統合失調症患者に対する簡易かつ対面式で行う精神（認知・行動・自律神経）指標検査の意義についての研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 戸田 達史, 東京大学准教授 金生 由紀子, 東京大学講師 荒木 剛, 東京大学教授 上別府 圭子, 東京大学講師 湯本 真人University of Tokyo(東京大学

Birth order and prosociality in the early adolescent brain

Birth order is a crucial environmental factor for child development. For example, later-born children are relatively unlikely to feel secure due to sibling competition or diluted parental resources. The positive effect of being earlier-born on cognitive intelligence is well-established. However, whether birth order is linked to social behavior remains controversial, and the neural correlates of birth order effects in adolescence when social cognition develops remain unknown. Here, we explored the birth order effect on prosociality using a large-scale population-based adolescent cohort. Next, since the amygdala is a key region for sociality and environmental stress, we examined amygdala substrates of the association between birth order and prosociality using a subset neuroimaging cohort. We found enhanced prosociality in later-born adolescents (N = 3160), and observed the mediating role of larger amygdala volume (N = 208) and amygdala-prefrontal functional connectivity with sex-selective effects (N = 183). We found that birth order, a non-genetic environmental factor, affects adolescent social development via different neural substrates. Our findings may indicate the later-born people’s adaptive survival strategy in stressful environments

Neurometabolic underpinning of the intergenerational transmission of prosociality

Parent-child personality transmission can occur via biological gene-driven processes as well as through environmental factors such as shared environment and parenting style. We recently revealed a negative association between prosociality, a highly valued personality attribute in human society, and anterior cingulate cortex (ACC) γ-aminobutyric acid (GABA) levels in children at the age of 10 years. We thus hypothesized that prosociality would be intergenerationally transmitted, and that transmission would be underwritten by neurometabolic heritability. Here, we collected prosociality data from children aged 10 years and their parents in a large-scale population-based birth cohort study. We also measured ACC GABA+ and glutamate plus glutamine (Glx) levels in a follow-up assessment with a subsample of the participants (aged 11 years) using magnetic resonance spectroscopy. We analyzed the associations among children’s and parents’ prosociality and GABA+/Glx ratios. We also examined the effect of socioeconomic status (SES) and verbalized parental affection (VPA) on these associations. We found a significant positive parent-child association for prosociality (N ​= ​3026; children’s mean age 10.2 years) and GABA+/Glx ratio (N ​= ​99; children’s mean age 11.4 years). There was a significant negative association between GABA+/Glx ratio and prosociality in both children (N ​= ​208) and parents (N ​= ​128). Our model accounting for the effects of neurometabolic heritability on prosociality transmission fitted well. Moreover, in this model, a significant positive effect of VPA but not SES on children’s prosociality was observed independently of the effect of neurometabolic transmission, while SES but not VPA was significantly associated with parental prosociality. Our results provide novel insights into the neurometabolic substrates of parent-child transmission of social behavior

Intergenerational transmission of the patterns of functional and structural brain networks.

There is clear evidence of intergenerational transmission of life values, cognitive traits, psychiatric disorders, and even aspects of daily decision making. To investigate biological substrates of this phenomenon, the brain has received increasing attention as a measurable biomarker and potential target for intervention. However, no previous study has quantitatively and comprehensively investigated the effects of intergenerational transmission on functional and structural brain networks. Here, by employing an unusually large cohort dataset (N = 84 parent-child dyads; 45 sons, 39 daughters, 81 mothers, and 3 fathers), we show that patterns of functional and structural brain networks are preserved over a generation. We also demonstrate that several demographic factors and behavioral/physiological phenotypes have a relationship with brain similarity. Collectively, our results provide a comprehensive picture of neurobiological substrates of intergenerational transmission and demonstrate the usability of our dataset for investigating the neurobiological substrates of intergenerational transmission

Abnormal asymmetries in subcortical brain volume in early adolescents with subclinical psychotic experiences.

Subcortical structures may have an important role in the pathophysiology of psychosis. Our recent mega-analysis of structural magnetic resonance imaging (MRI) data has reported subcortical volumetric and lateralization alterations in chronic schizophrenia, including leftward asymmetric increases in pallidal volume. The question remains, however, whether these characteristics may represent vulnerability to the development of psychosis or whether they are epiphenomena caused by exposure to medication or illness chronicity. Subclinical psychotic experiences (SPEs) occur in some adolescents in the general population and increase the odds of developing psychosis in young adulthood. Investigations into the association between SPEs and MRI-measured volumes of subcortical structures in the general adolescent population would clarify the issue. Here, we collected structural MRI data in a subsample (10.5-13.3 years old) of a large-scale population-based cohort and explored subcortical volume and lateralization alterations related to SPEs (N = 203). Adolescents with SPEs demonstrated significant volumetric increases in the left hippocampus, right caudate, and right lateral ventricle, as well as a marginally significant increase in the left pallidum. Furthermore, adolescents with SPEs showed significantly more leftward laterality of pallidal volume than individuals without SPEs, which replicates our mega-analysis findings in chronic schizophrenia. We suggest that leftward asymmetries in pallidal volume already present in early adolescence may underlie the premorbid predisposition for developing psychosis in later life

Smaller anterior subgenual cingulate volume mediates the effect of girls\u27 early sexual maturation on negative psychobehavioral outcome.

Early-maturing girls are relatively likely to experience compromised psychobehavioral outcomes. Some studies have explored the association between puberty and brain morphology in adolescents, while the results were non-specific for females or the method was a region-of-interest analysis. To our knowledge, no large-scale study has comprehensively explored the effects of pubertal timing on whole-brain volumetric development or the neuroanatomical substrates of the association in girls between pubertal timing and psychobehavioral outcomes. We collected structural magnetic resonance imaging (MRI) data of a subsample (N ​= ​203, mean age 11.6 years) from a large-scale population-based birth cohort. Tanner stage, a scale of physical maturation in adolescents, was rated almost simultaneously with MRI scan. The Strengths and Difficulties Questionnaire total difficulties (SDQ-TD) scores were rated by primary parents some duration after MRI scan (mean age 12.1 years). In each sex group, we examined brain regions associated with Tanner stage using whole-brain analysis controlling for chronological age, followed by an exploration of brain regions also associated with the SDQ-TD scores. We also performed mediation analyses. In girls, Tanner stage was significantly negatively correlated with gray matter volumes (GMVs) in the anterior/middle cingulate cortex (ACC/MCC), of which the subgenual ACC (sgACC) showed a negative correlation between GMVs and SDQ-TD scores. Smaller GMVs in the sgACC mediated the association between higher Tanner stages and higher SDQ-TD scores. We found no significant results in boys. Our results from a minimally biased, large-scale sample provide new insights into neuroanatomical correlates of the effect of pubertal timing on developmental psychological difficulties emerging in adolescence

Association between duration of breastfeeding based on maternal reports and dorsal and ventral striatum and medial orbital gyrus volumes in early adolescence.

Maternal breastfeeding has an impact on motor and emotional development in children of the next generation. Elucidating how breastfeeding during infancy affects brain regional structural development in early adolescence will be helpful for promoting healthy development. However, previous studies that have shown relationships between breastfeeding during infancy and cortical brain regions in adolescence are usually based on maternal retrospective recall of breastfeeding, and the accuracy of the data is unclear. In this study, we investigated the association between breastfeeding duration and brain regional volume in a population-neuroimaging study of early adolescents in Japan (N ​= ​207; 10.5-13.4 years) using voxel-based morphometry, which enabled us to analyze the whole brain. We evaluated breastfeeding duration as indexed by maternal and child health handbook records during infancy. The results showed a significant positive correlation between the duration of breastfeeding and gray matter volume in the dorsal and ventral striatum and the medial orbital gyrus. Post hoc exploratory analyses revealed that the duration of breastfeeding was significantly correlated with emotional behavior. Additionally, the volume in the medial orbital gyrus mediated an association between breastfeeding duration and emotional behavior. This is the first study to evaluate the effect of breastfeeding during infancy on regional brain volumes in early adolescence based on maternal and child health handbook records. Our findings shed light upon the importance of maternal breastfeeding for brain development related to emotional and motivational processing in early adolescence