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SECTIONOur Divisions

Division of Development of Functional Brain Activities
Division of Affective and Cognitive Development
Division of Psychosocial Support for Nurturing
Division of Community Mental Health Support
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Division of Development of Functional Brain Activities

Our research labs are working at research aimed at elucidating the mechanism of brain development at the molecular and cellular level. Specifically, it aims to clarify the process of neural circuit formation and development from the cerebral cortex to the basal ganglia, limbic system, and olfactory bulb, which are considered to be the main basis of the mind. In addition, we develop translational research with a view to the application to medical care and support for individuals with developmental disorders based on the study results.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social disorder and stereotypical behavior, but the cause is unknown and there are no biological treatments. Abnormalities of bioenergetic metabolism contributing to the ASD pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the metabolism in ASD and to explore a biomarker for clinical evaluation. Our recent results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology (Usui et al. eBioMedicine 2020). In addition, we used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a diagnostic tool for children with ASD (Hirayama et al. Sci Rep 2020). We are now focusing on the relationship between ASD and mitochondrial dysfunction, and trying to establish a treatment method for ASD by using 5‐Amino levulinic acid (5-ALA).
Zinc finger and BTB domain containing 16 (ZBTB16) plays the roles in the neural progenitor cell proliferation and neuronal differentiation during development, however how the function of ZBTB16 is involved in brain function and behaviors unknown. Here we show the deletion of Zbtb16 in mice leads to social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we conducted histological analyses and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the prefrontal cortex (PFC) of Zbtb16 KO mice. Using genomics approaches, we identified the Zbtb16 transcriptome that includes genes involved in neocortical maturation such as neurogenesis and myelination, and both ASD and SCZ pathobiology. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the novel roles of ZBTB16 in behaviors and neocortical development related to the disorders (Usui et al. Transl Psychiatry. 2021).
In the other hands, we have focused on the serotonergic system but its underlying molecular mechanisms remain controversial. In our previous report, we reidentified N-ethylmaleimide-sensitive factor (NSF) as new serotonin transporter (SERT) binding protein (Iwata et al 2014). We generated the NSF+/- mice and investigated their phenotypes. Our results suggest that cellular trafficking turbulence of synaptic molecules by lacking NSF gene might be related to the pathophysiology of autistic properties, providing novel insights into the ASD pathophysiology (Xie et al. in submission).
Children’s mental health problems are associated with low self-esteem. Harter has proposed the theory that recognizing competence in areas of personal importance and social support would improve students’ self-esteem. However, no study has examined the Harter’s theory for primary school children. This study aimed to test the effectiveness of the Treasure File Program for improving primary school child’s self-esteem using a quasi-experimental study design. The effectiveness of the program was evaluated in terms of the students’ self-esteem, physical well-being, emotional well-being, family relationships, friendships, and school performance. A total of 794 primary school students (aged 6–11 years) in the intervention group and 592 in the control group completed the assessments. As a result, the intervention group showed significant improvement in self-esteem domain (P<0.001) compared to the control group. No effects of the intervention were observed on the other domains. These findings indicate that this program is effective in improving self-esteem in primary school students. Given the importance of self-esteem in children’s mental health, this program may be helpful as a primary educational program option to address mental health problems in primary school children (Iwahori et al. in submission).
In mammals, odor information detected by olfactory sensory neurons is converted to a topographic map of activated glomeruli in the olfactory bulb. Mitral cells and tufted cells transmit signals sequentially to the olfactory cortex for behavioral outputs. To elicit innate behavioral responses, odor signals are directly transmitted by distinct subsets of mitral cells from particular functional domains in the olfactory bulb to specific amygdala nuclei. As for the learned decisions, input signals are conveyed by tufted cells as well as by mitral cells to the olfactory cortex. Behavioral scene cells link the odor information to the valence cells in the amygdala to elicit memory-based behavioral responses. Olfactory decision and perception take place in relation to the respiratory cycle. We are working on the study of neural circuits involved in decision making in the mouse olfactory system (Sakano. Dev Growth Differ. 2020; Mori and Sakano. Annu Rev Physiol. 2021)
The brain function unit is composed of neural circuits formed by nerve cells via synapses. Therefore, we are aiming to understand the correspondence between synaptic structure and function by clarifying the amount and spatial distribution of functional molecules that work at synapses in each neural circuit in the brain, and to elucidate the information processing mechanism of the brain (Nakamoto et al. J Comp Neurol. 2020; Parajuli et al. eNeuro 2020; Tanaka et al Cereb Cortex. 2020; Eguchi et al. Front Cell Neurosci. 2020; Murata et al. J Comp Neurol. 2020; Kasahara et al. Neurosci Res. 2020; Martín-Belmonte et al. Brain Pathol. 2020; Kleindienst et al. Int J Mol Sci. 2020)
ハートマーク

Division of Affective and Cognitive Development

This Division has several aims. Focusing especially on structural and functional MRI studies of the human brain, we will elucidate brain mechanisms in children with neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We also will look for biomarkers that can be useful in clinical settings. In addition, in collaboration with the Division of Psychosocial Support for Nurturing at the Research Center for Child Mental Development at University of Fukui, we study the pathophysiology of attachment disorders due to child maltreatment and develop novel treatments and support systems for children and their caregivers.

We conduct the most advanced clinical imaging research in the world in order to clarify characteristics of brain structure and function in children with neurodevelopmental disorders (ADHD･ASD) and attachment disorders using 3T MRI and PET/MRI. The ultimate goal is not only to elucidate the pathology but also to develop practical treatments and support systems for clinical settings. We aim to develop biomarkers for objective evaluation, and novel treatments based on the biological mechanisms.

In order to carry out the above-mentioned research, advanced knowledge and skills are required in a wide range of fields such as developmental pediatrics, child and adolescent psychiatry, radiology, psychology, neuroscience, informatics, and pedagogy. Therefore, we are actively promoting collaboration with researchers from various fields and backgrounds. Specifically, we will collaborate with multiple departments here at the University of Fukui – including Pediatrics, Psychiatry, Radiology and the Biomedical Imaging Research Center – and also with researchers at other institutions including United Graduate School of Child Development (Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University), National Institute for Physiological Sciences, Stanford University and the Korean Brain Research Institute.

Utilizing databases such as ABCD (Adolescent Brain Cognitive Development) study, a large-scale study in which 21 research institutions in the United States longitudinally collect brain images, genes, and behavior data of about 12,000 children, we obtain a large number of samples required for analysis. In addition, we will construct an original data base by multi-institutional collaborative research based on United Graduate School of Child Development, and pursue reproducible results in independent sample groups.

[Research achievement]

We have been actively promoting collaborative research mainly regarding brain imaging research for neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We have achieved research results by domestic multi-institutional collaborative study with Osaka University based on data base in United Graduate School of Child Development. We also have been internationally collaborating with Stanford University in the United States, and Korean Brain Research Institute.

  • Structural brain classification features in children with ADHD using machine learning (collaboration with Korean Brain Research Institute)

    We identified 16 specific brain regions in children with ADHD which can distinguish between ADHD and typical developing children as an accuracy of about 80% using machine learning. Being verified using another data base in the United States and China based on the findings, then accuracy was 73%. Our study suggests the findings could be applied as international diagnostic measures (Jung & Mizuno et al., Cerebral Cortex, 2018).

  • Structural brain abnormalities in children and adolescents with comorbid ASD and ADHD (collaboration with Osaka University)

    A multi-institutional collaborative study with Osaka University based on data base in the United Graduate School of Child Development exhibited that patients with comorbid ASD and ADHD had significantly lower left postcentral gyrus volumes compared with typically developing children. In addition, we observed significantly lower postcentral gyrus volumes exclusively in children and preadolescents, and not in adolescents. Our findings suggest that abnormal somatosensory, attributed to delayed maturation of the left postcentral gyrus, leads to the core symptoms experienced by patients with comorbid ASD and ADHD. (Mizuno et al., Translational Psychiatry, 2019).

  • Effects of methylphenidate on aberrant brain network dynamics in children with ADHD (collaboration with Stanford University)

    In an international collaboration with Stanford University, a randomized placebo-controlled double-blind crossover study demonstrated, for the first time, that methylphenidate can improve sustained attention and remediate aberrant brain circuit dynamics in cognitive control circuits in children with ADHD (Mizuno et al., under review). In addition, we obtain large samples in ABCD (Adolescent Brain Cognitive Development) study, a large-scale longitudinal study in the United States, and then work on development of ADHD subtype based on neural network using unsupervised machine learning.

ハートマーク

Division of Psychosocial Support for Nurturing

The Research Division works with researchers in Japan and overseas to conduct the following research.

The painful press of child abuse is not stopped, and early and appropriate response is an urgent issue. The aim is to carry out research that contributes to methylation of oxytocin receptors that mediate effects on the brain and support of nurturers, and to establish the results in local communities, in addition to the effects on the reward system of adult-impaired brains caused by abuse, as well as the susceptibility period that has a large effect on the later years.

Furthermore, JST is implementing social implementation in two core cities in Osaka Prefecture with the aim of establishing R&D results in "Establishing a New Public/Private Space for Creating a Safe Life" "Establishing a System to Reduce Child Abuse by Supporting Nursing Persons" as a subject of the JST Social Technology Research and Development (RISTEX).

For the research and development of new scientific evaluation method of the unidentified developmental disability, the challenge of visualizing the features of brain structure and function of the attention lack/hyperactivity (ADHD) infant and autistic spectroscopy (ASD) infant by the brain image is developed.

In recent years, there has been an increasing number of so-called "delicious children" who suddenly explode emotions, causing major confusion at home and in educational settings. The present study aims to investigate the actual conditions of "Kirei Children" (IED), to verify the usefulness of the resting functional MRI and the nonlinear analysis method of electroencephalogram in diagnosis, disease state and treatment evaluation, to establish a practical objective evaluation method in the IED of children, and to construct an effective and comprehensive support system based on medical evaluation.

Measurements of daytime activity rhythm, nighttime sleep rhythm, sensory evaluation, and measurement of endocrine system (salivary melatonin, cortisol) of ASD infant are carried out. The purpose of this study is to clarify the biological rhythm of ASD infant from the comparison between ASD infant and typical developing infant. Furthermore, since the sleeping habits of infants have become a social problem in recent years, a multicenter study with Osaka University, Kanazawa University, and Hirosaki University is being promoted to study interventions for caregivers through smartphone apps aimed at improving the sleeping habits of infants.

To determine whether programs related to the raising of children with developmental disabilities are associated with improved maternal stress and parent-child relationships. In addition, functional MRI is used to verify whether the effect on the program also affects the brain function of parents and children.

ハートマーク

Division of Community Mental Health Support

The division of Child and Adolescent Mental Health Specialist Training was established in FY2017, and all the faculty members were in office in the fall of the same year, and the division is now in a full operation. The main purpose of this division is to train child and adolescent mental health specialists (hereinafter referred to as child and adolescent psychiatrists), and this year we trained four new residents, and we actively recruited residents through web media and briefing sessions, and eventually two new residents will start their training next year. Not restricted to the main training environment at the Children's Mental Health Clinic in University of Fukui Hospital, the occasion of residency training has been steadily developing over the past year, and the number of patients referred from medical institutions in and outside of the prefecture has been steadily increasing. Case studies by visiting professor Toshiro Sugiyama and clinical psychologist Masako Okada are held stably once a month, and guidance on therapeutic interventions has been enhanced. In addition to the Fukui Prefectural Hospital and Rehabilitation Center, permission has been obtained to visit the Child Guidance Center and Juvenile Detention Center, and opportunities for training at related institutions outside the hospital have been enhanced.

This department was established at the request of the Disability Welfare Division of the Fukui Prefectural Government and has been asked to provide support for the improvement of skills in the prefecture, including mental health welfare and co-medical services. Faculty members provide training and supervision in and outside of the prefecture. Specifically, they have lectured at the Association of Clinical Psychologists, child guidance centers, rehabilitation centers, and university nursing departments. In addition, the Hokuriku-Kohoku Cognitive-Behavioral Therapy Study Group and the Fukui Children's Mental Health Study Group are held on a regular basis.

Furthermore, as a contribution to child and adolescent psychiatry in the region of this department, the following activities have been conducted.

  • Medical treatment at the clinic opened by the resident as the deputy director
  • Medical treatment at the Fukui Prefectural Rehabilitation and Education Center
  • Commissioned medical services at the prefectural general welfare consultation center
  • Medical treatment at the Fukui University Hospital In addition, at the Prefectural Child Rehabilitation Center, study sessions for parents have been held six times and have been well received.

Finally, as for research, we have started translating the K-SADS-PL-5 and studying its usefulness in actual clinical practice.