Shota Nishitani

All Publications

• Multi-epigenome-wide analyses and meta-analysis of child maltreatment in judicial autopsies and intervened children and adolescents. Molecular psychiatry Nishitani, S., Fujisawa, T. X., Takiguchi, S., Yao, A., Murata, K., Hiraoka, D., Mizuno, Y., Ochiai, K., Kawata, N. Y., Makita, K., Saito, D. N., Mizushima, S., Suzuki, S., Kurata, S., Ishiuchi, N., Taniyama, D., Nakao, N., Namera, A., Okazawa, H., Nagao, M., Tomoda, A. 2025

  Abstract

  Child maltreatment (CM) is associated with adverse physical, psychological, and neurodevelopmental outcomes later in life. Epigenetic modifications, particularly DNA methylation, have been proposed as potential mechanisms underlying these long-term effects. To identify robust CM-associated methylation signatures, we conducted epigenome-wide analyses across three independent cohorts: judicial autopsy cases (CM:11, Controls:7), toddlers shortly after social intervention (CM:36, Controls:49), and adolescents who underwent brain MRI (CM:61, Controls:62). Each cohort was analyzed separately, followed by a meta-analysis to identify common methylation sites associated with CM exposure. The meta-analysis identified four significant CpG sites located within the ATE1, SERPINB9P1, CHST11, and FOXP1 genes. Among these, methylation of FOXP1 was consistently associated with structural brain alterations, including increased gray matter volume (GMV) in the orbitofrontal cortex (OFrC) and middle/posterior cingulate gyrus (MPCG), and decreased GMV in the occipital fusiform gyrus (OFuG). These brain regions are implicated in emotional regulation, memory retrieval, and social cognition, suggesting a potential neurobiological mechanism linking CM to later psychopathology. Furthermore, methylation risk scores (MRS) derived from these four CpGs successfully discriminated individuals who experienced early-life adversity in an independent validation dataset, achieving an area under the receiver operating characteristic curve (AUC) of 0.672, highlighting their potential utility as biomarkers. Gene ontology and pathway analyses revealed enrichment of cholinergic and glutamatergic synaptic transmission pathways, supporting their involvement in traumatic memory formation. Our findings provide novel insights into the epigenetic mechanisms underlying CM and identify potential biomarkers for early detection, prevention, and therapeutic intervention, ultimately contributing to breaking the intergenerational cycle of maltreatment.

  View details for DOI 10.1038/s41380-025-03236-1

  View details for PubMedID 40957904

  View details for PubMedCentralID 7896059

• Random forest and Shapley Additive exPlanations predict oxytocin targeted effects on brain functional networks involved in salience and sensorimotor processing, in a randomized clinical trial in autism NEUROPSYCHOPHARMACOLOGY Andari, E., Gopinath, K., O'Leary, E., Caceres, G. A., Nishitani, S., Smith, A. K., Ousley, O., Rilling, J. K., Cubells, J. F., Young, L. J. 2025: 1385-1394

  Abstract

  Intranasal oxytocin (IN-OXT) has shown some promises in rescuing social deficits in autism spectrum disorder (ASD) as well as some inconsistencies in long-term trials. We conducted a target engagement study to study the precise effects of different doses of IN-OXT on brain resting-state functional connectivity (rsFC) in ASD. We examined the effects of varying doses of IN-OXT (0 IU, 8 IU, 24 IU, 48 IU) on rsFC in a double-blind, placebo-controlled, within-subject design in 30 male adults with ASD and 17 neurotypical controls (NT) receiving placebo. Random forest analysis was used to classify individuals as ASD or NT. Shapely Additive explanations values were calculated to rank brain functional networks by level of contribution to ASD deficits and to evaluate IN-OXT dose effects. The model predicted ASD diagnosis with an AUC of 94%. Hypoconnectivity between salience/empathy and visual networks, and hyperconnectivity between reward and sensorimotor networks and theory of mind networks were among the strongest predictors of ASD deficits. IN-OXT had a dose-dependent effect on rescuing both deficits described above. Overall, 48 IU dose was more effective, and 24 IU dose was more effective in those who have lower DNA OXT receptor methylation and lower severity of clinical symptoms. Higher doses of OXT might be necessary to enhance empathic responses, and ASD individuals with less support needs and with a preserved OXT system might benefit most from OXT treatment. Applying machine learning approaches in OXT research can provide data-driven unbiased results that can inform future clinical trials.

  View details for DOI 10.1038/s41386-025-02095-2

  View details for Web of Science ID 001457963600001

  View details for PubMedID 40175527

  View details for PubMedCentralID PMC12260019

• Glial Contribution to the Pathogenesis of Post-Operative Delirium Revealed by Multi-omic Analysis of Brain Tissue from Neurosurgery Patients. bioRxiv : the preprint server for biology Ishii, T., Wang, T., Shibata, K., Nishitani, S., Yamanashi, T., Wahba, N. E., Seki, T., Thompson, K. J., Yamanishi, K., Nishiguchi, T., Shimura, A., Aoyama, B., Gorantla, N., Phuong, N. J., Nguyen, H. D., Santiago, T. A., Nishizawa, Y., Nagao, T., Howard, M. A., Kawasaki, H., Hino, K., Ikeda, A., Snyder, M. P., Shinozaki, G. 2025

  Abstract

  Post-operative delirium (POD) is a common complication after surgery especially in elderly patients, characterized by acute disturbances in consciousness and cognition, which negatively impacts long-term outcomes. Effective treatments remain elusive due to the unclear pathophysiology of POD. To address the knowledge gap, we investigated DNA methylation profiles and gene expression changes in brain cells from POD and non-POD patients who underwent brain resection surgery for medication refractory epilepsy. DNA methylation analysis revealed alteration in epigenetic status of immune and inflammation-related genes. Single-nucleus RNA sequencing (snRNAseq) identified POD-specific glial cell alterations, particularly in microglia, where neuroinflammation was strongly enhanced, consistent with epigenetic findings. Astrocytes exhibited changes in synapse-related functions and migration. Furthermore, downstream analysis indicated similarities between POD-associated glial cell states and pathologies such as encephalitis and dementia. Overall, this study-the first multi-omics analysis of brain tissue from POD patients-provides direct evidence of glial cell contributions to POD pathogenesis, and highlights potential therapeutic targets.

  View details for DOI 10.1101/2025.03.13.643155

  View details for PubMedID 40161597

  View details for PubMedCentralID PMC11952519

• Effects of childhood maltreatment on mothers' empathy and parenting styles in intergenerational transmission SCIENTIFIC REPORTS Kawaguchi, Y., Kurata, S., Kawata, N. Y. S., Yao, A., Nishitani, S., Fujisawa, T. X., Tomoda, A. 2025; 15 (1): 7787

  Abstract

  Understanding the intergenerational transmission of childhood maltreatment (CM) is crucial to prevent its perpetuation to future generations. The literature has revealed parental empathy to be a pivotal factor in this process. Parental empathy is the ability to comprehend and empathetically respond to the emotions and mental states of children; therefore, its impairment may result in challenges in parenting, ultimately contributing to CM. In this study, we explored the factors that undermine empathy and how they alter parenting practices, to uncover the process of intergenerational transmission of CM. To investigate actual instances of CM, a comparative study was conducted between 13 mothers with a history of social interventions owing to CM and 42 mothers in the control group. Path analysis was performed to examine the trajectory from adverse childhood experiences to maltreatment and explore their correlations with variables including affective and cognitive empathy, depressive symptoms, and parenting styles. The results showed that experiences of CM specifically enhanced empathy in the emotional domain in the maltreatment group. Furthermore, heightened empathy in the maltreatment group influenced parenting style mediated by depressive symptoms. These results provide important insights into the intergenerational transmission process in the context of parental empathy.

  View details for DOI 10.1038/s41598-025-92804-0

  View details for Web of Science ID 001486621500014

  View details for PubMedID 40044920

  View details for PubMedCentralID PMC11882814

• Behavioral and emotional difficulties in maltreated children: Associations with epigenetic clock changes and visual attention to social cues PLOS ONE Ochiai, K., Nishitani, S., Yao, A., Hiraoka, D., Kawata, N. Y. S., Suzuki, S., Fujisawa, T. X., Tomoda, A. 2025; 20 (5): e0321952

  Abstract

  Research indicates that childhood maltreatment leads to adverse outcomes later in life and accelerated aging. However, few studies have investigated how age acceleration manifests during childhood. This study aimed to investigate the impact of child maltreatment on DNA methylation age (mAge) acceleration using a case-control study design and its association with visual attention and behavioral and emotional outcomes in maltreated children (CM). We hypothesized that CM experience atypical aging, which adversely affects their behavioral and emotional outcomes by disrupting the cognitive development necessary for forming interpersonal relationships. The study included 36 CM and 60 typically developing (TD) children with an average age of 4-5 years. We compared their DNA mAge acceleration, measured through buccal DNA samples. Additionally, we conducted a behavioral assessment of their cognitive functions related to interpersonal interactions, using an eye-tracking system to measure their gaze points at various social stimuli. Behavioral and emotional outcomes were evaluated using the Strength and Difficulties Questionnaire (SDQ). The results showed that CM exhibited significantly higher mAge acceleration and spent significantly less time gazing at the eye region during facial expression presentations. While a significant association between these attributes was observed, a comprehensive path analysis revealed that each attribute independently correlated with higher SDQ scores, suggesting that child maltreatment leads to these difficulties through accelerated aging and decreased eye contact. This study provides significant insights into how child maltreatment impacts children's development. It demonstrates that mAge acceleration and reduced attention to the eye region are critical factors associated with the adverse behavioral and emotional outcomes observed in maltreated children. These findings highlight the importance of early intervention and support for maltreated children to mitigate the long-term effects of accelerated aging and social cognitive deficits.

  View details for DOI 10.1371/journal.pone.0321952

  View details for Web of Science ID 001499546000001

  View details for PubMedID 40445999

  View details for PubMedCentralID PMC12124526

• Assessing childhood maltreatment exposure using the child behavior checklist. Frontiers in child and adolescent psychiatry Makino, T., Nishitani, S., Takiguchi, S., Yao, A., Fujisawa, T. X., Tomoda, A. 2025; 4: 1493432

  Abstract

  Introduction: Childhood maltreatment (CM) has broad and severe adverse effects in later life, but there are not enough studies conducted during childhood close to the time of maltreatment. Most studies have focused only on a single symptom and have not attempted to capture the global picture of CM.Methods: We used the Child Behavior Checklist (CBCL) to assess children's behavioral/emotional problems more comprehensively. This study leveraged 32 CM children and 29 typically developing (TD) children who have been assessed using the CBCL 4-18 from our dataset. Group comparisons of the eight subscales were conducted to characterize each behavioral/emotional problem. Receiver Operating Characteristic (ROC) curve analysis was conducted to assess the classification performance. Finally, sensitive period and type analyses were performed based on the children's maltreatment history.Results: The CM group showed significantly higher behavioral/emotional problems in seven out of the eight subscales. Logistic regression analysis was performed using all combinations of CBCL subscale T-scores and age, sex, and IQ. We created 2047 models and performed ROC analysis for each. Three models were generated: the most accurate model (comprising CBCL T-score, age, sex, and IQ; sensitivity: 0.906, specificity: 0.966), a model excluding IQ (sensitivity: 0.875, specificity: 0.931), and a model consisting only of CBCL (sensitivity: 0.906, specificity: 0.862). The CBCL demonstrated robust predictive capacity for CM by utilizing information provided by caregivers, without directly inquiring about trauma. The sensitive period analysis revealed that the temporal predictor of severity for "withdrawn" and "thought problems" were exposure to CM at age five. Similarly, exposure to CM between the ages of five and seven predicted "somatic complaints". In the case of type, physical abuse was the predictor for "somatic complaints" and "delinquent behavior", and emotional abuse was the predictor for "anxious/depressed" and "thought problems".Conclusion: Maltreated children present a wider range of behavioral/emotional problems, which must be considered when supporting them. Perspectives gained from sensitive analyses of maltreatment history will help clinicians provide more appropriate interventions.

  View details for DOI 10.3389/frcha.2025.1493432

  View details for PubMedID 40406734

• Subclinical structural atypicality of retinal thickness and its association with gray matter volume in the visual cortex of maltreated children SCIENTIFIC REPORTS Yao, A., Nishitani, S., Yamada, Y., Oshima, H., Sugihara, Y., Makita, K., Takiguchi, S., Kawata, N. Y. S., Fujisawa, T. X., Okazawa, H., Inatani, M., Tomoda, A. 2024; 14 (1): 11465

  Abstract

  Childhood maltreatment is reportedly associated with atypical gray matter structures in the primary visual cortex (V1). This study explores the hypothesis that retinal structures, the sensory organs of vision, are associated with brain atypicality and child maltreatment and examines their interrelation. General ophthalmologic examinations, visual cognitive tasks, retinal imaging, and structural magnetic resonance imaging (MRI) were conducted in children and adolescents aged 9-18 years with maltreatment experiences (CM) and typically developing (TD) children. The retinal nerve fiber layer (RNFL), the most superficial of the ten distinct retinal layers, was found to be significantly thinner in both eyes in CM. While whole-brain analysis using Voxel-based morphometry revealed a significantly larger gray matter volume (GMV) in the thalamus in CM, no significant correlation with RNFL thickness was observed. However, based on region-of-interest analysis, a thinner RNFL was associated with a larger GMV in the right V1. Although it cannot be ruled out that this outcome resulted from maltreatment alone, CM demonstrated subclinical structural atypicality in the retina, which may also correlate with the immaturity of V1 development. Examination of retinal thickness offers a novel clinical approach to capturing characteristics associated with childhood maltreatment.

  View details for DOI 10.1038/s41598-024-62392-6

  View details for Web of Science ID 001228252900013

  View details for PubMedID 38769421

  View details for PubMedCentralID PMC11106279

• Brain structures and functional connectivity in neglected children with no other types of maltreatment NEUROIMAGE Kawata, N. Y. S., Nishitani, S., Yao, A., Takiguchi, S., Mizuno, Y., Mizushima, S., Makita, K., Hamamura, S., Saito, D. N., Okazawa, H., Fujisawa, T. X., Tomoda, A. 2024; 292: 120589

  Abstract

  Child maltreatment can adversely affect brain development, leading to vulnerabilities in brain structure and function and various psychiatric disorders. Among the various types of child maltreatment, neglect has the highest incidence rate (76.0%); however, data on its sole adverse influence on the brain remain limited. This case-control brain magnetic resonance imaging (MRI) study identified the changes in gray matter structure and function that distinguish neglected children with no other type of maltreatment (Neglect group, n = 23) from typically developing children (TD group, n = 140), and investigated the association between these structural and functional differences and specific psychosocial phenotypes observed in neglected children. Our results showed that the Neglect group had a larger right and left anterior cingulate cortex (R/L.ACC) and smaller left angular gyrus (L.AG) gray matter volume. The larger R/L.ACC was associated with hyperactivity and inattention. Resting-state functional analysis showed increased functional connectivity (FC) between the left supramarginal gyrus (L.SMG) in the salience network (SN) and the right middle frontal gyrus (R.MFG) simultaneously with a decrease in FC with the L.ACC for the same seed. The increased FC for the R.MFG was associated with difficulty in peer problems and depressive symptoms; a mediating effect was evident for depressive symptoms. These results suggest that the structural atypicality of the R/L.ACC indirectly contributes to the disturbed FCs within the SN, thereby exacerbating depressive symptoms in neglected children. In conclusion, exposure to neglect in childhood may lead to maladaptive brain development, particularly neural changes associated with depressive symptoms.

  View details for DOI 10.1016/j.neuroimage.2024.120589

  View details for Web of Science ID 001225571600001

  View details for PubMedID 38575041

• The neurobiological effects of childhood maltreatment on brain structure, function, and attachment EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE Tomoda, A., Nishitani, S., Takiguchi, S., Fujisawa, T. X., Sugiyama, T., Teicher, M. H. 2024

  Abstract

  Childhood maltreatment is a risk factor for psychopathologies, and influences brain development at specific periods, particularly during early childhood and adolescence. This narrative review addresses phenotypic alterations in sensory systems associated with specific types of childhood maltreatment exposure, periods of vulnerability to the neurobiological effects of maltreatment, and the relationships between childhood maltreatment and brain structure, function, connectivity, and network architecture; psychopathology; and resilience. It also addresses neurobiological alterations associated with maternal communication and attachment disturbances, and uses laboratory-based measures during infancy and case-control studies to elucidate neurobiological alterations in reactive attachment disorders in children with maltreatment histories. Moreover, we review studies on the acute effects of oxytocin on reactive attachment disorder and maltreatment and methylation of oxytocin regulatory genes. Epigenetic changes may play a critical role in initiating or producing the atypical structural and functional brain alterations associated with childhood maltreatment. However, these changes could be reversed through psychological and pharmacological interventions, and by anticipating or preventing the emergence of brain alterations and subsequent psychopathological risks.

  View details for DOI 10.1007/s00406-024-01779-y

  View details for Web of Science ID 001179803100001

  View details for PubMedID 38466395

  View details for PubMedCentralID 3406538

• Diffusion tensor imaging of white-matter structural features of maltreating mothers and their associations with intergenerational chain of childhood abuse SCIENTIFIC REPORTS Kurata, S., Nishitani, S., Kawata, N. Y. S., Yao, A., Fujisawa, T. X., Okazawa, H., Tomoda, A. 2024; 14 (1): 5671

  Abstract

  Child abuse causes lifelong adverse outcomes for both physical and mental health, although many are resilient. Efforts to prevent this issue from the parental side require an understanding of the neurobiological basis that leads abusive parents to perpetrate abuse and the influence of the intergenerational chain of childhood abuse. Therefore, this study was conducted to compare the brain white-matter fiber structures between 11 maltreating mothers who had been recognized as having conducted child abuse prior to the intervention and 40 age-matched control mothers using tract-based spatial statistics. There was a significantly reduced axial diffusivity (AD) and a similar trend in fractional anisotropy (FA) in the right corticospinal tract in maltreating mothers compared to control mothers. Therefore, maltreating mothers may have excessive control over the forcefulness of voluntary movements. These features also decreased as the number of childhood abuse experiences increased, suggesting that an intergenerational chain of child abuse may also be involved. Other aspects observed were that the higher the current depressive symptoms, the lower the AD and FA values; however, they were not related to parental practice or empathy. These results corroborate the neurobiological features that perpetrate behaviors in abusive mothers.

  View details for DOI 10.1038/s41598-024-53666-0

  View details for Web of Science ID 001185083700105

  View details for PubMedID 38453944

  View details for PubMedCentralID PMC10920819

• Data science using the human epigenome for predicting multifactorial diseases and symptoms EPIGENOMICS Nishitani, S., Smith, A. K., Tomoda, A., Fujisawa, T. X. 2024; 16 (5): 273-276

  Abstract

  Tweetable abstract This article reviews machine learning models that leverages epigenomic data for predicting multifactorial diseases and symptoms as well as how such models can be utilized to explore new research questions.

  View details for DOI 10.2217/epi-2023-0321

  View details for Web of Science ID 001157503100001

  View details for PubMedID 38312014

• Evaluation of the pooled sample method in Infinium MethylationEPIC BeadChip array by comparison with individual samples CLINICAL EPIGENETICS Nishitani, S., Fujisawa, T. X., Yao, A., Takiguchi, S., Tomoda, A. 2023; 15 (1): 138

  Abstract

  The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach for small amounts of DNA. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina Infinium Methylation 450K BeadChip array; however, subsequent reports on the updated 850K 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 quantification method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become fluorescence-based, 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.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 450K BeadChip array. However, 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 sufficient effect size.The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is sample amount-effective and cost-effective and can be utilized for screening by carefully understanding the effective features and disadvantages of the pooled sample method and combining it with candidate gene analyses.

  View details for DOI 10.1186/s13148-023-01544-3

  View details for Web of Science ID 001056961300001

  View details for PubMedID 37641110

  View details for PubMedCentralID PMC10463626

• Validity and reliability of the Japanese versions of the coronavirus anxiety scale for adolescents and obsession with COVID-19 scale for adolescents PEERJ Makino, T., Ide, S., Shiino, T., Hiraoka, D., Ishibashi, S., Suzuki, F., Nishitani, S. 2023; 11: e15710

  Abstract

  The coronavirus disease 2019 (COVID-19) has caused mental health issues in both adults and adolescents. The Coronavirus Anxiety Scale (CAS) and Obsession with COVID-19 Scale (OCS) questionnaires measure anxiety and persistent and disturbed thoughts (also known as obsessions) related to COVID-19. We developed Japanese versions of the CAS (i.e., CAS-JA) and OCS (i.e., OCS-JA) questionnaires to make them suitable for adolescents and validated the characteristics of these scales.Two online surveys were administered to high school students aged 15-18 years. A total of 263 students participated in the first survey and almost half of them participated in the second survey. In the first survey, participants responded to the CAS-JA, OCS-JA, generalized anxiety and obsessive-compulsive subscales of the Spence Children's Anxiety Scale (SCAS), and Kessler 6 Scale (K6). The SCAS and K6 were used to verify discriminant validity and inter-scale correlations. In the second survey, the participants completed the CAS-JA and OCS-JA again to verify test-retest reliability. We performed a confirmatory factor analysis and calculated the model fit indices. Additionally, we examined the internal consistency reliability, convergent validity, and inter-item correlations of the CAS-JA and OCS-JA. Moreover, differences in CAS-JA and OCS-JA responses by gender and region of residence (state of emergency and non-emergency areas) were examined.The results of the single-factor model confirmatory factor analysis of model fit indices were above the threshold. The required criteria for internal consistency reliability, test-retest reliability, and discriminant and convergent validity were met in both the CAS-JA and OCS-JA. No statistically significant differences attributed to residence and gender were found in both questionnaires.The results indicate that the CAS-JA and OCS-JA questionnaires are useful in measuring COVID-19-related anxiety, and persistent and disturbed thoughts in Japanese adolescents.

  View details for DOI 10.7717/peerj.15710

  View details for Web of Science ID 001050784900001

  View details for PubMedID 37576515

  View details for PubMedCentralID PMC10422950

• Child Developmental MRI (CDM) project: protocol for a multi-centre, cross-sectional study on elucidating the pathophysiology of attention-deficit/hyperactivity disorder and autism spectrum disorder through a multi-dimensional approach BMJ OPEN Yamashita, M., Kagitani-Shimono, K., Hirano, Y., Hamatani, S., Nishitani, S., Yao, A., Kurata, S., Kosaka, H., Jung, M., Yoshida, T., Sasaki, T., Matsumoto, K., Kato, Y., Nakanishi, M., Tachibana, M., Mohri, I., Tsuchiya, K. J., Tsujikawa, T., Okazawa, H., Shimizu, E., Taniike, M., Tomoda, A., Mizuno, Y. 2023; 13 (6): e070157

  Abstract

  Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have demonstrated differences in extensive brain structure, activity and network. However, there remains heterogeneity and inconsistency across these findings, presumably because of the diversity of the disorders themselves, small sample sizes, and site and parameter differences in MRI scanners, and their overall pathogenesis remains unclear. To address these gaps in the literature, we will apply the travelling-subject approach to correct site differences in MRI scanners and clarify brain structure and network characteristics of children with ADHD and ASD using large samples collected in a multi-centre collaboration. In addition, we will investigate the relationship between these characteristics and genetic, epigenetic, biochemical markers, and behavioural and psychological measures.We will collect resting-state functional MRI (fMRI) and T1-weighted and diffusion-weighted MRI data from 15 healthy adults as travelling subjects and 300 children (ADHD, n=100; ASD, n=100; and typical development, n=100) with multi-dimensional assessments. We will also apply data from more than 1000 samples acquired in our previous neuroimaging studies on ADHD and ASD.The study protocol has been approved by the Research Ethics Committee of the University of Fukui Hospital (approval no: 20220601). Our study findings will be submitted to scientific peer-reviewed journals and conferences.

  View details for DOI 10.1136/bmjopen-2022-070157

  View details for Web of Science ID 001021531400023

  View details for PubMedID 37355265

  View details for PubMedCentralID PMC10314540

• Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues. Translational psychiatry Nishitani, S., Isozaki, M., Yao, A., Higashino, Y., Yamauchi, T., Kidoguchi, M., Kawajiri, S., Tsunetoshi, K., Neish, H., Imoto, H., Arishima, H., Kodera, T., Fujisawa, T. X., Nomura, S., Kikuta, K., Shinozaki, G., Tomoda, A. 2023; 13 (1): 72

  Abstract

  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 when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva-brain correlation (r=0.90) was higher than that for blood-brain (r=0.87) and buccal-brain (r=0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r=0.27, saliva: r=0.18, and buccal: r=0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

  View details for DOI 10.1038/s41398-023-02370-0

  View details for PubMedID 36843037

• Endogenous oxytocin levels in extracted saliva elevates during breastfeeding correlated with lower postpartum anxiety in primiparous mothers BMC PREGNANCY AND CHILDBIRTH Nagahashi-Araki, M., Tasaka, M., Takamura, T., Eto, H., Sasaki, N., Fujita, W., Miyazaki, A., Morifuji, K., Honda, N., Miyamura, T., Nishitani, S. 2022; 22 (1): 711

  Abstract

  Breastfeeding in the early postpartum period is expected to have mental benefits for mothers; however, the underlying psychobiological mechanisms remain unclear. Previously, we hypothesized that the release of oxytocin in response to the suckling stimuli during breastfeeding would mediate a calming effect on primiparous mothers, and we examined salivary oxytocin measurements in primiparous mothers at postpartum day 4 using saliva samples without extraction, which was erroneous. Thus, further confirmation of this hypothesis with a precise methodology was needed.We collected saliva samples at three time points (baseline, feeding, and post-feeding) to measure oxytocin in 24 primiparous mothers on postpartum day 2 (PD2) and 4 (PD4) across the breastfeeding cycle. Salivary oxytocin levels using both extracted and unextracted methods were measured and compared to determine the qualitative differences. State and trait anxiety and clinical demographics were evaluated to determine their association with oxytocin changes.Breastfeeding elevated salivary oxytocin levels; however, it was not detected to a significant increase in the extraction method at PD4. We found a weak but significant positive correlation between changes in extracted and unextracted oxytocin levels during breastfeeding (feeding minus baseline); there were no other significant positive correlations. Therefore, we used the extracted measurement index for subsequent analysis. We showed that the greater the increase in oxytocin during breastfeeding, the lower the state anxiety, but not trait anxiety. Mothers who exclusively breastfed at the 1-month follow-up tended to be associated with slightly higher oxytocin change at PD2 than those who did not.Breastfeeding in early postpartum days could be accompanied by the frequent release of oxytocin and lower state anxiety, potentially contributing to exclusive breastfeeding.

  View details for DOI 10.1186/s12884-022-05026-x

  View details for Web of Science ID 000854860000003

  View details for PubMedID 36115939

  View details for PubMedCentralID PMC9482205

• Epigenetic Clock Deceleration and Maternal Reproductive Efforts: Associations With Increasing Gray Matter Volume of the Precuneus FRONTIERS IN GENETICS Nishitani, S., Kasaba, R., Hiraoka, D., Shimada, K., Fujisawa, T. X., Okazawa, H., Tomoda, A. 2022; 13: 803584

  Abstract

  Reproductive efforts, such as pregnancy, delivery, and interaction with children, make maternal brains optimized for child-rearing. However, extensive studies in non-human species revealed a tradeoff between reproductive effort and life expectancy. In humans, large demographic studies have shown that this is the case for the most part; however, molecular marker studies regarding aging remain controversial. There are no studies simultaneously evaluating the relationship between reproductive effort, aging, and brain structures. We therefore examined the associations between reproductive efforts (parity status, number of deliveries, motherhood period, and cumulative motherhood period), DNA methylation age (mAge) acceleration (based on Horvath's multi-tissue clock and the skin & blood clock), and the regional gray matter volumes (obtained through brain magnetic resonance imaging (MRI) using voxel-based morphometry) in 51 mothers aged 27-46 years of children in early childhood. We found that increasing reproductive efforts were significantly associated with decelerated aging in mothers with one to four children, even after adjusting for the confounding effects in the multiple linear regression models. We also found that the left precuneus gray matter volume was larger as deceleration of aging occurred; increasing left precuneus gray matter volume, on the other hand, mediates the relationship between parity status and mAge deceleration. Our findings suggest that mothers of children in early childhood, who have had less than four children, may benefit from deceleration of aging mediated via structural changes in the precuneus.

  View details for DOI 10.3389/fgene.2022.803584

  View details for Web of Science ID 000771665300001

  View details for PubMedID 35309114

  View details for PubMedCentralID PMC8926035

• The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults CEREBRAL CORTEX Cheong, Y., Nishitani, S., Yu, J., Habata, K., Kamiya, T., Shiotsu, D., Omori, I. M., Okazawa, H., Tomoda, A., Kosaka, H., Jung, M. 2022; 32 (24): 5654-5663

  Abstract

  DNA methylation age has been used in recent studies as an epigenetic marker of accelerated cellular aging, whose contribution to the brain structural changes was lately acknowledged. We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. Using the multi-tissue method (Horvath S. DNA methylation age of human tissues and cell types. 2013. Genome Biol 14), epigenetic age was computed with saliva sample. Epigenetic age acceleration was derived from residuals after adjusting epigenetic age for chronological age. Multiple regression models were computed for 148 brain regions for surface area, cortical thickness, and volume using epigenetic age or accelerated epigenetic age as a predictor and controlling for sex. Epigenetic age was associated with surface area reduction of the left insula. It was also associated with cortical thinning and volume reduction in multiple regions, with prominent changes of cortical thickness in the left temporal regions and of volume in the bilateral orbital gyri. Finally, accelerated epigenetic age was negatively associated with right cuneus gyrus volume. Our findings suggest that understanding the mechanisms of epigenetic age acceleration in young individuals may yield valuable insights into the relationship between epigenetic aging and the cortical change and on the early development of neurocognitive pathology among young adults.

  View details for DOI 10.1093/cercor/bhac043

  View details for Web of Science ID 000759769900001

  View details for PubMedID 35196707

• Association of Epigenetic Differences Screened in a Few Cases of Monozygotic Twins Discordant for Attention-Deficit Hyperactivity Disorder With Brain Structures FRONTIERS IN NEUROSCIENCE Fujisawa, T. X., Nishitani, S., Makita, K., Yao, A., Takiguchi, S., Hamamura, S., Shimada, K., Okazawa, H., Matsuzaki, H., Tomoda, A. 2022; 15: 799761

  Abstract

  The present study examined the relationship between DNA methylation differences and variations in brain structures involved in the development of attention-deficit hyperactivity disorder (ADHD). First, we used monozygotic (MZ) twins discordant (2 pairs of 4 individuals, 2 boys, mean age 12.5 years) for ADHD to identify candidate DNA methylation sites involved in the development of ADHD. Next, we tried to replicate these candidates in a case-control study (ADHD: N = 18, 15 boys, mean age 10.0 years; Controls: N = 62, 40 boys, mean age 13.9 years). Finally, we examined how methylation rates at those sites relate to the degree of local structural alterations where significant differences were observed between cases and controls. As a result, we identified 61 candidate DNA methylation sites involved in ADHD development in two pairs of discordant MZ twins, among which elevated methylation at a site in the sortilin-related Vps10p domain containing receptor 2 (SorCS2) gene was replicated in the case-control study. We also observed that the ADHD group had significantly reduced gray matter volume (GMV) in the precentral and posterior orbital gyri compared to the control group and that this volume reduction was positively associated with SorCS2 methylation. Furthermore, the reduced GMV regions in children with ADHD are involved in language processing and emotional control, while SorCS2 methylation is also negatively associated with emotional behavioral problems in children. These results indicate that SorCS2 methylation might mediate a reduced GMV in the precentral and posterior orbital gyri and therefore influence the pathology of children with ADHD.

  View details for DOI 10.3389/fnins.2021.799761

  View details for Web of Science ID 000752732100001

  View details for PubMedID 35145374

  View details for PubMedCentralID PMC8823258

• Effects of intranasal oxytocin on neural reward processing in children and adolescents with reactive attachment disorder: A randomized controlled trial. Frontiers in child and adolescent psychiatry Takiguchi, S., Makita, K., Fujisawa, T. X., Nishitani, S., Tomoda, A. 2022; 1: 1056115

  Abstract

  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.

  View details for DOI 10.3389/frcha.2022.1056115

  View details for PubMedID 39839202

• Influence of the COVID-19 Pandemic on Parenting Stress Across Asian Countries: A Cross-National Study FRONTIERS IN PSYCHOLOGY Kurata, S., Hiraoka, D., Ahmad Adlan, A., Jayanath, S., Hamzah, N., Ahmad-Fauzi, A., Fujisawa, T. X., Nishitani, S., Tomoda, A. 2021; 12: 782298

  Abstract

  Background: In a previous study, we demonstrated that the accumulation of parenting stress during prolonged school closures and restrictions on daily activities due to the COVID-19 pandemic in Japan indicates the need for mental health intervention for parents at higher risk of parenting stress. However, few studies have focused on parenting stress in other Asian countries, although they have experienced higher numbers of infections. The aim of the present study was to investigate whether parenting stress among caregivers increased across Asia due to school closures and restrictions on activities during the COVID-19 pandemic and to examine whether there were any country-specific, cross-country, or cross-regional risk factors for increased parenting stress. Methods: We conducted an online survey immediately after the number of new cases in India significantly increased (September-November 2020). We measured parenting stress, anxiety, and fear associated with the COVID-19 crisis, as evaluated by the Parenting Stress Index, Short-Form (PSI-SF), and the Coronavirus Anxiety Scale (CAS), across three Asian countries-India (n = 142), Malaysia (n = 69), and Japan (n = 182)-in addition to the United States (n = 203). We also investigated whether respondents had adverse childhood experiences (ACE) as a risk factor for parenting stress. Results: For all countries, we found significant increases in participants' current parenting stress levels, compared to what they recalled regarding their lives before COVID-19-related restrictions and school closures were enacted. Textual analysis qualitatively identified common terms related to parenting stress across all countries. We also found a statistical model that indicated ACE in parents was a critical risk factor for higher parenting stress via increasing anxiety and fear related to the pandemic. Conclusion: These results indicate the need to improve the mental health of caregivers who are at risk for higher levels of parenting stress during the COVID-19 pandemic in Asian countries as well as Western countries. These results indicate that there is a need to improve the mental health of caregivers who are at risk for higher levels of parenting stress during the COVID-19 pandemic globally.

  View details for DOI 10.3389/fpsyg.2021.782298

  View details for Web of Science ID 000738905200001

  View details for PubMedID 34992567

  View details for PubMedCentralID PMC8724041

• A multi-modal MRI analysis of brain structure and function in relation to <i>OXT</i> methylation in maltreated children and adolescents TRANSLATIONAL PSYCHIATRY Nishitani, S., Fujisawa, T. X., Hiraoka, D., Makita, K., Takiguchi, S., Hamamura, S., Yao, A., Shimada, K., Smith, A. K., Tomoda, A. 2021; 11 (1): 589

  Abstract

  Child maltreatment dysregulates the brain's oxytocinergic system, resulting in dysfunctional attachment patterns. However, how the oxytocinergic system in children who are maltreated (CM) is epigenetically affected remains unknown. We assessed differences in salivary DNA methylation of the gene encoding oxytocin (OXT) between CM (n = 24) and non-CM (n = 31), alongside its impact on brain structures and functions using multi-modal brain imaging (voxel-based morphometry, diffusion tensor imaging, and task and resting-state functional magnetic resonance imaging). We found that CM showed higher promoter methylation than non-CM, and nine CpG sites were observed to be correlated with each other and grouped into one index (OXTmi). OXTmi was significantly negatively correlated with gray matter volume (GMV) in the left superior parietal lobule (SPL), and with right putamen activation during a rewarding task, but not with white matter structures. Using a random forest regression model, we investigated the sensitive period and type of maltreatment that contributed the most to OXTmi in CM, revealing that they were 5-8 years of age and physical abuse (PA), respectively. However, the presence of PA (PA+) was meant to reflect more severe cases, such as prolonged exposure to multiple types of abuse, than the absence of PA. PA+ was associated with significantly greater functional connectivity between the right putamen set as the seed and the left SPL and the left cerebellum exterior. The results suggest that OXT promoter hypermethylation may lead to the atypical development of reward and visual association structures and functions, thereby potentially worsening clinical aspects raised by traumatic experiences.

  View details for DOI 10.1038/s41398-021-01714-y

  View details for Web of Science ID 000719889200001

  View details for PubMedID 34789725

  View details for PubMedCentralID PMC8599663

• Pathways linking adverse environments to emerging adults' substance abuse and depressive symptoms: A prospective analysis of rural African American men DEVELOPMENT AND PSYCHOPATHOLOGY Kogan, S. M., Bae, D., Cho, J., Smith, A. K., Nishitani, S. 2021; 33 (4): 1496-1506

  Abstract

  For African American emerging adult men, developmental challenges are evident in their escalating substance abuse and depressive symptoms; this is particularly true for men from low-resource communities. The present study tests a developmental model linking childhood adversity and contemporaneous contextual stressors to increases in emerging adults' substance use and depressive symptoms, indirectly, via increases in defensive/hostile relational schemas and social developmental risk factors (e.g., risky peers and romantic partners, lack of involvement in school or work). We also advance exploratory hypotheses regarding DNA methylation in the oxytocin receptor gene (OXTR) as a moderator of the effects of stress on relational schemas. Hypotheses were tested with three waves of data from 505 rural African American men aged 19-25 years. Adverse childhood experiences predicted exposure to emerging adult contextual stressors. Contextual stressors forecast increases in defensive/hostile relational schemas, which increased social developmental risk factors. Social developmental risk factors proximally predicted increases in substance abuse and depressive symptoms. OXTR DNA methylation moderated the effects of contextual stressors on defensive/hostile relational schemas. Findings suggest that early exposures to stress carry forward to affect the development of social developmental risk factors in emerging adulthood, which place rural African American men at risk for increased substance abuse and depressive symptoms during the emerging adult years.

  View details for DOI 10.1017/S0954579420000632

  View details for Web of Science ID 000756713200024

  View details for PubMedID 32693849

  View details for PubMedCentralID PMC7855061

• Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women. Comprehensive psychoneuroendocrinology Hack, L. M., Nishitani, S., Knight, A. K., Kilaru, V., Maddox, S. A., Seligowski, A. V., Jovanovic, T., Ressler, K. J., Smith, A. K., Michopoulos, V. 2021; 6: 100045

  Abstract

  17β-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r ​= ​0.75, p ​= ​1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (β ​= ​-0.38, p ​= ​0.01) and major depressive disorder (MDD) diagnoses (β ​= ​-0.45, p ​= ​0.02), as well as a continuous measure of PTSD symptom severity (β ​= ​-2.3, p ​= ​0.007) in females. Finally, we tested our predictor in an independent data set (n ​= ​85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r ​= ​0.48, p ​= ​3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.

  View details for DOI 10.1016/j.cpnec.2021.100045

  View details for PubMedID 35757356

  View details for PubMedCentralID PMC9216622

• Mismatch negativity of preschool children at risk of developing mental health problems NEUROPSYCHOPHARMACOLOGY REPORTS Aoi, T., Fujisawa, T. X., Nishitani, S., Tomoda, A. 2021; 41 (2): 185-191

  Abstract

  This study examined the relationship between mismatch negativity (MMN) during the passive oddball task and clinical assessment using a behavioral scale in nonclinical preschool children to identify neurobiological endophenotypes associated with the risk of developing mental health problems. We assessed the risk of developing mental health problems in preschool children using the Strengths and Difficulties Questionnaire, which is used worldwide as a behavior-based screening tool for assessing mental health risks, and examined its relevance to amplitude and latency MMN. As a result, we found that children at a higher risk of mental health problems had smaller MMN amplitudes than those at lower risk. It was also found that MMN amplitude was negatively correlated with the assessed higher risk of mental health problems. Although it is not clear what neural mechanisms underlie the functional association between MMN and risk of mental health problems in preschool children, the findings of this study indicate that there is an involvement of individual differences in auditory processing in childhood mental health problems. The findings suggest that such neurological changes may be prodromal symptoms of the onset of psychiatric disorders and applicable as endophenotypic markers for the early detection of various psychiatric disorders.

  View details for DOI 10.1002/npr2.12168

  View details for Web of Science ID 000621478200001

  View details for PubMedID 33606363

  View details for PubMedCentralID PMC8340815

• Epigenetic modification of the oxytocin gene is associated with gray matter volume and trait empathy in mothers (Withdrawn Publication. See vol. 144, 2022) PSYCHONEUROENDOCRINOLOGY Hiraoka, D., Nishitani, S., Shimada, K., Kasaba, R., Fujisawa, T. X., Tomoda, A. 2021; 123: 105026

  Abstract

  This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). The Editor has concluded that the acceptance of this article was partly based upon the positive advice of an unreliable reviewer report. The report was provided to the journal by a reviewer suggested by the authors, and there were inappropriate communications between the authors and reviewer during the peer-review process. The Editor has therefore concluded that the review was not appropriate or independent. This manipulation of the peer-review process represents a clear violation of the fundamentals of peer review, our publishing policies, and publishing ethics standards. Apologies are offered to the readers of the journal that this deception was not detected during the submission process.

  View details for DOI 10.1016/j.psyneuen.2020.105026

  View details for Web of Science ID 000596506700014

  View details for PubMedID 33130408

• Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women Comprehensive Psychoneuroendocrinology Hack, L. M., Nishitani, S., Knight, A. K., Kilaru, V., Maddox, S. A., Seligowski, A. V., Jovanovic, T., Ressler, K. J., Smith, A. K., Michopoulous, V. 2021; 6

  View details for DOI 10.1016/j.cpnec.2021.100045

• Altered epigenetic clock in children exposed to maltreatment PSYCHIATRY AND CLINICAL NEUROSCIENCES Nishitani, S., Suzuki, S., Ochiai, K., Yao, A., Fujioka, T., Fujisawa, T. X., Tomoda, A. 2021; 75 (3): 110-112

  View details for DOI 10.1111/pcn.13183

  View details for Web of Science ID 000601542400001

  View details for PubMedID 33305449

• Methylation of OXT and OXTR genes, central oxytocin, and social behavior in female macaques HORMONES AND BEHAVIOR De Leon, D., Nishitani, S., Walum, H., McCormack, K. M., Wilson, M. E., Smith, A. K., Young, L. J., Sanchez, M. M. 2020; 126: 104856

  Abstract

  Oxytocin (OXT) and its receptor (OXTR) are encoded by OXT and OXTR, respectively. Variable methylation of these genes has been linked to variability in sociability and neuroendophenotypes. Here we examine whether OXTR or OXT methylation in blood predicts concentrations of OXT in cerebrospinal fluid (CSF) (n = 166) and social behavior (n = 207) in socially-housed female rhesus macaques. We report a similarity between human and rhesus CpG sites for OXT and OXTR and a putative negative association between methylation of two OXTR CpG units with aggressive behavior (both P = 0.003), though this finding does not survive the most stringent correction for multiple comparison testing. We did not detect a statistically significant association between methylation of any CpG sites and CSF OXT concentrations, either. Because none of the tested associations survived statistical corrections, if there is any relationship between blood-derived methylation of these genes and the behavioral and physiological outcomes measured here, the effect size is too small to be detected reliably with this sample size. These results do not support the hypothesis that blood methylation of OXT or OXTR is robustly associated with CSF OXT concentration or social behavior in rhesus. It is possible, though, that methylation of these loci in the brain or in cheek epithelia may be associated with central OXT release and behavior. Finally, we consider the limitations of this exploratory study in the context of statistical power.

  View details for DOI 10.1016/j.yhbeh.2020.104856

  View details for Web of Science ID 000609622100007

  View details for PubMedID 32979349

  View details for PubMedCentralID PMC7725942

• Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity NEUROPSYCHOPHARMACOLOGY Andari, E., Nishitani, S., Kaundinya, G., Caceres, G. A., Morrier, M. J., Ousley, O., Smith, A. K., Cubells, J. F., Young, L. J. 2020; 45 (7): 1150-1158

  Abstract

  The role of oxytocin in social cognition has attracted tremendous interest in social neuroscience and psychiatry. Some studies have reported improvement in social symptoms following oxytocin treatment in autism spectrum disorders (ASD), while others point to endogenous factors influencing its efficiency and to mixed results in terms of long-term clinical benefits. Epigenetic modification to the oxytocin receptor gene (OXTR) in ASD could be an informative biomarker of treatment efficacy. Yet, little is known about the relationship between OXTR methylation, clinical severity, and brain function in ASD. Here, we investigated the relationship between OXTR methylation, ASD diagnosis (in N = 35 ASD and N = 64 neurotypical group), measures of social responsiveness, and resting-state functional connectivity (rsFC) between areas involved in social cognition and reward processing (in a subset of ASD, N = 30). Adults with ASD showed higher OXTR methylation levels in the intron 1 area compared with neurotypical subjects. This hypermethylation was related to clinical symptoms and to a hypoconnectivity between cortico-cortical areas involved in theory of mind. Methylation at a CpG site in the exon 1 area was positively related to social responsiveness deficits in ASD and to a hyperconnectivity between striatal and cortical brain areas. Taken together, these findings provide initial evidence for OXTR hypermethylation in the intron area as a potential biomarker for adults with ASD with less severe developmental communication deficits, but with impairments in theory of mind and self-awareness. Also, OXTR methylation in the exon 1 area could be a potential biomarker of sociability sensitive to life experiences.

  View details for DOI 10.1038/s41386-020-0610-6

  View details for Web of Science ID 000508322600001

  View details for PubMedID 31931508

  View details for PubMedCentralID PMC7235273

• <i>OXTR</i> methylation modulates exogenous oxytocin effects on human brain activity during social interaction GENES BRAIN AND BEHAVIOR Chen, X., Nishitani, S., Haroon, E., Smith, A. K., Rilling, J. K. 2020; 19 (1): e12555

  Abstract

  Oxytocin (OT) effects on brain function and behavior are mediated by the oxytocin receptor (OXTR). The distribution of OXTR in the brain can profoundly influence social behavior. Emerging evidence suggests that DNA methylation of OXTR influences OXTR expression. Previously, we conducted a pharmaco-functional Magnetic Resonance Imaging (fMRI) study in which healthy subjects were randomized to 24 IU intranasal OT or placebo and imaged with fMRI while playing a dyadic social interaction task known as the iterated Prisoner's Dilemma (PD) game with same-sex partners. Here, we investigate whether DNA methylation of OXTR modulates the effect of intranasal OT on the neural response to positive and negative social interactions in the PD game. OXTR methylation did not modulate OT effects within brain regions where we previously reported OT effects in response to reciprocated (caudate nucleus) and unreciprocated cooperation (amygdala and anterior insula). However, OXTR methylation did modulate OT effects on the response to both reciprocated and unreciprocated cooperation in other brain regions such as the precuneus and visual cortex. Further restricting the analysis to OXTR rs53576 GG individuals revealed that OXTR methylation modulated OT effects on the precuneus response to reciprocated cooperation in men, the lateral septum response to reciprocated cooperation in women, and the visual cortex response to unreciprocated cooperation in men. These results suggest that OXTR methylation status may influence OT effects on mentalizing, attention and reward processing during social interactions. OXTR methylation may be important to consider if exogenous OT is used to treat social behavioral disorders in the future.

  View details for DOI 10.1111/gbb.12555

  View details for Web of Science ID 000507377800005

  View details for PubMedID 30624029

• Epigenetic Modifications of the Oxytocin Receptor Gene and Autism Spectrum Disorders Andari, E., Nishitani, S., Kaundinya, G., Caceres, G., Morrier, M., Ousley, O., Smith, A., Cubells, J., Young, L. NATURE PUBLISHING GROUP. 2019: 98

  View details for Web of Science ID 000509665600200

• Oxytocin receptor DNA methylation and alterations of brain volumes in maltreated children NEUROPSYCHOPHARMACOLOGY Fujisawa, T. X., Nishitani, S., Takiguchi, S., Shimada, K., Smith, A. K., Tomoda, A. 2019; 44 (12): 2045-2053

  Abstract

  Although oxytocin (OXT) plays an important role in secure attachment formation with a primary caregiver, which is impaired in many children with childhood maltreatment (CM), epigenetic regulation in response to CM is a key factor in brain development during childhood. To address this issue, we first investigated differences in salivary DNA methylation of the oxytocin receptor (OXTR) between CM and Non-CM groups of Japanese children (CM: n = 44; Non-CM: n = 41) and its impact on brain structures in subgroup analysis using brain imaging and full clinical data (CM: n = 24; Non-CM: n = 31). As a result, we observed that the CM group showed higher CpG 5,6 methylation than did the Non-CM group and confirmed negative correlations of gray matter volume (GMV) in the left orbitofrontal cortex (OFC) with CpG 5,6 methylation. In addition, the CM group showed significantly lower GMV in the left OFC than did the Non-CM group. Furthermore, as a result of examining the relationship between GMV in the left OFC and psychiatric symptoms in CM, we observed a negative association with insecure attachment style and also confirmed the mediation effect of left-OFC GMV reduction on the relationship between OXTR methylation and insecure attachment style. These results suggest that any modulation of the oxytocin signaling pathway induced by OXTR hypermethylation at CpG 5,6 leads to atypical development of the left OFC, resulting in distorted attachment formation in children with CM.

  View details for DOI 10.1038/s41386-019-0414-8

  View details for Web of Science ID 000490174900008

  View details for PubMedID 31071720

  View details for PubMedCentralID PMC6898679

• Childhood Adversity, Socioeconomic Instability, Oxytocin-Receptor-Gene Methylation, and Romantic-Relationship Support Among Young African American Men PSYCHOLOGICAL SCIENCE Kogan, S. M., Bae, D., Cho, J., Smith, A. K., Nishitani, S. 2019; 30 (8): 1234-1244

  Abstract

  Men's emerging adult romantic relationships forecast downstream relationship behavior, including commitment and quality. Accumulating evidence implicates methylation of the oxytocin-receptor-gene (OXTR) system in regulating relationship behavior. We tested hypotheses regarding the links between (a) childhood adversity and (b) socioeconomic instability in emerging adulthood on supportive romantic relationships via their associations with OXTR methylation. Hypotheses were tested using path analysis with data from 309 participants in the African American Men's Project. Consistent with our hypotheses, results showed that OXTR methylation proximally predicted changes in relationship support during a 1.5-year period. Childhood adversity was not directly associated with OXTR methylation but, rather, with contemporaneous socioeconomic instability, which in turn predicted elevated OXTR methylation. Findings suggest that early adversity is indirectly associated with OXTR methylation by links with downstream socioeconomic instability. Findings must be considered provisional, however, because preregistered replications are needed to establish more firmly the relations among these variables.

  View details for DOI 10.1177/0956797619854735

  View details for Web of Science ID 000477165000001

  View details for PubMedID 31318641

  View details for PubMedCentralID PMC6690095

• Longitudinal Epigenome-Wide Changes From Trauma to PTSD Diagnosis Nishitani, S., Kilaru, V., Michopoulos, V., Winters, S., Rothbaum, B., Ressler, K., Jovanovic, T., Smith, A. ELSEVIER SCIENCE INC. 2019: S10-S11

  View details for DOI 10.1016/j.biopsych.2019.03.039

  View details for Web of Science ID 000472661000026

• Prospective Longitudinal Epigenome-Wide Association Study of the Development of PTSD in Traumatized ED Patients Nishitani, S., Kilaru, V., Michopoulos, V., Winters, S., Rothbaum, B., Ressler, K., Jovanovic, T., Smith, A. NATURE PUBLISHING GROUP. 2018: S391

  View details for Web of Science ID 000509546600715

• Oxytocin receptor gene methylation and substance use problems among young African American men DRUG AND ALCOHOL DEPENDENCE Kogan, S. M., Cho, J., Beach, S. R. H., Smith, A. K., Nishitani, S. 2018; 192: 309-315

  Abstract

  Stressful or supportive social environments promote biological changes with regulatory implications for future relationships and substance abuse. Recent research suggests links between adverse social environments, prosocial relationships, methylation at the oxytocin receptor gene (OXTR), and substance abuse. The potential for OXTR methylation to act as the mechanism linking social environments to substance abuse has yet to be investigated. We hypothesized that, for young African American men, childhood adversity increases, and supportive, prosocial bonds with parents, peers, partners, and community mentors decrease OXTR methylation levels, which in turn predict increases in substance-related symptoms.A sample of 358 rural African American men (age 19 at baseline) provided self-report data at three time points separated by 18 months and a genetic specimen at Time 2.Early adversity was associated with OXTR methylation indirectly via contemporary prosocial relationships. OXTR methylation was a proximal predictor of changes in substance-related symptoms. We found no evidence for a direct association of self-reported childhood trauma with OXTR methylation status.Findings suggest that OXTR methylation is linked to substance use symptomatology, ostensibly resulting in increased expression of oxytocin (OT) in peripheral and central nervous systems. OXTR may act as a mechanism to explain how prosocial ties deter substance abuse and related problems. Despite conjectures in the literature that early adversity may become physiologically embedded via methylation in the OT system, direct effects were not evident. Rather, early adversity may affect OXTR methylation via influence on contemporary prosocial relationships.

  View details for DOI 10.1016/j.drugalcdep.2018.08.022

  View details for Web of Science ID 000449447400045

  View details for PubMedID 30308385

  View details for PubMedCentralID PMC6202060

• Epigenetic Modification ofOXTRis Associated with Openness to Experience. Personality neuroscience Haas, B. W., Smith, A. K., Nishitani, S. 2018; 1: e7

  Abstract

  Oxytocin is a neuropeptide known to influence social and cognitive processing across several mammalian species. There currently exists a mixed and controversial pattern of evidence that oxytocin pathway genes confer individual differences in social cognition and personality in humans. Inconsistencies across studies may in part be explained by the presence of intermediary, epigenetic, variables that exist between genotype and phenotype. This study was designed to investigate the association between epigenetic modification of the Oxytocin Receptor Gene (OXTR), via DNA methylation, and Big-5 personality traits. Genetic data were collected via saliva samples and analyzed to quantify DNA methylation within the promoter region of OXTR. The results indicate that Openness to Experience is associated with OXTR DNA methylation, while controlling for the remaining Big-5 personality dimensions (Neuroticism, Extraversion, Agreeableness, and Conscientiousness) and sex and age. This finding provides additional support for models associating oxytocin with individual differences in personality and identity in humans.

  View details for DOI 10.1017/pen.2018.7

  View details for PubMedID 32435727

• DNA methylation analysis from saliva samples for epidemiological studies EPIGENETICS Nishitani, S., Parets, S. E., Haas, B. W., Smith, A. K. 2018; 13 (4): 352-362

  Abstract

  Saliva is a non-invasive, easily accessible tissue, which is regularly collected in large epidemiological studies to examine genetic questions. Recently, it is becoming more common to use saliva to assess DNA methylation. However, DNA extracted from saliva is a mixture of both bacterial and human DNA derived from epithelial and immune cells in the mouth. Thus, there are unique challenges to using salivary DNA in methylation studies that can influence data quality. This study assesses: (1) quantification of human DNA after extraction; (2) delineation of human and bacterial DNA; (3) bisulfite conversion (BSC); (4) quantification of BSC DNA; (5) PCR amplification of BSC DNA from saliva and; (6) quantitation of DNA methylation with a targeted assay. The framework proposed will allow saliva samples to be more widely used in targeted epigenetic studies.

  View details for DOI 10.1080/15592294.2018.1461295

  View details for Web of Science ID 000443868100002

  View details for PubMedID 29912612

  View details for PubMedCentralID PMC6140812

• Oxytocin Receptor DNA Methylation and Gray Matter Volume in Maltreated Children Nishitani, S., Fujisawa, T. X., Takiguchi, S., Shimada, K., Smith, A. K., Tomoda, A. NATURE PUBLISHING GROUP. 2017: S130-S131

  View details for Web of Science ID 000416846301032

• Oxytocin Mediates a Calming Effect on Postpartum Mood in Primiparous Mothers BREASTFEEDING MEDICINE Niwayama, R., Nishitani, S., Takamura, T., Shinohara, K., Honda, S., Miyamura, T., Nakao, Y., Oishi, K., Araki-Nagahashi, M. 2017; 12 (2): 103-109

  Abstract

  The current study sought to characterize changes in salivary oxytocin (OT) secretion patterns across the breastfeeding cycle, and to evaluate whether breastfeeding has a positive effect on mood disturbances related to postpartum depression, via endogenous OT release.Twenty-four primiparous mothers who delivered vaginally at term and were exclusively breastfeeding were examined 4-5 days postpartum. Salivary OT was measured using enzyme immunoassays at 30 minutes before breastfeeding (baseline), during breastfeeding (feeding), and 30 minutes after completing breastfeeding (postfeeding). In addition, maternal mood changes were evaluated at baseline and postfeeding using the Profile of Mood States (POMS) questionnaire.OT levels rose significantly during feeding (pcorr < .05) and postfeeding (pcorr < 0.05), compared with baseline. POMS scores for Tension-Anxiety were decreased postfeeding compared with baseline (p < 0.001). This decrease was significantly associated with increased OT (feeding minus baseline: r = -0.52, rpart = -0.51, postfeeding minus baseline: r = -0.53, rpart = -0.52, ps < 0.05). POMS scores for Fatigue and Confusion also decreased, while Vigor significantly increased. Significant correlations were found between Fatigue decreases and OT increases (feeding minus baseline: r = -0.48, rpart = -0.53, postfeeding minus baseline: rpart = -0.60, ps < 0.05). This result partially contradicted with the finding of no correlation between increased Vigor and increased OT.OT is released across the breastfeeding cycle and can be detected with salivary measurement. This OT release exhibited a temporary anxiolytic-like calming effect on postpartum maternal mood disturbances.

  View details for DOI 10.1089/bfm.2016.0052

  View details for Web of Science ID 000395783500008

  View details for PubMedID 28103103

• Genetic variants in <i>oxytocin receptor</i> and <i>arginine-vasopressin receptor</i> <i>1A</i> are associated with the neural correlates of maternal and paternal affection towards their child HORMONES AND BEHAVIOR Nishitani, S., Ikematsu, K., Takamura, T., Honda, S., Yoshiura, K., Shinohara, K. 2017; 87: 47-56

  Abstract

  There is extensive evidence in animal studies, particularly in vole species (Microtus), that oxytocin (OT) receptor and arginine-vasopressin (AVP) receptor 1a is critical for the regulation of maternal and paternal behavior, respectively. Human studies have gained insight into the relationship between both hormone receptor gene variants and behavior, but not between the variants and the underlying brain activity. To study this, we investigated the association between neural activation of the anterior prefrontal cortex (APFC) in mothers and fathers in response to their child smiling video stimuli to induce the positive affect related to attachment with their child, and genetic variants of OT receptor (OXTR) and AVP receptor 1A (AVPR1A). Overall, 43 mothers and 41 fathers participated, and each parent's child smiling was video recorded. Participants were then genotyped and underwent near-infrared spectroscopy to measure neural activation of the APFC while observing their own child smiling compared with an unfamiliar child. We found that the right inferior APFC was activated in response to child video stimuli in mothers and differential hemispheric activation of the inferior APFC in OXTR rs2254298-G/G mothers compared with -A carrier mothers, but not in fathers. Furthermore, we found a difference in the left inferior APFC activation between AVPR1A RS3-non-334 and -334 carrier fathers, but not mothers. Our results indicate a sex-dependent association between the genetic variants and the inferior APFC activations of maternal and paternal positive affect, analogous to the results reported in voles.

  View details for DOI 10.1016/j.yhbeh.2016.09.010

  View details for Web of Science ID 000392905500006

  View details for PubMedID 27743766

• Non-linear patterns in age-related DNA methylation may reflect CD4<SUP>+</SUP> T cell differentiation EPIGENETICS Johnson, N. D., Wiener, H. W., Smith, A. K., Nishitani, S., Absher, D. M., Arnett, D. K., Aslibekyan, S., Conneely, K. N. 2017; 12 (6): 492-503

  Abstract

  DNA methylation (DNAm) is an important epigenetic process involved in the regulation of gene expression. While many studies have identified thousands of loci associated with age, few have differentiated between linear and non-linear DNAm trends with age. Non-linear trends could indicate early- or late-life gene regulatory processes. Using data from the Illumina 450K array on 336 human peripheral blood samples, we identified 21 CpG sites that associated with age (P<1.03E-7) and exhibited changing rates of DNAm change with age (P<1.94E-6). For 2 of these CpG sites (cg07955995 and cg22285878), DNAm increased with age at an increasing rate, indicating that differential DNAm was greatest among elderly individuals. We observed significant replication for both CpG sites (P<5.0E-8) in a second set of peripheral blood samples. In 8 of 9 additional data sets comprising samples of monocytes, T cell subtypes, and brain tissue, we observed a pattern directionally consistent with DNAm increasing with age at an increasing rate, which was nominally significant in the 3 largest data sets (4.3E-15

  View details for DOI 10.1080/15592294.2017.1314419

  View details for Web of Science ID 000404624400009

  View details for PubMedID 28387568

  View details for PubMedCentralID PMC5501198

• Association of Aryl Hydrocarbon Receptor-Related Gene Variants with the Severity of Autism Spectrum Disorders FRONTIERS IN PSYCHIATRY Fujisawa, T. X., Nishitani, S., Iwanaga, R., Matsuzaki, J., Kawasaki, C., Tochigi, M., Sasaki, T., Kato, N., Shinohara, K. 2016; 7

  View details for DOI 10.3389/fpsyt.2016.00184

  View details for Web of Science ID 000387813400001

• Heritable epigenetic patterns of stress-responsive genes in traumatized children Smith, A., Kilaru, V., Klengel, T., Nishitani, S., Binder, E., Ressler, K., Bradley, B., Jovanovic, T. PERGAMON-ELSEVIER SCIENCE LTD. 2016: 43

  View details for DOI 10.1016/j.psyneuen.2016.07.112

  View details for Web of Science ID 000382594500100

• Epigenome-wide association study to focus on the development of PTSD in traumatized ED patients Smith, A. K., Nishitani, S., Michopoulos, V., Jovanovic, T., Nemeroff, C. B., Meyers, A. J., Rothbaum, B., Ressler, K. J. PERGAMON-ELSEVIER SCIENCE LTD. 2016: 11-12

  View details for DOI 10.1016/j.psyneuen.2016.07.039

  View details for Web of Science ID 000382594500029

• Epigenetic modification of <i>OXT</i> and human sociability PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Haas, B. W., Filkowski, M. M., Cochran, R., Denison, L., Ishak, A., Nishitani, S., Smith, A. K. 2016; 113 (27): E3816-E3823

  Abstract

  Across many mammalian species there exist genetic and biological systems that facilitate the tendency to be social. Oxytocin is a neuropeptide involved in social-approach behaviors in humans and others mammals. Although there exists a large, mounting body of evidence showing that oxytocin signaling genes are associated with human sociability, very little is currently known regarding the way the structural gene for oxytocin (OXT) confers individual differences in human sociability. In this study, we undertook a comprehensive approach to investigate the association between epigenetic modification of OXT via DNA methylation, and overt measures of social processing, including self-report, behavior, and brain function and structure. Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT We observed a consistent pattern of results across sociability measures. People that exhibit lower OXT DNA methylation (presumably linked to higher OXT expression) display more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume than people that exhibit higher OXT DNA methylation. These findings provide empirical evidence that epigenetic modification of OXT is linked to several overt measures of sociability in humans and serve to advance progress in translational social neuroscience research toward a better understanding of the evolutionary and genetic basis of normal and abnormal human sociability.

  View details for DOI 10.1073/pnas.1602809113

  View details for Web of Science ID 000379021700005

  View details for PubMedID 27325757

  View details for PubMedCentralID PMC4941462

• Epigenome-wide association study of PTSD and the psychophysiological assessment of the inter-mediate phenotype of the core symptom Nishitani, S., Jovanovic, T., Ressler, K. J., Smith, A. K. ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD. 2016: 639

  View details for Web of Science ID 000413720404725

• Female-Specific Patterns of Methylation Associated with Risk of PTSD Development: A Prospective Study Michopoulos, V., Nishitani, S., Jovanovic, T., Gould, F., Nemeroff, C. B., Meyers, A. J., Rothbaum, B. O., Ressler, K. J. ELSEVIER SCIENCE INC. 2016: 410S-411S

  View details for Web of Science ID 000432440805155

• DNA Methylation of OXTR Modulates the Effect of Oxytocin on the Neural Response to Positive and Negative Social Interactions Chen, X., Nishitani, S., Haroon, E., Smith, A. K., Rilling, J. ELSEVIER SCIENCE INC. 2016: 99S-100S

  View details for Web of Science ID 000432440801082

• Epigenome-wide Association Study to Focus on the Development of PTSD in Traumatized ED Patients Nishitani, S., Michopoulos, V., Jovanovic, T., Gould, F., Nemeroff, C. B., Meyers, A. J., Rothbaum, B. O., Ressler, K. J., Smith, A. K. ELSEVIER SCIENCE INC. 2016: 97S

  View details for Web of Science ID 000432440801076

• Association of estrogen receptor alpha polymorphisms with symptoms of autism among Chinese Han children NEUROENDOCRINOLOGY LETTERS Wang, X., Liang, S., Fujisawa, T. X., Nishitani, S., Tomoda, A., Zou, M., Li, Y., Wu, L., Shinohara, K. 2016; 37 (6): 439-444

  Abstract

  Autism has a significant sex difference. This implies that the sex hormones might have effect on autism. Estrogens play an important role in early nervous system development and sex differentiation through estrogen receptors in brain. Thus, we tested the hypothesis that estrogen receptor alpha (ESR1) gene affects the pathogenesis of autism and related symptoms.Genotypes of rs11155819 and rs2234693 were determined in boys with autism and normal boys from Chinese Han population. A case-control study was performed to explore the association between polymorphisms in ESR1 gene and autism susceptibility. Assessment tool was used to evaluate the neuropsychological developmental level of autistic children. Finally, we analyzed the association of these single nucleotide polymorphisms (SNPs) with specific symptoms.The results showed no significant differences between cases and controls in the distribution of genotypes and allele frequencies of the two SNPs. However, rs11155819 TT genotype showed a lower neuropsychological development level among autistic children, especially in the aspects of fine motor and adaptation ability (p=0.028; p=0.042).Polymorphisms of ESR1 are relevant to autism symptoms in Chinese Han children.

  View details for Web of Science ID 000398579900006

  View details for PubMedID 28315628

• Developmental changes in the neural responses to own and unfamiliar mother's smiling face throughout puberty FRONTIERS IN NEUROSCIENCE Takamura, T., Nishitani, S., Suegami, T., Doi, H., Kakeyama, M., Shinohara, K. 2015; 9: 200

  Abstract

  An attachment relationship between boys and their mother is important for subsequent development of the ability to sustain peer relationships. Affective responses to attachment figure, especially mother, is supposed to change drastically during puberty. To elucidate the neural correlates underlying this behavioral change, we compared the neural response of boys at three different developmental stages throughout puberty to visual image of their own mothers. Subjects included 27 pre-puberty boys (9.0 ± 0.6 years), 31 middle puberty boys (13.5 ± 1.2 years), and 27 post-puberty boys (20.8 ± 1.9 years), and their mother's smile was video recorded. We measured their neural response in the anterior part of the prefrontal cortex (APFC) to their own mother's smile compared with an unfamiliar-mother's. We found that in response to their own mother's smiling, the right inferior and medial part of the APFC (Ch6) was activated in the pre-puberty group. By contrast, the left inferior and medial (Ch4) and superior (Ch2 and Ch5) APFC were activated in the middle-puberty group, which is presumably linked to empathic feelings fostered by memories of mutual experience with own mother. These findings suggest that different patterns of APFC activation are associated with qualitative changes in affective response to own mother around puberty.

  View details for DOI 10.3389/fnins.2015.00200

  View details for Web of Science ID 000361995300002

  View details for PubMedID 26089774

  View details for PubMedCentralID PMC4452823

• Sex difference in the relationship between salivary testosterone and inter-temporal choice HORMONES AND BEHAVIOR Doi, H., Nishitani, S., Shinohara, K. 2015; 69: 50-58

  Abstract

  Humans often prefer a small immediate reward to large reward in the future. This myopic tendency in inter-temporal choice is termed delay discounting, and has been the focus of intensive research in the past decades. Recent studies indicate that the neural regions underlying delay discounting are influenced by the gonadal steroids. However, the specific relationship between the testosterone levels and delay discounting is unclear at this point, especially in females. The present study investigated the relationship between salivary testosterone concentrations and discounting rates in delay- and probability-discounting tasks with healthy males and females. The results revealed a positive correlation between testosterone concentrations and delay-discounting rates in females and a negative correlation in males. Testosterone concentrations were unrelated to probability-discounting rates. Although causal effects of testosterone cannot be certain in this correlational study, if testosterone directly influenced this behavior, observed sex differences in delay discounting may be evidence of a curvilinear effect of testosterone. Alternatively, the findings may reflect inverse pattern of responsiveness to testosterone between male and female neural systems, or basic sex-difference in the neural mechanism underlying delay-discounting independent of testosterone itself.

  View details for DOI 10.1016/j.yhbeh.2014.12.005

  View details for Web of Science ID 000352118500006

  View details for PubMedID 25530487

• Association between catechol-O-methyltransferase Val<SUP>158</SUP>Met polymorphism and configural mode of face processing NEUROSCIENCE LETTERS Doi, H., Nishitani, S., Shinohara, K. 2015; 586: 19-23

  Abstract

  Human visual system heavily relies on the spatial configuration among facial parts in discriminating faces. There are individual differences in the ability of configural face processing, which are supposed to be partly attributable to genetic predispositions. However, few studies have identified a specific gene linked to configural face processing ability. The present study investigated an association between configural mode of face processing and a single-nucleotide polymorphism in codon 158 of catechol-O-methyltransferase gene (COMT Val(158)Met polymorphism) using part-spacing paradigm. The results have revealed superior sensitivity to the changes in facial configuration in participants with Met/Met genotype of COMT Val(158)Met polymorphism compared to the other genotypes. This effect was virtually eliminated when the faces were presented upside-down. There was no group-difference in the ability to detect the change in morphological features of individual facial parts. These results indicate that COMT Val(158)Met polymorphism partly explains the individual differences in the ability of configural face processing.

  View details for DOI 10.1016/j.neulet.2014.12.001

  View details for Web of Science ID 000349198200004

  View details for PubMedID 25481766

• No association between catechol-<i>O</i>-methyltransferase (<i>COMT</i>) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children BRAIN & DEVELOPMENT Yatsuga, C., Toyohisa, D., Fujisawa, T. X., Nishitani, S., Shinohara, K., Matsuura, N., Ikeda, S., Muramatsu, M., Hamada, A., Tomoda, A. 2014; 36 (7): 620-625

  Abstract

  This study ascertained the association between attention deficit/hyperactivity disorder (ADHD) in Japanese children and a polymorphism of catechol-O-methyltransferase (COMT), a dopamine-control gene. The secondary aim of the study was the evaluation of a putative association between methylphenidate (MPH) effect/adverse effects and the COMT genotype.To ascertain the distribution of the Val158Met variant of COMT, 50 children meeting ADHD inclusion criteria were compared with 32 healthy children. Clinical improvement and the occurrence of adverse effects were measured before and 3 months after MPH administration in children with ADHD, and analyzed for genotype association. Wechsler Intelligence Scale for Children-Third Edition (WISC-III), age, MPH dose were included as co-variables.The occurrence of the COMT Val/Val genotype was significantly higher in children with ADHD (χ(2)(1)=7.13, p<0.01). However, there was no significant difference in the Val/Val genotype according to disorder, and WISC and ADHD rating scale scores, after correcting for the interaction between disorder and COMT genotype. Furthermore, no significant difference in MPH effect/adverse effects was observed in association with the COMT genotype in the ADHD group.These results showed a lack of association between the COMT Val/Val genotype and ADHD in Japan.

  View details for DOI 10.1016/j.braindev.2013.08.006

  View details for Web of Science ID 000349429000010

  View details for PubMedID 24035255

• Maternal Prefrontal Cortex Activation by Newborn Infant Odors CHEMICAL SENSES Nishitani, S., Kuwamoto, S., Takahira, A., Miyamura, T., Shinohara, K. 2014; 39 (3): 195-202

  Abstract

  Mothers are attracted by infant cues of a variety of different modalities. To clarify the possible neural mechanisms underlying maternal attraction to infant odor cues, we used near-infrared spectroscopy to examine prefrontal cortex (PFC) activity during odor detection tasks in which 19 mothers and 19 nulliparous females (nonmothers) were presented with infant or adult male odors. They were instructed to make a judgment about whether they smelled an odor during each task. We estimated the PFC activity by measuring the relative oxyhemoglobin (oxyHb) concentrations. The results showed that while detecting the infant odors, bilateral PFC activities were increased in mothers but not in nonmothers. In contrast, adult male odors activated the PFC similarly in mothers and nonmothers. These findings suggest that maternal activation of the PFC in response to infant odors explains a part of the neural mechanisms for maternal attraction to infant odors.

  View details for DOI 10.1093/chemse/bjt068

  View details for Web of Science ID 000331846100002

  View details for PubMedID 24403536

• I love my grandkid! An NIRS study of grandmaternal love in Japan BRAIN RESEARCH Kida, T., Nishitani, S., Tanaka, M., Takamura, T., Sugawara, M., Shinohara, K. 2014; 1542: 131-137

  Abstract

  Grandmaternal love is essential for the grandmother–grandchild attachment relationship and thus aids an infant's development and mental health, but the underlying neural mechanism is unknown. Recent studies have shed light on involvement of the prefrontal cortex (PFC) in maternal and romantic love. Here, we investigated the involvement of the PFC in grandmaternal love by examining cerebral hemoglobin concentration changes using near-infrared spectroscopy (NIRS). Seventeen grandmothers viewed video clips which included their own or other's (unknown) grandchild smiling or showing a neutral expression while the oxy-hemoglobin (oxy-Hb) concentration was measured from the anterior prefrontal cortex (APFC). The sight of one's own grandchild activated the inferior and medial APFC irrespective of their expression. In addition, the sight of the smiling grandchild induced an increased activation in the medial APFC involved in reward monitoring and mentalizing and an additional activation in the superior APFC involved in cognitive and attentional control. Both medial and superior activations significantly correlated with emotional mood rating. These findings indicate that the different regions of the APFC are involved in grandmaternal love.

  View details for DOI 10.1016/j.brainres.2013.10.028

  View details for Web of Science ID 000330420500014

  View details for PubMedID 24505627

• NIRS as a tool for assaying emotional function in the prefrontal cortex FRONTIERS IN HUMAN NEUROSCIENCE Doi, H., Nishitani, S., Shinohara, K. 2013; 7: 770

  Abstract

  Despite having relatively poor spatial and temporal resolution, near-infrared spectroscopy (NIRS) has several methodological advantages compared with other non-invasive measurements of neural activation. For instance, the unique characteristics of NIRS give it potential as a tool for investigating the role of the prefrontal cortex (PFC) in emotion processing. However, there are several obstacles in the application of NIRS to emotion research. In this mini-review, we discuss the findings of studies that used NIRS to assess the effects of PFC activation on emotion. Specifically, we address the methodological challenges of NIRS measurement with respect to the field of emotion research, and consider potential strategies for mitigating these problems. In addition, we show that two fields of research, investigating (i) biological predisposition influencing PFC responses to emotional stimuli and (ii) neural mechanisms underlying the bi-directional interaction between emotion and action, have much to gain from the use of NIRS. With the present article, we aim to lay the foundation for the application of NIRS to the above-mentioned fields of emotion research.

  View details for DOI 10.3389/fnhum.2013.00770

  View details for Web of Science ID 000327936300002

  View details for PubMedID 24302904

  View details for PubMedCentralID PMC3831266

• No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents BMC PSYCHIATRY Tomoda, A., Nishitani, S., Matsuura, N., Fujisawa, T. X., Kawatani, J., Toyohisa, D., Ono, M., Shinohara, K. 2013; 13: 134

  Abstract

  Identification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes.This study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother's history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients' depression symptoms.Binary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression.To assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.

  View details for DOI 10.1186/1471-244X-13-134

  View details for Web of Science ID 000332249800001

  View details for PubMedID 23663729

  View details for PubMedCentralID PMC3653806

• Prenatal Exposure to a Polychlorinated Biphenyl (PCB) Congener Influences Fixation Duration on Biological Motion at 4-Months-Old: A Preliminary Study PLOS ONE Doi, H., Nishitani, S., Fujisawa, T. X., Nagai, T., Kakeyama, M., Maeda, T., Shinohara, K. 2013; 8 (3): e59196

  Abstract

  Adverse effects of prenatal exposure to polychlorinated biphenyl (PCB) congeners on postnatal brain development have been reported in a number of previous studies. However, few studies have examined the effects of prenatal PCB exposure on early social development. The present study sought to increase understanding of the neurotoxicity of PCBs by examining the relationship between PCB congener concentrations in umbilical cord blood and fixation patterns when observing upright and inverted biological motion (BM) at four-months after birth. The development of the ability to recognize BM stimuli is considered a hallmark of socio-cognitive development. The results revealed a link between dioxin-like PCB #118 concentration and fixation pattern. Specifically, four-month-olds with a low-level of prenatal exposure to PCB #118 exhibited a preference for the upright BM over inverted BM, whereas those with a relatively high-level of exposure did not. This finding supports the proposal that prenatal PCB exposure impairs the development of social functioning, and indicates the importance of congener-specific analysis in the risk analysis of the adverse effects of PCB exposure on the brain development.

  View details for DOI 10.1371/journal.pone.0059196

  View details for Web of Science ID 000317262200014

  View details for PubMedID 23555630

  View details for PubMedCentralID PMC3610708

• OXTR and AVPR1A polymorphisms modulation of prefrontal activations of mothers and fathers in response to their own infant's smiling Nishitani, S., Ikematsu, K., Takamura, T., Honda, S., Yoshiura, K., Shinohara, K. SPRINGER JAPAN KK. 2013: S289

  View details for Web of Science ID 000322352200957

• Phosphorylation of cAMP response element-binding protein in the extended amygdala of male rats is induced by novel environment and attenuated by estrous female-bedding NEUROENDOCRINOLOGY LETTERS Nishitani, S., Funabashi, T., Shinohara, K., Kimura, F. 2013; 34 (2): 118-123

  Abstract

  We examined whether female pheromone, which would be contained in female-soiled bedding, affected the expression of phosphorylated cAMP response element-binding protein-like (pCREB) immunoreactive cells in the extended amygdala.Male rats were exposed to following conditions: maintained in their home cage (home cage group), or relocated to a cage containing clean bedding (clean-bedding exposed group), ovariectomized (OVX) rat-soiled bedding (OVX-bedding exposed group) or estrogen-treated OVX rat-soiled bedding (OVX+E2-bedding exposed group). Rats were sacrificed 10-20 min after exposure and brain sections were subject to immunocytochemical processing.In the medial subdivision of the bed nucleus of the stria terminalis (BST) and the central amygdala (CeA), the number of pCREB immunoreactive (pCREB-ir) cells in the clean-bedding exposed group was significantly larger than in the home cage group, while the number of pCREB-ir cells in the OVX+E2-bedding exposed group did not differ from that in the home cage group. The bedding soiled by OVX rats was less effective. No significant difference in the number of pCREB-ir cells was detected in the other regions of the extended amygdala among all groups.The present study suggests that the exposure of clean bedding to male rats induces the expression of pCREB-ir in the medial BST and the CeA; exposure to female pheromone attenuates this expression.

  View details for Web of Science ID 000330898800006

  View details for PubMedID 23645308

• Neural correlates of maternal love, paternal love and children's love for their parents Shinohara, K., Nishitani, S., Takamura, T. SPRINGER JAPAN KK. 2013: S48

  View details for Web of Science ID 000322352200110

• Perceived Parental Rejection Mediates the Influence of Serotonin Transporter Gene (5-HTTLPR) Polymorphisms on Impulsivity in Japanese Adults PLOS ONE Nishikawa, S., Nishitani, S., Fujisawa, T. X., Noborimoto, I., Kitahara, T., Takamura, T., Shinohara, K. 2012; 7 (10): e47608

  Abstract

  This study examined (1) the interrelationships among 5-HTTLPR genotype, perceived parental rejection, and impulsivity, and (2) meditational models in which perceived paternal/maternal rejection mediates the relationship between the 5-HTTLPR genotype and impulsive behaviour. Participants included 403 adults (152 males and 252 females, mean age = 24.20) who provided genetic data and a set of the questionnaires (BIS11; Barratt Impulsiveness Scale-11 and EMBU; Egna Minnen av Bätraffande Uppfostran). Using SEM (Structural Equation Modeling), we evaluated 3 models for both direct and indirect relationships between 5-HTTLPR (5HTT) and Impulsivity (IMP), via maternal/fraternal rejection (MAT/FAT). In model 1, the direct path from 5HTT and IMP was not significant across the mother's and father's analysis. Models 2 and 3 assessed the indirect influence of 5HTT on IMP through MOT/FAT. The paths of models 2 and 3 were all significant and showed a good fit between the hypothesized model and data. Furthermore, the effects of the 5-HTTLPR genotype on impulsiveness in this Japanese sample were particularly accounted for by perceived rejection from the mother or father. The effects from the parents appeared to be robust especially among males. These results may help elucidate the specific pathways of risk in relation to genetic and environment influences on impulsive phenotypes.

  View details for DOI 10.1371/journal.pone.0047608

  View details for Web of Science ID 000310310200056

  View details for PubMedID 23112823

  View details for PubMedCentralID PMC3480406

• Loneliness depends on salivary estradiol levels in adolescent females NEUROENDOCRINOLOGY LETTERS Fujisawa, T. X., Nishitani, S., Obara, T., Shinohara, K. 2012; 33 (5): 525-529

  Abstract

  Loneliness is one of the psychological characteristics in adolescence, during which sex hormones are elevated. The elevation of sex steroid hormones is known to sculpture and remodel neuronal circuits, which cause behavioral characteristics in adolescence. The aim of the present study is to investigate the relationship between loneliness and sex steroid hormones, testosterone (T) and 17β-estradiol (E2).Fifty-eight adolescents (28 boys and 30 girls) participated in this study. The salivary levels of T and E2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Loneliness was assessed by the UCLA loneliness scale, which is widely used as a self-administered questionnaire.The results showed that Salivary E2 levels had positive relevance to loneliness in females, whereas there was no relationship in males. Salivary T level was not shown to be relevant with loneliness in either sex group.These findings suggest that E2 has gender specific effects on loneliness in adolescent females.

  View details for Web of Science ID 000311470400010

  View details for PubMedID 23090271

• Loneliness depends on salivary estradiol levels in adolescent females ACTIVITAS NERVOSA SUPERIOR REDIVIVA Fujisawa, T. X., Nishitani, S., Obara, T., Shinohara, K. 2012; 54 (3): 131-135

  View details for Web of Science ID 000420822100006

• Differential prefrontal response to infant facial emotions in mothers compared with non-mothers NEUROSCIENCE RESEARCH Nishitani, S., Doi, H., Koyama, A., Shinohara, K. 2011; 70 (2): 183-188

  Abstract

  A considerable body of research has focused on neural responses evoked by emotional facial expressions, but little is known about mother-specific brain responses to infant facial emotions. We used near-infrared spectroscopy to investigate prefrontal activity during discriminating facial expressions of happy, angry, sad, fearful, surprised and neutral of unfamiliar infants and unfamiliar adults by 14 mothers and 14 age-matched females who have never been pregnant (non-mothers). Our results revealed that discriminating infant facial emotions increased the relative oxyHb concentration in mothers' right prefrontal cortex but not in their left prefrontal cortex, compared with each side of the prefrontal cortices of non-mothers. However, there was no difference between mothers and non-mothers in right or left prefrontal cortex activation while viewing adult facial expressions. These results suggest that the right prefrontal cortex is involved in human maternal behavior concerning infant facial emotion discrimination.

  View details for DOI 10.1016/j.neures.2011.02.007

  View details for Web of Science ID 000291520200006

  View details for PubMedID 21352862

• Development of synchrony between activity patterns of mother-infant pair from 4 to 18 months after birth JOURNAL OF PHYSIOLOGICAL SCIENCES Doi, H., Kato, M., Nishitani, S., Shinohara, K. 2011; 61 (3): 211-216

  Abstract

  Motor activities of interacting agents get temporally coordinated to form synchronized actions. Such activity synchrony is observed in several mammalian species and is supposed to play vital roles in human social interactions. Therefore, it has long been proposed that the activity patterns of mother and infant get temporally synchronized. However, few studies to date have empirically investigated the developmental course of such synchrony. The present study simultaneously measured motor activities of mother-infant pairs for about 3.5 consecutive days by actigraph, and investigated the developmental course of mother-infant synchrony. The multiple regression analysis revealed an increase of mother-infant synchrony from 4 to 18 months after birth, giving support to the notion that activity patterns of mother and infant mutually entrain each other through the course of development.

  View details for DOI 10.1007/s12576-011-0138-y

  View details for Web of Science ID 000289858800005

  View details for PubMedID 21424393

  View details for PubMedCentralID PMC10717710

• Differential modulation of impulsive behavior by loneliness and testosterone in adolescent females NEUROENDOCRINOLOGY LETTERS Fujisawa, T. X., Nishitani, S., Ishii, S., Shinohara, K. 2011; 32 (6): 836-840

  Abstract

  Adolescence is characterized by increases in loneliness, impulsiveness and circulating testosterone levels. We investigated the relationship between these characteristics in adolescent females.For this purpose, we measured impulsivity and loneliness by means of a Go/No-go task and the UCLA loneliness scale, respectively. Testosterone levels in saliva were measured by Enzyme-Linked Immunosorbent Assay (ELISA).The results showed that testosterone and loneliness have a positive relevance to impulsivity in adolescent females, whereas there was no relationship between loneliness and testosterone levels.These results suggest that testosterone and loneliness modulate impulsivity via distinctive pathways.

  View details for Web of Science ID 000300544000016

  View details for PubMedID 22286788

• The ability to recognize emotion is modulated by the aryl hydrocarbon receptor (AhR) variants in normal human adolescents Fujisawa, T., Nishitani, S., Doi, H., Shinohara, K. ELSEVIER IRELAND LTD. 2011: E387

  View details for DOI 10.1016/j.neures.2011.07.1697

  View details for Web of Science ID 000308218102169

• Fetal response to induced maternal emotions JOURNAL OF PHYSIOLOGICAL SCIENCES Araki, M., Nishitani, S., Ushimaru, K., Masuzaki, H., Oishi, K., Shinohara, K. 2010; 60 (3): 213-220

  Abstract

  This study investigated the relationship between fetal movements and acute maternal emotional changes during pregnancy. Two empirically validated feature film clips were used for the external generation of two subjectively and facially well-characterized target emotions: happiness and sadness. We simultaneously monitored separate fetal arm, leg, and trunk movements by means of two ultrasound apparatuses while maternal emotions were manipulated by film clip presentation. The number of fetal arm movements, but not the duration, was increased when pregnant women were being shown a happy film. Both the number and the duration of fetal arm movements decreased with the sad film presentation. Neither the presentation of happiness nor the presentation of sadness affected fetal leg or trunk movements. These findings suggest that induced emotions in pregnant women primarily affect arm movements of their fetuses, and that positive and negative emotions have the opposite effects on fetus movement.

  View details for DOI 10.1007/s12576-010-0087-x

  View details for Web of Science ID 000276541800006

  View details for PubMedID 20169432

  View details for PubMedCentralID PMC10717758

• Associations between the oxytocin receptor gene (OXTR) and sensitivity for vocal emotions in normal children Fujisawa, T., Nishitani, S., Inoue, T., Takamura, T., Ikematsu, K., Shinohara, K. SPRINGER TOKYO. 2010: S180

  View details for Web of Science ID 000278587800601

• The effect of high-frequency components of cry stimulus on the breast hemodynamics in lactating mothers Inoue, T., Nishitani, S., Doi, H., Onaka, T., Shinohara, K. ELSEVIER IRELAND LTD. 2010: E271

  View details for DOI 10.1016/j.neures.2010.07.1205

  View details for Web of Science ID 000208443701589

• The pubertal development of the neural basis of attachment in humans Takamura, T., Nishitani, S., Tanaka, M., Yoshimoto, T., Baba, Y., Tsunawake, N., Shinohara, K. SPRINGER TOKYO. 2010: S156

  View details for Web of Science ID 000278587800512

• The effect of inaudible high-frequency sounds of infant crying on the breast hemodynamics of lactating mothers Inoue, T., Doi, H., Nishitani, S., Iwata, S., Kanazawa, M., Shinohara, K. SPRINGER TOKYO. 2010: S183

  View details for Web of Science ID 000278587800613

• Sex difference of the neural basis of the maternal and paternal attachment in humans Nishitani, S., Takamura, T., Yamashita, S., Araki, M., Shinohara, K. SPRINGER TOKYO. 2010: S156

  View details for Web of Science ID 000278587800513

• The ability to recognize affective voices is modulated by the oxytocin receptor gene (OXTR) variants in normal human subjects Fujisawa, T., Nishitani, S., Inoue, T., Takamura, T., Ikematsu, K., Shinohara, K. ELSEVIER IRELAND LTD. 2010: E79

  View details for DOI 10.1016/j.neures.2010.07.114

  View details for Web of Science ID 000208443700349

• The neural basis of the maternal attachment in human grandmothers Tanaka, M., Nishitani, S., Takamura, T., Sugawara, M., Shinohara, K. SPRINGER TOKYO. 2010: S186

  View details for Web of Science ID 000278587800625

• Sex difference in the neural basis of parental bonding Nishitani, S., Takamura, T., Yamashita, S., Shinohara, K. ELSEVIER IRELAND LTD. 2010: E78

  View details for DOI 10.1016/j.neures.2010.07.111

  View details for Web of Science ID 000208443700346

• A comparative NIRS study of the prefrontal activity between mothers, non-mother nursery nurses and other non-mother females Nishitani, S., Baba, Y., Yoshimoto, T., Omori, A., Kisanuki, Y., Doi, H., Ikeda, E., Takamura, T., Onaka, T., Shinohara, K. ELSEVIER IRELAND LTD. 2009: S228

  View details for DOI 10.1016/j.neures.2009.09.1279

  View details for Web of Science ID 000272421101643

• THE RECRUITMENT OF THE RIGHT PARIETAL CORTEX IN INEFFICIENT SEARCH REVEALED BY fNIRS MEASUREMENT Doi, H., Kato, M., Nishitani, S., Shinohara, K. SPRINGER TOKYO. 2009: 427

  View details for Web of Science ID 000271023103002

• THE PREFRONTAL CORTEX WAS ACTIVATED IN MOTHERS DURING THE ODOR DETECTION TASK OF THE NEWBORN INFANT Nishitani, S., Kuwamoto, S., Takahira, A., Shinohara, K. SPRINGER TOKYO. 2009: 192

  View details for Web of Science ID 000271023101228

• INFLUENCE OF HIGH-FREQUENCY ACOUSTIC COMPONENT OF INFANT CRYING ON MOTHERS' PERCEPTION Inoue, T., Ikeda, E., Doi, H., Nishitani, S., Shinohara, K. SPRINGER TOKYO. 2009: 477

  View details for Web of Science ID 000271023103305

• The calming effect of a maternal breast milk odor on the human newborn infant NEUROSCIENCE RESEARCH Nishitani, S., Miyamura, T., Tagawa, M., Sumi, M., Takase, R., Doi, H., Moriuchi, H., Shinohara, K. 2009; 63 (1): 66-71

  Abstract

  We examined the effects of the odors from mother's milk, other mother's milk and formula milk on pain responses in newborns undergoing routine heelsticks. Forty-eight healthy infants were assigned to four groups, an own mother's breast milk odor group (Own MM), another mother's breast milk odor group (Other MM), a formula milk odor group (Formula M) and a control group. To assess infant distress in response to the heelsticks, their crying, grimacing and motor activities were recorded during the experiment as behavioral indices of the pain response. After the heelstick, the behavioral indices of the Own MM group were lower than those of other groups. By contrast, the Other MM and Formula M groups showed no significant changes compared with the Control group. We also measured salivary cortisol concentration as a biochemical index in Control and Own MM infants before and after heelstick. After the heelstick, the level of salivary cortisol was significantly increased in Control infants, but not in Own MM infants. These results suggest that pain is relieved in human newborns when they are exposed to odors from their mother's milk.

  View details for DOI 10.1016/j.neures.2008.10.007

  View details for Web of Science ID 000262768200011

  View details for PubMedID 19010360

• The olfactory conditioning in the early postnatal period stimulated neural stem/progenitor cells in the subventricular zone and increased neurogenesis in the olfactory bulb of rats NEUROSCIENCE So, K., Moriya, T., Nishitani, S., Takahashi, H., Shinohara, K. 2008; 151 (1): 120-128

  Abstract

  The olfactory memory acquired during the early postnatal period is known to be maintained for a long period, however, its neural mechanism remains to be clarified. In the present study, we examined the effect of olfactory conditioning during the early postnatal period on neurogenesis in the olfactory bulb of rats. Using the bromodeoxyuridine-pulse chase method, we found that the olfactory conditioning, which was a paired presentation of citral odor (conditioned stimulus) and foot shock (unconditioned stimulus) in rat pups on postnatal day 11, stimulated the proliferation of neural stem/progenitor cells in the anterior subventricular zone (aSVZ), but not in the olfactory bulb, at 24 h after the conditioning. However, the number of newborn cells in the olfactory bulb was increased at 2 weeks, but not 8 weeks, after such conditioning. Neither the exposure of a citral odor alone nor foot shock alone affected the proliferation of neural stem/progenitor cells in the aSVZ at 24 h after and the number of newborn cells in the olfactory bulb at 2 weeks after. The majority of newborn cells in the olfactory bulb of either the conditioned rats or the unconditioned rats expressed the neural marker NeuN, thus indicating that the olfactory conditioning stimulated neurogenesis in the olfactory bulb. These results suggest that olfactory conditioning during the early postnatal period temporally stimulates neurogenesis in the olfactory bulb of rats.

  View details for DOI 10.1016/j.neuroscience.2007.07.051

  View details for Web of Science ID 000252608800012

  View details for PubMedID 18093744

• Emotion Detection in Infants' Cries Based on a Maximum Likelihood Approach Matsunaga, S., Sakaguchi, S., Yamashita, M., Miyahara, S., Nishitani, S., Shinohara, K., ISCA ISCA-INT SPEECH COMMUNICATION ASSOC. 2006: 1834-+

  View details for Web of Science ID 000269965901196

• Newborn infant body odor attenuates their mother's postpartum moods Nishitani, S., Kokuryo, M., Miyamura, T., Shinohara, K. ELSEVIER IRELAND LTD. 2006: S249

  View details for Web of Science ID 000238609702422

• Induction of Fos immunoreactivity in oxytocin neurons in the paraventricular nucleus after female odor exposure in male rats: Effects of sexual experience CELLULAR AND MOLECULAR NEUROBIOLOGY Nishitani, S., Moriya, T., Kondo, Y., Sakuma, Y., Shinohara, K. 2004; 24 (2): 283-291

  Abstract

  1. We examined whether oxytocin (OT) neurons in the paraventricular nucleus of the hypothalamus (PVN) were activated by estrus female odor and sexual contact in sexually naïve and experienced Long-Evans rats. 2. Male rats were not presented to anesthetized estrus females (control) or presented to the females without (exposure to the female odor without sexual contact) or with direct contact (exposure to the female odor with sexual contact). 3. Exposure to the female odor with sexual contact significantly increased OT neurons with Fos-ir in both males. Exposure to the female odor without contact increased OT neurons with Fos-immunoreactive cells (Fos-ir) in sexually experienced males but not in naïve males, suggesting that the female odor without sexual contact activated the oxytocinergic neuronal system in the PVN in the experienced males. 4. Therefore, exposure to the estrus female odor itself may exert different effects on sexually naïve and experienced males.

  View details for DOI 10.1023/B:CEMN.0000018622.44317.14

  View details for Web of Science ID 000220053200008

  View details for PubMedID 15176441

  View details for PubMedCentralID PMC11529925