Akemi Tomoda - Academia.edu (original) (raw)

Papers by Akemi Tomoda

Background Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in J... more Background Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. Methods The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatm...

Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibite... more Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibited behaviors and reduced neural responses to rewards. Children and adolescents with RAD show aberrant attachment behaviors, and existing psychotherapies are difficult to maintain; therefore, pharmacological interventions to aid and boost treatment responses are needed. Oxytocin (OT) administration is known to promote reward functioning. We investigated whether single-use intranasal OT administration improved neural responses during reward processing in patients with RAD compared with healthy controls. Twenty-four male children and adolescents with RAD (10-18 years old) and 27 age-and sex-matched typically developing individuals (10-17 years old) were included in this randomized, double-blind, placebo-controlled, cross-over, functional magnetic resonance imaging study. Following a single intranasal OT (24 IU) or placebo administration, neural responses were investigated using a monetary reward task. In the RAD group, OT significantly increased subjective motivation scores, significantly enhanced activation in the right middle frontal gyrus, and reduced activation in the right precentral gyrus during the monetary reward task. Additional analyses revealed increased activation in the bilateral caudate at a more lenient threshold. Under placebo conditions, the severity of internalizing problems in patients with RAD was negatively correlated with ventral striatal activity. Moreover, the effect of OT on ventral striatum activity was positively associated with the severity of internalizing problems in patients with RAD. Intranasal OT administration enhanced activity in the reward pathway in male children and adolescents with RAD, suggesting that exogenous OT promotes reward processing and reward-related motivational behavior in these individuals. Further investigation is needed to fully understand the neural mechanisms of intranasal OT and identify novel targets for pediatric cases with RAD. Clinical trial registration: UMIN-CTR; UMIN000013215. URL: https://upload. umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000015419 KEYWORDS reactive attachment disorder (RAD), intranasal oxytocin, functional magnetic resonance imaging (fMRI), reward, childhood maltreatment, randomized controlled trial TYPE

Nihon Shinri Gakkai Taikai happyo ronbunshu, Sep 25, 2018

Human Brain Mapping, Jul 16, 2021

Child‐rearing mothers with high levels of trait anxiety have a tendency for less adaptive sensory... more Child‐rearing mothers with high levels of trait anxiety have a tendency for less adaptive sensory processing, which causes parenting stress. However, the neural mechanisms underlying this sensory processing and trait anxiety remain unclear. We aimed to determine the whole‐brain spontaneous neural activity and sensory processing characteristics in mothers with varying parenting stress levels. Using resting‐state functional magnetic resonance imaging, we assessed mothers caring for more than one preschool aged (2–5 years) child and presenting with varying levels of sensory processing, trait anxiety, and parenting stress. Spontaneous neural activities in select brain regions were evaluated by whole‐brain correlation analyses based on the fractional amplitude of low‐frequency fluctuations (fALFF). We found significant positive correlations between levels of sensory processing with trait anxiety and parenting stress. Mothers having less adaptive sensory processing had significantly increased resting‐state network activities in the left lobule VI of the cerebellum. Increased fALFF values in the left lobule VI confirmed the mediation effect on the relationship between trait anxiety and sensory processing. A tendency for less adaptive sensory processing involving increased brain activity in lobule VI could be an indicator of maternal trait anxiety and the risk of parenting stress.

Research Square (Research Square), May 15, 2023

Background: The pooled sample method is used in epigenomic research and expression analysis and i... more Background: The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina In nium Methylation 450 K BeadChip array; however, subsequent reports on the updated 850 K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quanti cation method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become uorescencebased, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples. Results: The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450 K BeadChip array. However, considering a dataset of 1,000 randomly extracted CpG sites, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a su cient effect size. Conclusions: The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is cost-effective and can be utilized for screening by carefully understanding the features for its effective points and disadvantages of the pooled sample method and combining it with candidate gene analyses. Background Research on epigenomes and their interaction with genetics which re ect the "nurture and environment" aspect has shifted the focus from solely studying genetic sequences in various elds (1). Epigenomic research, initially dominated by cancer research (2), has recently expanded to include studies on the relationship between various phenotypes, such as aging (3-7), nutrition and diet (8), environmental pollutants (9, 10), immunity (11, 12), neurological disorders (13), psychiatric disorders (14-17), and psychological traits (18, 19), and is expected to increase further (20). Converse to data-driven genome-wide association analysis, hypothesis-driven candidate gene analysis is the primary approach for conducting epigenomic studies. However, studies that focus on the results of candidate gene analysis and candidate gene-by-environment interactions alone for understanding complex traits without replication experiments have been becoming outdated (21). As genome-wide data,

Brain Imaging and Behavior

This randomized controlled study examined neurological changes in socioemotional processing skill... more This randomized controlled study examined neurological changes in socioemotional processing skills through parent training in caregivers of children with attention-deficit/hyperactivity disorder. Thirty mothers of children with attention-deficit/hyperactivity disorder were stratified into parent training and non-parent training groups. Functional magnetic resonance imaging was performed during the “Reading the Mind in the Eyes” test, and parenting difficulties were evaluated using the Parenting Stress Index and the Parenting Scale, twice (before and after parent training). Only mothers in the parent training group showed a significant decrease in Parenting Stress Index and Parenting Scale scores. They also demonstrated increased activity in the left occipital fusiform gyrus during the task of estimating emotions from facial pictures. We presumed that these changes might reflect the potential impact of enrollment in parent training in reducing stress, which might have increased activ...

Translational Psychiatry

Neuroepigenetics considers genetic sequences and the interplay with environmental influences to e... more Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with...

This randomized controlled study examined neurological changes in socioemotional processing skill... more This randomized controlled study examined neurological changes in socioemotional processing skills through parent training in caregivers of children with attention-deficit/hyperactivity disorder. Thirty mothers of children with attention-deficit/hyperactivity disorder were stratified into parent training and non-parent training groups. Functional magnetic resonance imaging was performed during the “Reading the Mind in the Eyes” test, and parenting difficulties were evaluated using the Parenting Stress Index and the Parenting Scale, twice (before and after parent training). Only mothers in the parent training group showed a significant decrease in Parenting Stress Index and Parenting Scale scores. They also demonstrated increased activity in the left occipital fusiform gyrus during the task of estimating emotions from facial pictures, with a trend towards a reduced response time while judging others’ emotional state in the “Reading the Mind in the Eyes” test. We presumed that these c...

Frontiers in Child and Adolescent Psychiatry

Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibite... more Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibited behaviors and reduced neural responses to rewards. Children and adolescents with RAD show aberrant attachment behaviors, and existing psychotherapies are difficult to maintain; therefore, pharmacological interventions to aid and boost treatment responses are needed. Oxytocin (OT) administration is known to promote reward functioning. We investigated whether single-use intranasal OT administration improved neural responses during reward processing in patients with RAD compared with healthy controls. Twenty-four male children and adolescents with RAD (10–18 years old) and 27 age- and sex-matched typically developing individuals (10–17 years old) were included in this randomized, double-blind, placebo-controlled, cross-over, functional magnetic resonance imaging study. Following a single intranasal OT (24 IU) or placebo administration, neural responses were investigated using a monetary r...

Neuroepigenetics considers genetic sequences and the interplay with environmental influences to e... more Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with...

Frontiers in Psychiatry

The purpose of this study was to examine whether the beneficial effects of behavioral parent trai... more The purpose of this study was to examine whether the beneficial effects of behavioral parent training (BPT), as an indirect type of psychosocial treatment, are extended to cognitive manifestations beyond behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Although previous studies of community families have shown an association between parenting quality and a child’s cognitive functions, little is known about the effects of BPT on cognitive manifestations in children with ADHD. In this study, we focused on inhibitory control among cognitive domains, which is considered to be the most malleable to direct types of psychosocial treatment for ADHD. We hypothesized that inhibitory control is affected by BPT, which uses parents as the primary agents of change to help their children. Thirty school-age children (6–12 years old) with ADHD and their parents (mothers) participated and were randomly assigned to either the standard BPT or waitlist control group. Using two obj...

Brain and Development

Aims: The current study aimed to validate the relationship between sensory characteristics and sl... more Aims: The current study aimed to validate the relationship between sensory characteristics and sleep dynamics among children with autism spectrum disorder (ASD) using an actigraph, which is an objective assessment device used for sleep monitoring. Methods: A total of 40 children (age range, 3-6 years) participated in this study (n = 20, with ASD and n = 20, age-matched children with typical development [TD]). We examined sleep dynamics using actigraph for 7 consecutive days, and the relationship between sleep parameters and sensory characteristics was analyzed using the Japanese Version of Sensory Profile (SP-J). Results: Significant differences were observed in terms of activities per minute during sleep (p = 0.02), sleep efficiency (SE) (p = 0.005), and wake after sleep onset (WASO) (p = 0.02) between the two groups. In the ASD group, significant positive correlations were observed between activities per minute during sleep and low thresholds for Vestibular Sensory stimuli (p = 0.046) and Oral Sensory stimuli (p = 0.006) using the SP-J. Based on a multiple regression analysis, the activities per minute during sleep were associated with low thresholds for Oral Sensory stimuli (b = 0.51, t = 2.29, p = 0.03), but not with other factors, in the ASD group. Conclusions: The current study showed that atypical Vestibular and Oral Sensory modulation may be a risk indicator for high activities during sleep among preschool children with ASD. Thus, whether the interventions for these sensory characteristics are effective in improving sleep quality, daytime activities, behaviors, and cognitive functions in this group of children must be considered.

Brain and Development, 2022

Neuropsychopharmacology Reports, 2022

Attention ability is one of the most important cognitive functions. It develops mainly during sch... more Attention ability is one of the most important cognitive functions. It develops mainly during school age. However, the neural basis for the typical development of attentional functions has not been fully investigated. To clarify the development of the aforementioned function and its neural basis, this study examined brain function in children and adolescents during the performance of an attention network test (ANT) using functional magnetic resonance imaging. One hundred and sixty‐three volunteers (8‐23 years, 80 female) participated in this study. Using a modified version of ANT, we assessed the efficiency of two attentional functions—orienting and executive attention—by measuring how reaction time is affected by spatial cue location and flanker congruency and examined the functional brain areas—attentional networks—associated with two attentional functions. Consistent with the findings of previous studies, the superior parietal lobule, visual association cortex, left precentral gy...

PLOS ONE, 2015

<p>*<i>p</i> < 0.05</p><p>** <i>p</i> < 0.01, n.s... more <p>*<i>p</i> < 0.05</p><p>** <i>p</i> < 0.01, n.s., not significant.</p><p><b>Abbreviations:</b> SD, Standard Deviation; PTGI, Posttraumatic Growth Inventory; IES-R, Impact of Event Scale–Revised; BDI, Beck Depression Inventory.</p><p>Means, standard deviations, and intercorrelations between the psychological measures.</p

Journal of the American Academy of Child & Adolescent Psychiatry, 2017

We investigated the feasibility of using physiological biomarkers to predict the onset of aggress... more We investigated the feasibility of using physiological biomarkers to predict the onset of aggression in minimally verbal (MV) youth with autism spectrum disorder (ASD). Methods: Nine MV youth with confirmed ASD wore a wristband-mounted E4 biosensor during repeated unstructured observation periods while they were hospitalized in a specialized child psychiatry unit. Physiological and three axis acceleration data were collected concurrent with coding of aggressive behavior. Physiological arousal was measured by: 1) heart rate and heart rate variability, both derived from blood volume pulse (BVP) and interbeat interval (IBI) via photoplethysmography at 64 Hz; and 2) electrodermal activity (EDA), which reflects autonomic innervation of sweat glands. Advanced signal processing and machine learning algorithms were then applied to predict aggression onset. The area under the curve (AUC) accuracy (based on true/false positive rates) was calculated to predict the onset of aggression in the next one minute from present time (t). The predictions were made through a ridge-regularized logistic regression using: 1) previous t ¼ 3 minutes of motor movement acceleration (ACC) signals; 2) time elapsed since last aggression event; 3) previous t ¼ 3 minutes of BVP, EDA, and IBI signals; and 4) all of the above signals combined. Results: All youth tolerated the sensor after desensitization, usable data were obtained in all cases, and there was an average of 9.67 (range ¼ 0-44) aggressive episodes per four-hour observation period. Time-synced coding of aggression and concurrent E4 signal data predicted the onset of aggression with AUC ranging from 0.69 to 0.78. Discriminative power increased by seven percent as each additional signal was added. Conclusions: Our pilot data indicate that it is feasible to obtain physiologic and motor movement data from wearable biosensors in MV youth with ASD and aggression. When all data streams were combined, three minutes of data predicted the occurrence of aggression in the following minute with an AUC of 0.79. This will likely improve after applying more advanced classification algorithms to a larger data set. Developing a biomarker-based predictive system for imminent aggression could open a new window for understanding and intervention in youth with MV-ASD and challenging behaviors.

PLOS ONE, 2015

<p>Brain regions showing positive correlations between the PTGI scores and the strength of ... more <p>Brain regions showing positive correlations between the PTGI scores and the strength of the activity in the RSNs from the superior parietal lobule seed as determined by multiple regression analysis. The statistical threshold for the contrasts was voxel-level <i>p</i> < 0.001 uncorrected for height and cluster-level <i>p</i> < 0.05 corrected for multiple comparisons. The scatter plots show the associations between the PTGI scores and the strength of the functional connectivity between the superior parietal lobule and superior temporal gyrus.</p

Psychoneuroendocrinology, 2021

Mother's empathy is an important ability for parenting behavior. Many studies have confirmed ... more Mother's empathy is an important ability for parenting behavior. Many studies have confirmed that oxytocin affects empathy, but the epigenetic background of oxytocin in maternal empathy has not yet been examined. This study examined the relationship between the oxytocin gene methylation and empathy in mothers of children in early childhood. Additionally, in order to understand a comprehensive mechanism, we also investigated changes in gray matter volume as a function of oxytocin gene methylation and empathy. The Interpersonal Reactivity Index was used to assess cognitive and affective dimensions of empathy of the 57 mothers who participated in this study. Genetic data were collected via saliva samples and analyzed to quantify DNA methylation of oxytocin gene. Gray matter volumes were investigated by means of voxel-based morphometry across the whole brain. A positive correlation was found between oxytocin gene methylation and Personal Distress, an aspect of affective empathy. Moreover, we found an inverse correlation between oxytocin gene methylation and the volume of the right inferior temporal gyrus. In a relationship with oxytocin gene methylation and empathy, the indirect effect of the inferior temporal gyrus gray matter volumes was not significant. Our findings provide empirical evidence for an epigenetic mechanism linking the oxytocin gene, structural variation of brain, and empathy in mothers. Taken together, the current imaging epigenetic findings shed new light on the understanding of the epigenetic basis of oxytocin and parental empathy.

Background Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in J... more Background Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. Methods The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatm...

Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibite... more Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibited behaviors and reduced neural responses to rewards. Children and adolescents with RAD show aberrant attachment behaviors, and existing psychotherapies are difficult to maintain; therefore, pharmacological interventions to aid and boost treatment responses are needed. Oxytocin (OT) administration is known to promote reward functioning. We investigated whether single-use intranasal OT administration improved neural responses during reward processing in patients with RAD compared with healthy controls. Twenty-four male children and adolescents with RAD (10-18 years old) and 27 age-and sex-matched typically developing individuals (10-17 years old) were included in this randomized, double-blind, placebo-controlled, cross-over, functional magnetic resonance imaging study. Following a single intranasal OT (24 IU) or placebo administration, neural responses were investigated using a monetary reward task. In the RAD group, OT significantly increased subjective motivation scores, significantly enhanced activation in the right middle frontal gyrus, and reduced activation in the right precentral gyrus during the monetary reward task. Additional analyses revealed increased activation in the bilateral caudate at a more lenient threshold. Under placebo conditions, the severity of internalizing problems in patients with RAD was negatively correlated with ventral striatal activity. Moreover, the effect of OT on ventral striatum activity was positively associated with the severity of internalizing problems in patients with RAD. Intranasal OT administration enhanced activity in the reward pathway in male children and adolescents with RAD, suggesting that exogenous OT promotes reward processing and reward-related motivational behavior in these individuals. Further investigation is needed to fully understand the neural mechanisms of intranasal OT and identify novel targets for pediatric cases with RAD. Clinical trial registration: UMIN-CTR; UMIN000013215. URL: https://upload. umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000015419 KEYWORDS reactive attachment disorder (RAD), intranasal oxytocin, functional magnetic resonance imaging (fMRI), reward, childhood maltreatment, randomized controlled trial TYPE

Nihon Shinri Gakkai Taikai happyo ronbunshu, Sep 25, 2018

Human Brain Mapping, Jul 16, 2021

Child‐rearing mothers with high levels of trait anxiety have a tendency for less adaptive sensory... more Child‐rearing mothers with high levels of trait anxiety have a tendency for less adaptive sensory processing, which causes parenting stress. However, the neural mechanisms underlying this sensory processing and trait anxiety remain unclear. We aimed to determine the whole‐brain spontaneous neural activity and sensory processing characteristics in mothers with varying parenting stress levels. Using resting‐state functional magnetic resonance imaging, we assessed mothers caring for more than one preschool aged (2–5 years) child and presenting with varying levels of sensory processing, trait anxiety, and parenting stress. Spontaneous neural activities in select brain regions were evaluated by whole‐brain correlation analyses based on the fractional amplitude of low‐frequency fluctuations (fALFF). We found significant positive correlations between levels of sensory processing with trait anxiety and parenting stress. Mothers having less adaptive sensory processing had significantly increased resting‐state network activities in the left lobule VI of the cerebellum. Increased fALFF values in the left lobule VI confirmed the mediation effect on the relationship between trait anxiety and sensory processing. A tendency for less adaptive sensory processing involving increased brain activity in lobule VI could be an indicator of maternal trait anxiety and the risk of parenting stress.

Research Square (Research Square), May 15, 2023

Background: The pooled sample method is used in epigenomic research and expression analysis and i... more Background: The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina In nium Methylation 450 K BeadChip array; however, subsequent reports on the updated 850 K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quanti cation method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become uorescencebased, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples. Results: The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450 K BeadChip array. However, considering a dataset of 1,000 randomly extracted CpG sites, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a su cient effect size. Conclusions: The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is cost-effective and can be utilized for screening by carefully understanding the features for its effective points and disadvantages of the pooled sample method and combining it with candidate gene analyses. Background Research on epigenomes and their interaction with genetics which re ect the "nurture and environment" aspect has shifted the focus from solely studying genetic sequences in various elds (1). Epigenomic research, initially dominated by cancer research (2), has recently expanded to include studies on the relationship between various phenotypes, such as aging (3-7), nutrition and diet (8), environmental pollutants (9, 10), immunity (11, 12), neurological disorders (13), psychiatric disorders (14-17), and psychological traits (18, 19), and is expected to increase further (20). Converse to data-driven genome-wide association analysis, hypothesis-driven candidate gene analysis is the primary approach for conducting epigenomic studies. However, studies that focus on the results of candidate gene analysis and candidate gene-by-environment interactions alone for understanding complex traits without replication experiments have been becoming outdated (21). As genome-wide data,

Brain Imaging and Behavior

This randomized controlled study examined neurological changes in socioemotional processing skill... more This randomized controlled study examined neurological changes in socioemotional processing skills through parent training in caregivers of children with attention-deficit/hyperactivity disorder. Thirty mothers of children with attention-deficit/hyperactivity disorder were stratified into parent training and non-parent training groups. Functional magnetic resonance imaging was performed during the “Reading the Mind in the Eyes” test, and parenting difficulties were evaluated using the Parenting Stress Index and the Parenting Scale, twice (before and after parent training). Only mothers in the parent training group showed a significant decrease in Parenting Stress Index and Parenting Scale scores. They also demonstrated increased activity in the left occipital fusiform gyrus during the task of estimating emotions from facial pictures. We presumed that these changes might reflect the potential impact of enrollment in parent training in reducing stress, which might have increased activ...

Translational Psychiatry

Neuroepigenetics considers genetic sequences and the interplay with environmental influences to e... more Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with...

This randomized controlled study examined neurological changes in socioemotional processing skill... more This randomized controlled study examined neurological changes in socioemotional processing skills through parent training in caregivers of children with attention-deficit/hyperactivity disorder. Thirty mothers of children with attention-deficit/hyperactivity disorder were stratified into parent training and non-parent training groups. Functional magnetic resonance imaging was performed during the “Reading the Mind in the Eyes” test, and parenting difficulties were evaluated using the Parenting Stress Index and the Parenting Scale, twice (before and after parent training). Only mothers in the parent training group showed a significant decrease in Parenting Stress Index and Parenting Scale scores. They also demonstrated increased activity in the left occipital fusiform gyrus during the task of estimating emotions from facial pictures, with a trend towards a reduced response time while judging others’ emotional state in the “Reading the Mind in the Eyes” test. We presumed that these c...

Frontiers in Child and Adolescent Psychiatry

Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibite... more Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibited behaviors and reduced neural responses to rewards. Children and adolescents with RAD show aberrant attachment behaviors, and existing psychotherapies are difficult to maintain; therefore, pharmacological interventions to aid and boost treatment responses are needed. Oxytocin (OT) administration is known to promote reward functioning. We investigated whether single-use intranasal OT administration improved neural responses during reward processing in patients with RAD compared with healthy controls. Twenty-four male children and adolescents with RAD (10–18 years old) and 27 age- and sex-matched typically developing individuals (10–17 years old) were included in this randomized, double-blind, placebo-controlled, cross-over, functional magnetic resonance imaging study. Following a single intranasal OT (24 IU) or placebo administration, neural responses were investigated using a monetary r...

Neuroepigenetics considers genetic sequences and the interplay with environmental influences to e... more Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with...

Frontiers in Psychiatry

The purpose of this study was to examine whether the beneficial effects of behavioral parent trai... more The purpose of this study was to examine whether the beneficial effects of behavioral parent training (BPT), as an indirect type of psychosocial treatment, are extended to cognitive manifestations beyond behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Although previous studies of community families have shown an association between parenting quality and a child’s cognitive functions, little is known about the effects of BPT on cognitive manifestations in children with ADHD. In this study, we focused on inhibitory control among cognitive domains, which is considered to be the most malleable to direct types of psychosocial treatment for ADHD. We hypothesized that inhibitory control is affected by BPT, which uses parents as the primary agents of change to help their children. Thirty school-age children (6–12 years old) with ADHD and their parents (mothers) participated and were randomly assigned to either the standard BPT or waitlist control group. Using two obj...

Brain and Development

Aims: The current study aimed to validate the relationship between sensory characteristics and sl... more Aims: The current study aimed to validate the relationship between sensory characteristics and sleep dynamics among children with autism spectrum disorder (ASD) using an actigraph, which is an objective assessment device used for sleep monitoring. Methods: A total of 40 children (age range, 3-6 years) participated in this study (n = 20, with ASD and n = 20, age-matched children with typical development [TD]). We examined sleep dynamics using actigraph for 7 consecutive days, and the relationship between sleep parameters and sensory characteristics was analyzed using the Japanese Version of Sensory Profile (SP-J). Results: Significant differences were observed in terms of activities per minute during sleep (p = 0.02), sleep efficiency (SE) (p = 0.005), and wake after sleep onset (WASO) (p = 0.02) between the two groups. In the ASD group, significant positive correlations were observed between activities per minute during sleep and low thresholds for Vestibular Sensory stimuli (p = 0.046) and Oral Sensory stimuli (p = 0.006) using the SP-J. Based on a multiple regression analysis, the activities per minute during sleep were associated with low thresholds for Oral Sensory stimuli (b = 0.51, t = 2.29, p = 0.03), but not with other factors, in the ASD group. Conclusions: The current study showed that atypical Vestibular and Oral Sensory modulation may be a risk indicator for high activities during sleep among preschool children with ASD. Thus, whether the interventions for these sensory characteristics are effective in improving sleep quality, daytime activities, behaviors, and cognitive functions in this group of children must be considered.

Brain and Development, 2022

Neuropsychopharmacology Reports, 2022

Attention ability is one of the most important cognitive functions. It develops mainly during sch... more Attention ability is one of the most important cognitive functions. It develops mainly during school age. However, the neural basis for the typical development of attentional functions has not been fully investigated. To clarify the development of the aforementioned function and its neural basis, this study examined brain function in children and adolescents during the performance of an attention network test (ANT) using functional magnetic resonance imaging. One hundred and sixty‐three volunteers (8‐23 years, 80 female) participated in this study. Using a modified version of ANT, we assessed the efficiency of two attentional functions—orienting and executive attention—by measuring how reaction time is affected by spatial cue location and flanker congruency and examined the functional brain areas—attentional networks—associated with two attentional functions. Consistent with the findings of previous studies, the superior parietal lobule, visual association cortex, left precentral gy...

PLOS ONE, 2015

<p>*<i>p</i> < 0.05</p><p>** <i>p</i> < 0.01, n.s... more <p>*<i>p</i> < 0.05</p><p>** <i>p</i> < 0.01, n.s., not significant.</p><p><b>Abbreviations:</b> SD, Standard Deviation; PTGI, Posttraumatic Growth Inventory; IES-R, Impact of Event Scale–Revised; BDI, Beck Depression Inventory.</p><p>Means, standard deviations, and intercorrelations between the psychological measures.</p

Journal of the American Academy of Child & Adolescent Psychiatry, 2017

We investigated the feasibility of using physiological biomarkers to predict the onset of aggress... more We investigated the feasibility of using physiological biomarkers to predict the onset of aggression in minimally verbal (MV) youth with autism spectrum disorder (ASD). Methods: Nine MV youth with confirmed ASD wore a wristband-mounted E4 biosensor during repeated unstructured observation periods while they were hospitalized in a specialized child psychiatry unit. Physiological and three axis acceleration data were collected concurrent with coding of aggressive behavior. Physiological arousal was measured by: 1) heart rate and heart rate variability, both derived from blood volume pulse (BVP) and interbeat interval (IBI) via photoplethysmography at 64 Hz; and 2) electrodermal activity (EDA), which reflects autonomic innervation of sweat glands. Advanced signal processing and machine learning algorithms were then applied to predict aggression onset. The area under the curve (AUC) accuracy (based on true/false positive rates) was calculated to predict the onset of aggression in the next one minute from present time (t). The predictions were made through a ridge-regularized logistic regression using: 1) previous t ¼ 3 minutes of motor movement acceleration (ACC) signals; 2) time elapsed since last aggression event; 3) previous t ¼ 3 minutes of BVP, EDA, and IBI signals; and 4) all of the above signals combined. Results: All youth tolerated the sensor after desensitization, usable data were obtained in all cases, and there was an average of 9.67 (range ¼ 0-44) aggressive episodes per four-hour observation period. Time-synced coding of aggression and concurrent E4 signal data predicted the onset of aggression with AUC ranging from 0.69 to 0.78. Discriminative power increased by seven percent as each additional signal was added. Conclusions: Our pilot data indicate that it is feasible to obtain physiologic and motor movement data from wearable biosensors in MV youth with ASD and aggression. When all data streams were combined, three minutes of data predicted the occurrence of aggression in the following minute with an AUC of 0.79. This will likely improve after applying more advanced classification algorithms to a larger data set. Developing a biomarker-based predictive system for imminent aggression could open a new window for understanding and intervention in youth with MV-ASD and challenging behaviors.

PLOS ONE, 2015

<p>Brain regions showing positive correlations between the PTGI scores and the strength of ... more <p>Brain regions showing positive correlations between the PTGI scores and the strength of the activity in the RSNs from the superior parietal lobule seed as determined by multiple regression analysis. The statistical threshold for the contrasts was voxel-level <i>p</i> < 0.001 uncorrected for height and cluster-level <i>p</i> < 0.05 corrected for multiple comparisons. The scatter plots show the associations between the PTGI scores and the strength of the functional connectivity between the superior parietal lobule and superior temporal gyrus.</p

Psychoneuroendocrinology, 2021

Mother's empathy is an important ability for parenting behavior. Many studies have confirmed ... more Mother's empathy is an important ability for parenting behavior. Many studies have confirmed that oxytocin affects empathy, but the epigenetic background of oxytocin in maternal empathy has not yet been examined. This study examined the relationship between the oxytocin gene methylation and empathy in mothers of children in early childhood. Additionally, in order to understand a comprehensive mechanism, we also investigated changes in gray matter volume as a function of oxytocin gene methylation and empathy. The Interpersonal Reactivity Index was used to assess cognitive and affective dimensions of empathy of the 57 mothers who participated in this study. Genetic data were collected via saliva samples and analyzed to quantify DNA methylation of oxytocin gene. Gray matter volumes were investigated by means of voxel-based morphometry across the whole brain. A positive correlation was found between oxytocin gene methylation and Personal Distress, an aspect of affective empathy. Moreover, we found an inverse correlation between oxytocin gene methylation and the volume of the right inferior temporal gyrus. In a relationship with oxytocin gene methylation and empathy, the indirect effect of the inferior temporal gyrus gray matter volumes was not significant. Our findings provide empirical evidence for an epigenetic mechanism linking the oxytocin gene, structural variation of brain, and empathy in mothers. Taken together, the current imaging epigenetic findings shed new light on the understanding of the epigenetic basis of oxytocin and parental empathy.