animals. In our previous study, a methyl-donors (folate, methionine, and choline)-deficient (FMCD) diet during the juvenile period could be shown to affect anxiety-like behavior and fear memory, accompanied by alteration in some gene expression and their methylations in the hippocampus. One question is whether the fear memory of a parent affects the fear responses of offspring. To explore this question in the present study, C57BL/6 J male (F0) mice were given a FMCD diet from 3 to 12 weeks of age. After confirming the effect of the FMCD diet on the behavior and gene expression of F0 mice, their male offspring (F1-FMCD mice) were examined using the same behavioral batteries and genetic analysis. F0 diet-based differences in F1 behavior were observed, accompanied by the differences in the expression of memory-related genes (Camk2α and PP1) and promoter methylation of the PP1 gene in the hippocampus. Our results add evidence that behavior and gene expression of the F1 generation could be altered due to differences in the father's intake of methyl-donor nutrients.

Spontaneous recovery of fear differs among early - late adolescent and adult male mice.

Adolescence is a vulnerable period for developing anxiety-related mental disorders such as post-traumatic stress disorder (PTSD), which requires a long-term course of therapy when a traumatic event has been experienced during childhood. However, the biological mechanism underlying these age-dependent characteristics remains unclear. In the present study, we used early adolescent, late adolescent and adult (4-, 8-, and 15-week old) male mice to examine age differences in fear memory, fear extinction, and spontaneous recovery of fear. We also measured the activation of extracellular signal-regulated kinase (ERK) 2 in the dorsal hippocampus (dHip) and the basolateral amygdala (BLA) following a spontaneous recovery test. Our major findings were as follows: (1) early adolescent and adult mice did not recover the fear response; only late adolescent mice recovered the fear response. (2) The ERK2 in the dHip was more activated after the spontaneous recovery test in late adolescent mice than in adult mice, and the ERK2 in the BLA was more activated after the spontaneous recovery test in adult mice than in late adolescent mice. These results suggest that there exists a unique period in which spontaneous recovery occurs and that these late adolescent behavioral signatures may be related to alteration in the ERK2 phosphorylation in the dHip and BLA.

Development of the fear regulation system from early adolescence to young adulthood in female mice.

Onset of fear-related disorders such as post-traumatic stress disorder is enhanced from adolescence until adulthood. However, the biological mechanisms underlying this vulnerability remain unclear. Therefore, we investigated contextual fear memory and extinction in 4-, 6-, 8-, 10-, and 15-week-old female mice. We also measured phosphorylation of ERK2 in the medial prefrontal cortex (mPFC) and the dorsal hippocampus following fear conditioning or extinction in 6- and 15-week-old mice. We found that 10- and 15-week-old mice showed stronger fear memory and more resistance to fear extinction than 6-week-old mice. Moreover, 15-week-old mice showed lower ERK2 phosphorylation levels following fear extinction in the mPFC than those 6 weeks old. Our results suggest that female mice acquire strong fear memory and resistance to fear extinction throughout adulthood, which may be related to alteration in ERK2 activation in the mPFC.

Repetitive Transcranial Magnetic Stimulation Changes Cerebral Oxygenation on the Left Dorsolateral Prefrontal Cortex in Bulimia Nervosa: A Near-Infrared Spectroscopy Pilot Study.

Previous studies showed that food craving in eating disorders can be weakened with high-frequency repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC). The aims of this study were to assess cerebral oxygenation change induced with rTMS and to assess the short-term impact of rTMS on food craving and other bulimic symptoms in patients with bulimia nervosa (BN). Eight women diagnosed with BN according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria participated in this study. We measured haemoglobin concentration changes in the DLPFC with near-infrared spectroscopy during cognitive tasks measuring self-regulatory control in response to food photo stimuli, both at baseline and after a single session of rTMS. Subjective ratings for food cravings demonstrated significant reduction. A significant decrease in cerebral oxygenation of the left DLPFC was also observed after a single session of rTMS. Measurement with NIRS after rTMS intervention may be applicable for discussing the mechanisms underlying rTMS modulation in patients with BN.

Sex differences in fear extinction and involvements of extracellular signal-regulated kinase (ERK).

Stress-related disorders, such as post-traumatic stress disorder (PTSD) and panic disorders, are disproportionately prevalent in females. However, the biological mechanism underlying these sex differences in the prevalence rate remains unclear. In the present study, we examined sex differences in fear memory, fear extinction, and spontaneous recovery of fear. We investigated the presence of sex differences in recent and remote fear memory in mice using contextual fear conditioning, as well as sex differences in spontaneous recovery of fear memory using a consecutive fear extinction paradigm. We examined the number of fear extinction days required to prevent spontaneous recovery of fear in either sex. We investigated whether ovariectomy affected fear extinction and spontaneous recovery. We also measured the activation of extracellular signal-regulated kinase (ERK) 1 and 2 in the dorsal hippocampus and the medial prefrontal cortex following fear extinction sessions. In our results, we found no sex difference in recent or remote fear memory. However, females required more fear extinction sessions compared to males to prevent spontaneous recovery. Within-extinction freezing also differed between males and females. Moreover, females required more extinction sessions than males to increase ERK2 phosphorylation in the dorsal hippocampus. Our data suggest that contextual fear extinction was unstable in females compared to males and that such sex differences may be related to the ERK2 phosphorylation in the hippocampus.

Perinatal exposure to bisphenol A enhances contextual fear memory and affects the serotoninergic system in juvenile female mice.

Perinatal exposure to bisphenol A (BPA), an endocrine-disrupting chemical, affects the central nervous system, including effects on emotional responses and neurotransmitter release. In this study, we investigated the effects of BPA (250 ng/kg/day, from gestational day 10 to postnatal day 20) on fear memory and serotonin (5-HT) metabolites in the brain using contextual fear conditioning (FC) and high-performance liquid chromatography (HPLC), respectively, in adult and juvenile mice of both sexes. Furthermore, we studied the effects of BPA on the gene expression of 5-HT metabolite-related enzymes and 5-HT receptors using quantitative real-time RT PCR in the brains of juvenile females. BPA enhanced fear memory and increased serotonin metabolite (5-HIAA) levels and 5-HIAA/5-HT in the hippocampus, the striatum, the midbrain, the pons, and the medulla oblongata of juvenile female mice. In contrast, alterations in those areas were much smaller in adult females and in both juvenile and adult males. Furthermore, BPA induced increases in the expression levels of Tph2, Slc6a4, and Maoa mRNA in the hippocampus of juvenile females, indicating that BPA induces hyper 5-HT turnover in the hippocampus. Our results suggest that perinatal exposure to a low dose of BPA enhances fear memory and the 5-HTergic system in juvenile mice.

[The Relationship between the Autistic Traits and Everyday Memory Processing in Adults with Autism Spectrum Disorder and Healthy Adults].

We investigated the association between everyday memory and autistic traits in adults with autism spectrum disorder (ASD, n=22) and healthy adults (n=20) by using the Rivermead Behavioral Memory Test (RBMT). A generalized linear model (GLM) was used to explore the relationships between the subjects' performance on the RBMT as the objective variable and the composite score of the Autism Spectrum Quotient (AQ) as the explanatory variable. Multiple models were created with the AQ subscales ('Social skills,' 'Attention-shifting,' 'Attention to details,' 'Communication,' 'Imagination'), age, gender, the full-scale intelligence quotient (FSIQ), the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale added as the moderator variables. The GLM revealed that the AQ subscale 'Social skills' significantly predicted the RBMT-total scores with age, gender, and psychological measures scores as the moderator variables (Model 4: B=0.752, 95%CI: 0.191 to 1.313, p<0.01). Also, The GLM revealed that the AQ subscale 'Communication', in addition to 'Social skills', significantly predicted the RBMT- 'Prospective memory' (Model 4: B=0.298, 95%CI: 0.19 to 0.578, p<0.05). These results indicate an influence of social skills on everyday memory functioning, highlighting the weakness of memory processing in everyday life situations among individuals with ASD.

Individual cognitive therapy reduces frontal-thalamic resting-state functional connectivity in social anxiety disorder.

Introduction: Previous neuroimaging studies in social anxiety disorders (SAD) have reported potential neural predictors of cognitive behavioral therapy (CBT)-related brain changes. However, several meta-analyses have demonstrated that cognitive therapy (CT) was superior to traditional exposure-based CBT for SAD. Objective: To explore resting-state functional connectivity (rsFC) to evaluate the response to individual CT for SAD patients. Methods: Twenty SAD patients who attended 16-week individual CT were scanned pre- and post-therapy along with twenty healthy controls (HCs). The severity of social anxiety was assessed with the Liebowitz Social Anxiety Scale (LSAS). Multi-voxel pattern analysis (MVPA) was performed on the pre-CT data to extract regions associated with a change in LSAS (∆LSAS). Group comparisons of the seed-based rsFC analysis were performed between the HCs and pre-CT patients and between the pre-and post-CT patients. Results: MVPA-based regression analysis revealed that rsFC between the left thalamus and the frontal pole/inferior frontal gyrus was significantly correlated with ∆LSAS (adjusted R2 = 0.65; p = 0.00002). Compared with HCs, the pre-CT patients had higher rsFCs between the thalamus and temporal pole and between the thalamus and superior/middle temporal gyrus/planum temporale (p < 0.05). The rsFC between the thalamus and the frontal pole decreased post-CT (p < 0.05). Conclusion: SAD patients had significant rsFC between the thalamus and temporal pole, superior/middle temporal gyrus, and planum temporale, which may be indicators of extreme anxiety in social situations. In addition, rsFC between the thalamus and the frontal pole may be a neuromarker for the effectiveness of individual CT.

Pharmacokinetics and cerebral distribution of glycine administered to rats.

High doses of glycine have been reported to improve negative schizophrenic symptoms, suggesting that ingested glycine activates glutamatergic transmission via N-methyl-D-aspartate (NMDA) receptors. However, the pharmacokinetics of administered glycine in the brain has not been evaluated. In the present study, the time- and dose-dependent distributions of administered glycine were investigated from a pharmacokinetic viewpoint. Whole-body autoradiography of radiolabeled glycine was performed, and time-concentration curves for glycine and serine in plasma, cerebrospinal fluid (CSF), and brain tissues were obtained. Furthermore, pharmacokinetic parameters were calculated. For a more detailed analysis, the amount of glycine uptake in the brain was evaluated using the brain uptake index method. Radiolabeled glycine was distributed among periventricular organs in the brain. Oral administration of 2 g/kg of glycine significantly elevated the CSF glycine concentration above the ED50 value for NMDA receptors. The glycine levels in CSF were 100 times lower than those in plasma. Glycine levels were elevated in brain tissue, but with a slower time-course than in CSF. Serine, a major metabolite of glycine, was elevated in plasma, CSF, and brain tissue. Glycine uptake in brain tissue increased in a dose-dependent manner. Time-concentration curves revealed that glycine was most likely transported via the blood-CSF barrier and activated NMDA receptors adjacent to the ventricles. The pharmacokinetic analysis and the brain uptake index for glycine suggested that glycine was transported into brain tissue by passive diffusion. These results provide further insight into the potential therapeutic applications of glycine.

Referred sensations induced by a mirror box in healthy subjects.

Twenty-one healthy subjects were instructed to observe the mirror image of the tactile stimulation of their own hand (control condition) or an assistant's hand (experimental condition) while being queried about the referred sensation (RS) in their own masked hand behind the mirror. The rated intensity of the RS under the experimental condition was significantly stronger than that under the control condition. In a second experiment, the experimental condition was replaced with the tactile stimulation of a prosthetic (rubber) hand, and was compared with the tactile stimulation of the subject's own hand (control condition). In both of the experiments, the rated intensity of RS was significantly stronger under the experimental condition than under the control condition. The qualitative characteristics of the induced RS on the mirror image hand--including the location, sense of ownership, and various subjective feelings--were also found to vary among subjects. In conclusion, an RS could be induced in healthy subjects on the mirror image of the hand by tactile stimulations, although this effect differed substantially among individuals.

Oral administration of glycine increases extracellular serotonin but not dopamine in the prefrontal cortex of rats.

AIM: Glycine, one of the non-essential amino acids, has been reported to be effective in reducing negative symptoms of schizophrenia. Recently, we found that glycine improves subjective sleep quality in humans. The aim of this study was to investigate the effects of oral glycine administration on endogenous 5-hydroxytryptamine (5-HT) and dopamine in the prefrontal cortex (PFC) of living rats. METHODS: Microdialysis probes were inserted stereotaxically into the rat prefrontal cortex. Cortical levels of 5-HT and dopamine were measured following oral administration of 1 or 2 g/kg glycine, 2 g/kg d-serine, or 2 g/kg L-serine. RESULTS: Both glycine and d-serine significantly increased extracellular 5-HT levels for 10 min, whereas dopamine levels remained unchanged. L-serine, in contrast, had no significant effects on 5-HT levels. CONCLUSIONS: It is possible that the increase in 5-HT in response to glycine and d-serine was mediated by N-methyl-D-aspartate receptors. The transient increase in 5-HT in the PFC might be associated with the alleviation of negative symptoms in patients with schizophrenia and the amelioration of sleep quality in patients with insomnia.

Associations between autism spectrum disorder and eating disorders with and without self-induced vomiting: an empirical study.

BACKGROUND: Although approximately 23% of anorexia nervosa (AN) patients have concomitant autism spectrum disorder (ASD), it is clinically difficult to determine ASD coexistence in patients with eating disorders. Restrictive AN is more common in younger patients and self-induced vomiting usually appears during adolescence/young adulthood, in order to prevent gaining weight caused by overeating. However, some patients are tolerant of weight gain even if they start overeating. It is important to understand the essential difference between those who vomit and those who do not vomit. In this study, we hypothesised that the absence of self-induced vomiting may be associated with the presence of ASD and aimed to assess the presence of ASD traits in each eating disorder (EDs). Clarifying this association helps to consider the coexistence of ASD in the clinical setting and can lead to the next detailed ASD evaluation, and as a result, helps to determine the appropriate treatment and support individually. METHODS: We retrospectively evaluated 43 females aged 15-45 years who attended Chiba University Hospital between 2012 and 2016 using the Eating Disorder Examination Questionnaire (EDE-Q) and Autism-Spectrum Quotient (AQ) to quantify the severity of the EDs and to identify whether ASD traits were present. RESULTS: There was no difference in the AQ score between bingeing-purging type AN and restricting type AN. However, there was significant difference in the AQ score between bulimia nervosa and binge EDs (BED). Of the 4 ED subtypes, BED had the highest ASD traits. The non-vomiting group with illness duration < 4 years had a significantly higher AQ communication score than the vomiting group with illness duration ≥4 years. CONCLUSIONS: There was a difference in the AQ score by the presence or absence of self-induced vomiting. The results of this study suggest an association between high scores on AQ and non-vomiting. Thus, evaluation of patients for the absence of self-induced vomiting while assessing them for EDs may help us to understand the association with ASD traits.

Associations between prenatal exposure to volatile organic compounds and neurodevelopment in 12-month-old children: The Japan Environment and Children's Study (JECS).

In recent years, there has been an increase in the number of problems associated with neurodevelopmental disorders in children, and there has been a growing interest in the relationship between environmental chemicals and children's health. The objective of this study was to examine whether an association exists between occupational or environmental prenatal maternal exposure to volatile organic compounds and the risk of neurodevelopmental disorders in children using Japanese translations of the Ages & Stages Questionnaires, Third Edition (J-ASQ-3). An increase in the risk of neurodevelopmental delay in 12-month-old children associated with maternal exposure to formalin or formaldehyde was identified in terms of problem-solving (odds ratio (OR): 1.76, 95% confidence interval (CI): 0.99-3.12) and personal-social skills (OR: 3.32, 95% CI: 1.46-7.55). It is not clear whether or not this tendency is reversible, and whether it is observed past 12 months of age. Further research and a preventive approach are needed.

Specific metabolites in the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia: a preliminary study.

We measured brain metabolites in the medial prefrontal cortex of 19 schizophrenic patients and 18 healthy controls by 3 T proton magnetic resonance spectroscopy ((1)H MRS), and examined the relationship between prefrontal cortex-related neurocognitive functions and brain metabolites in the medial prefrontal cortex. The patients with schizophrenia exhibited deficits on the verbal fluency, Wisconsin card sorting test (WCST), trail making test, Stroop test and digit span distraction test (DSDT), but not on the Iowa gambling test. The patients showed statistical significant changes in the ratio of glutamine/glutamate, the ratio of N-acetyl-l-aspartate (NAA)/glycerophosphorylcholine plus phosphorylcholine (GPC+PC) and the levels of taurine in the medial prefrontal cortex compared with normal controls. Furthermore, we found significant correlations of the ratio of glutamine/glutamate with WCST and DSDT scores, the ratio of NAA/(GPC+PC) with verbal fluency and WCST scores, and the levels of taurine with scores on the Stroop test and Trail making test A among the participants. The ratios of NAA/(GPC+PC) and (GPC+PC)/(Cr+PCr) had significant relationships with the duration of untreated psychosis of the schizophrenic patients. The glutamine/glutamate ratio and levels of taurine were significantly related to the duration of illness of the patients. These data suggest that specific metabolites of the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia.

Cognitive-behavioral family therapy as psychoeducation for adolescents with high-functioning autism spectrum disorders: Aware and Care for my Autistic Traits (ACAT) program study protocol for a pragmatic multisite randomized controlled trial.

BACKGROUND: One aim of an autism spectrum disorder (ASD) diagnosis is to obtain special support for the disorder, though this does not guarantee practical support. We developed a psychoeducational program using cognitive-behavioral therapy (CBT) and Aware and Care for my Autistic Traits (ACAT) for Japanese adolescents with high-functioning ASD and their parents. METHODS: This multisite study is a randomized controlled trial. In total, 24 participants will be assigned to the ACAT group and 24 to the treatment-as-usual (TAU) group. The ACAT group will receive a weekly 100-min session for 6 weeks, regular medical care, and one follow-up session. In this ongoing clinical trial, we will compare the scores of the measures recorded in the pre- and post-intervention stages between the ACAT and TAU groups. A total of 41 patients out of a target of 48 have participated in the trial to date. The primary outcome measure is the Autism Knowledge Questionnaire. Secondary outcome measures include Barriers to Access to Care Evaluation 3rd Edition, the Strengths and Difficulties Questionnaire, the Vineland Adaptive Behavior Scales second edition, the Parenting Resilience Elements Questionnaire, the General Health Questionnaire 12, and the Depression Self-Rating Scale for Children assessments, as well as an electroencephalographic recording. DISCUSSION: It is expected that participants in the ACAT group will significantly increase their self-understanding and awareness of ASD symptoms compared to those in the TAU group. Additionally, the ACAT group is expected to exhibit improved social adaptation and mental health if children and parents are able to better understand the ASD characteristics through sessions. This intervention will contribute to the establishment of an effective evidence-based treatment strategy for adolescents with ASD. TRIAL REGISTRATION: UMIN Register 000029851 . Registered on January 06, 2018.

Dopaminergic hypofunctions and prepulse inhibition deficits in mice lacking midkine.

Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(-/-)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(-/-) mice. The Mdk(-/-) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(-/-) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system.

Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population.

Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes.

Insensitivity of auditory mismatch negativity to classical fear conditioning and extinction in healthy humans.

The relationship between auditory mismatch negativity (MMN) and the neural cognitive processes of fear has been suggested in both healthy participants and patients with fear-related mental disorders such as post-traumatic stress disorder and panic disorder. The present study sought to confirm whether the MMN is affected by classical fear conditioning in healthy participants. MMN amplitude, N1 amplitude, and skin conductance level (SCL) in 20 healthy volunteers during a fear-conditioning paradigm consisting of three phases (habituation, fear acquisition, and fear extinction) were recorded. Red and blue light signals were presented as the conditioned stimuli CS+ (threat cue) and CS- (safety cue), respectively. In addition, an aversive electrical stimulus was delivered as the unconditioned stimulus with CS+ in the fear-acquisition phase. No MMN amplitude changes were observed between the CS types during the three phases. In the acquisition phase, the mean SCL during CS+ was significantly higher than that during CS-. The MMN amplitude and deviant N1 amplitude in the extinction phase were significantly lower than those in the other phases regardless of the CS type. Despite the clear alteration of SCL between CS types in the acquisition phase, no significant differences in MMN were observed. Decreased MMN and deviant N1 in the fear-extinction phase were considered to be mainly due to decreased arousal or attention level. Results indicate that the auditory MMN amplitude was not affected by the cognitive process of fear recognized by other sense modalities.