Sex-Dependent Effects of the APOE ɛ4 Allele on Behavioral Traits and White Matter Structures in Young Adults.

The APOE ɛ4 allele is associated with a risk of Alzheimer's disease in the elderly, with the association being pronounced in females. Conversely, findings of the effects of the APOE ɛ4 allele in young adults are mixed. Here, we investigated the sex-genotype interaction effects of the APOE ɛ4 allele on cognitive functions as well as brain structures among 1258 young adults. After adjusting for multiple comparisons, there were significant effects of the interaction between sex and the number of APOE ɛ4 allele on some speed tasks (e.g., simple processing speed tasks and the reverse Stroop task) as well as on regional white matter volume (rWMV). The observed sex-genotype interaction conferred better cognitive performance and greater rWMV in the anterior frontal and precentral white matter areas in females having more APOE ɛ4 alleles and reduced rWMV in the same areas in male having more APOE ɛ4 alleles. These findings support the long-debated antagonistic pleiotropic effects of the APOE ɛ4 allele in females.

Originality of divergent thinking is associated with working memory-related brain activity: Evidence from a large sample study.

The originality of creativity measured by divergent thinking (CMDT) is a unique variable that is positively correlated with psychometric intelligence and other psychological measures. Here, we aimed to determine the associations of CMDT originality/fluency scores and brain activity associated with working memory (WM) and simple cognitive processes during the N-back paradigm in a cohort of 1221 young adults. We observed that originality/fluency scores were associated with greater brain activity during the 0-back simple cognitive task and 2-back WM task in key nodes of the ventral attention system in the right hemisphere. Further, subjects with higher originality/fluency scores showed lower task-induced deactivations in areas of the default mode network, especially during the 2-back task. Psychological analyses revealed the associations of originality/fluency scores with both psychometric intelligence and systemizing. We also observed the effects of interaction between sex and originality/fluency scores on functional activity during the 0-back task in posterior parts of the default mode network together with other areas as well as simple processing speed. These results indicate that the originality of CMDT is associated with (a) greater activation of the ventral attention system, which is involved in reorienting attention and (b) reduced task-induced deactivation of the default mode network, which is indicative of alterations in attentional reallocation, and (c) cognitive correlates of originality of CMDT and revealed sex differences in these associations.

Increased grey matter volume of the right superior temporal gyrus in healthy children with autistic cognitive style: A VBM study.

The empathizing-systemizing model describes human cognitive style using empathizing (the drive to identify another's mental state and respond appropriately) and systemizing (the drive to assess or construct rule-based systems). 'Brain type' was envisioned to explain individual differences in cognitive style based on the discrepancy of the two drives. In this model, individuals with autism spectrum disorder (ASD), a neurodevelopmental disorder, have extremely stronger systemizing. Revealing the underlying mechanisms of individual differences in cognitive style might contribute to elucidation of the pathology of ASD. We used voxel-based morphometry to compare the brain structures among the brain types (those who have stronger empathizing, those who have equally stronger drive to both, and those who have stronger systemizing) in 207 healthy children (age range: 5-15). Results showed that children with stronger systemizing had significantly greater grey matter volume of the right superior temporal gyrus (rSTG) than the others. The brain region, a distinctive brain structure of those with stronger systemizing, was overlapped with that of children with ASD. The rSTG is involved in detailed perceptual processing in social cognition, which is partially related to stronger systemizing. Our results contribute to elucidation of the underlying mechanisms of individual differences in cognitive style.

A Common CACNA1C Gene Risk Variant has Sex-Dependent Effects on Behavioral Traits and Brain Functional Activity.

Genome-wide association studies have suggested that allelic variations in the CACNA1C gene confer susceptibility to schizophrenia and bipolar disorder only in women. Here we investigated the sex-specific effects of the CACNA1C variant rs1024582 on psychiatry-related traits, brain activity during tasks and rest, and brain volume in 1207 normal male and female subjects. After correcting for multiple comparisons, there were significant interaction effects between sex and the minor allele of this polymorphism on the hostile behavior subscale scores of the Coronary-Prone Type Scale mediated by higher scores in female carriers of the minor allele. Imaging analyses revealed significant interaction effects between sex and the minor allele on fractional amplitude of low-frequency fluctuations in the right dorsolateral prefrontal cortex and on brain activity during the 2-back task in areas of the right posterior cingulate cortex, right thalamus, and right hippocampus, which were all mediated by reduced activity in female carriers of the minor allele. Our results demonstrated that the rs1024582 risk variant of CACNA1C is associated with reduced activity in the frontolimbic regions at rest and during a working memory task as well as with greater hostility in females in the healthy population.

Impact of frequency of internet use on development of brain structures and verbal intelligence: Longitudinal analyses.

Excessive internet use is shown to be cross sectionally associated with lower cognitive functioning and reduced volume of several brain areas. However, the effects of daily internet use on the development of verbal intelligence and brain structures have not been investigated. Here, we cross sectionally examined the effects of the frequency of internet use on regional gray/white matter volume (rGMV/rWMV) and verbal intelligence as well as their longitudinal changes after 3.0 ± 0.3 (standard deviation) years in a large sample of children recruited from the general population (mean age, 11.2 ± 3.1 years; range, 5.7-18.4 years). Although there were no significant associations in cross sectional analyses, a higher frequency of internet use was found to be associated with decrease of verbal intelligence and smaller increase in rGMV and rWMV of widespread brain areas after a few years in longitudinal analyses. These areas involve areas related to language processing, attention and executive functions, emotion, and reward. In conclusion, frequent internet use is directly or indirectly associated with decrease of verbal intelligence and development to smaller gray matter volume at later stages.

Regional homogeneity, resting-state functional connectivity and amplitude of low frequency fluctuation associated with creativity measured by divergent thinking in a sex-specific manner.

Brain connectivity is traditionally thought to be important for creativity. Here we investigated the associations of creativity measured by divergent thinking (CMDT) with resting-state functional magnetic imaging (fMRI) measures and their sex differences. We examined these relationships in the brains of 1277 healthy young adults. Whole-brain analyses revealed a significant interaction between verbal CMDT and sex on (a) regional homogeneity within an area from the left anterior temporal lobe (b) on the resting state functional connectivity (RSFC) between the mPFC and the left inferior frontal gyrus and (c) on fractional amplitude of low frequency fluctuations (fALFF) in several distinct areas, including the precuneus and middle cingulate gyrus, left middle temporal gyrus, right middle frontal gyrus, and cerebellum. These interactions were mediated by positive correlations in females and negative correlations in males. These findings suggest that greater CMDT in females is reflected by (a) regional coherence (regional homogeneity) of brain areas responsible for representing and combining concepts as well as (b) the efficient functional connection (RSFC) between the key areas for the default state of cognitive activity and speech production, and (c) greater spontaneous neural activity (fALFF) during the resting of brain areas involved in frontal lobe functions, default cognitive activities, and language functions. Furthermore, these findings suggest that the associations between creativity and resting state brain connectivity patterns are different between males and females.

Creative females have larger white matter structures: Evidence from a large sample study.

The importance of brain connectivity for creativity has been theoretically suggested and empirically demonstrated. Studies have shown sex differences in creativity measured by divergent thinking (CMDT) as well as sex differences in the structural correlates of CMDT. However, the relationships between regional white matter volume (rWMV) and CMDT and associated sex differences have never been directly investigated. In addition, structural studies have shown poor replicability and inaccuracy of multiple comparisons over the whole brain. To address these issues, we used the data from a large sample of healthy young adults (776 males and 560 females; mean age: 20.8 years, SD = 0.8). We investigated the relationship between CMDT and WMV using the newest version of voxel-based morphometry (VBM). We corrected for multiple comparisons over whole brain using the permutation-based method, which is known to be quite accurate and robust. Significant positive correlations between rWMV and CMDT scores were observed in widespread areas below the neocortex specifically in females. These associations with CMDT were not observed in analyses of fractional anisotropy using diffusion tensor imaging. Using rigorous methods, our findings further supported the importance of brain connectivity for creativity as well as its female-specific association. Hum Brain Mapp 38:414-430, 2017. © 2016 Wiley Periodicals, Inc.

The VEGF gene polymorphism impacts brain volume and arterial blood volume.

Vascular endothelial growth factor (VEGF) plays a critical role in the angiogenesis and proliferation of various types of cells such as neurons, astroglia, and endothelial cells in the brain. A common polymorphism in the VEGF gene (-2578 C/A) is associated with circulating VEGF levels, cancers and Alzheimer's disease. Nonetheless, the effects of this polymorphism on normal human brain volume, arterial blood volume, and blood supply remain unclear. In this study, the effects of this polymorphism on the total gray matter volume (TGMV) and total white matter volume (TWMV) using T1-weighted structural images and the total arterial blood volume (TABV) and mean cerebral blood flow (mCBF) during rest using arterial spin labeling (ASL) in 765 young adult humans were investigated. Voxel-by-voxel whole-brain analyses of these measures were also performed. Multiple regression analyses with age and sex as covariates revealed that the VEGF genotype (number of C alleles) was significantly and positively correlated with TGMV, TWMV, and TABV as well as with regional gray and white matter volumes in widespread areas and regional arterial blood volume in some areas with high arterial blood volume. However, these regional associations were not seen when the corresponding global signal was included as a covariate in the multiple regression analyses, indicating that we failed to obtain evidence of region-specific associations between these brain measures and the genotype. The results suggest that the VEGF-2578C allele, is associated with changes in the vascular system that lead to increased blood volume and larger brain volume. Hum Brain Mapp 38:3516-3526, 2017. © 2017 Wiley Periodicals, Inc.

The impact of parent-child interaction on brain structures: cross-sectional and longitudinal analyses.

There is a vast amount of evidence from psychological studies that the amount of parent-child interaction affects the development of children's verbal skills and knowledge. However, despite the vast amount of literature, brain structural development associated with the amount of parent-child interaction has never been investigated. In the present human study, we used voxel-based morphometry to measure regional gray matter density (rGMD) and examined cross-sectional correlations between the amount of time spent with parents and rGMD among 127 boys and 135 girls. We also assessed correlations between the amount of time spent with parents and longitudinal changes that occurred a few years later among 106 boys and 102 girls. After correcting for confounding factors, we found negative effects of spending time with parents on rGMD in areas in the bilateral superior temporal gyrus (STG) via cross-sectional analyses as well as in the contingent areas of the right STG. We also confirmed positive effects of spending time with parents on the Verbal Comprehension score in cross-sectional and longitudinal analyses. rGMD in partly overlapping or contingent areas of the right STG was negatively correlated with age and the Verbal Comprehension score in cross-sectional analyses. Subsequent analyses revealed verbal parent-child interactions have similar effects on Verbal Comprehension scores and rGMD in the right STG in both cross-sectional and longitudinal analyses. These findings indicate that parent-child interactions affect the right STG, which may be associated with verbal skills.

Impact of reading habit on white matter structure: Cross-sectional and longitudinal analyses.

Psychological studies showed the quantity of reading habit affects the development of their reading skills, various language skills, and knowledge. However, despite a vast amount of literature, the effects of reading habit on the development of white matter (WM) structures critical to language and reading processes have never been investigated. In this study, we used the fractional anisotropy (FA) measure of diffusion tensor imaging to measure WM microstructural properties and examined cross-sectional and longitudinal correlations between reading habit and FA of the WM bundles in a large sample of normal children. In both cross-sectional and longitudinal analyses, we found that greater strength of reading habit positively affected FA in the left arcuate fasciculus (AF), in the left inferior fronto-occipital fasciculus (IFOF), and in the left posterior corona radiata (PCR). Consistent with previous studies, we also confirmed the significance or a tendency for positive correlation between the strength of reading habit and the Verbal Comprehension score in cross-sectional and longitudinal analyses. These cross-sectional and longitudinal findings indicate that a healthy reading habit may be directly or indirectly associated with the advanced development of WM critical to reading and language processes. Future intervention studies are needed to determine the causal effects of reading habits on WM in normal children.

The impact of television viewing on brain structures: cross-sectional and longitudinal analyses.

Television (TV) viewing is known to affect children's verbal abilities and other physical, cognitive, and emotional development in psychological studies. However, the brain structural development associated with TV viewing has never been investigated. Here we examined cross-sectional correlations between the duration of TV viewing and regional gray/white matter volume (rGMV/rWMV) among 133 boys and 143 girls as well as correlations between the duration of TV viewing and longitudinal changes that occurred a few years later among 111 boys and 105 girls. After correcting for confounding factors, we found positive effects of TV viewing on rGMV of the frontopolar and medial prefrontal areas in cross-sectional and longitudinal analyses, positive effects of TV viewing on rGMV/rWMV of areas of the visual cortex in cross-sectional analyses, and positive effects of TV viewing on rGMV of the hypothalamus/septum and sensorimotor areas in longitudinal analyses. We also confirmed negative effects of TV viewing on verbal intelligence quotient (IQ) in cross-sectional and longitudinal analyses. These anatomical correlates may be linked to previously known effects of TV viewing on verbal competence, aggression, and physical activity. In particular, the present results showed effects of TV viewing on the frontopolar area of the brain, which has been associated with intellectual abilities.

Effects of Fast Simple Numerical Calculation Training on Neural Systems.

Cognitive training, including fast simple numerical calculation (FSNC), has been shown to improve performance on untrained processing speed and executive function tasks in the elderly. However, the effects of FSNC training on cognitive functions in the young and on neural mechanisms remain unknown. We investigated the effects of 1-week intensive FSNC training on cognitive function, regional gray matter volume (rGMV), and regional cerebral blood flow at rest (resting rCBF) in healthy young adults. FSNC training was associated with improvements in performance on simple processing speed, speeded executive functioning, and simple and complex arithmetic tasks. FSNC training was associated with a reduction in rGMV and an increase in resting rCBF in the frontopolar areas and a weak but widespread increase in resting rCBF in an anatomical cluster in the posterior region. These results provide direct evidence that FSNC training alone can improve performance on processing speed and executive function tasks as well as plasticity of brain structures and perfusion. Our results also indicate that changes in neural systems in the frontopolar areas may underlie these cognitive improvements.

Comprehensive neural networks for guilty feelings in young adults.

Feelings of guilt are associated with widespread self and social cognitions, e.g., empathy, moral reasoning, and punishment. Neural correlates directly related to the degree of feelings of guilt have not been detected, probably due to the small numbers of subjects, whereas there are growing numbers of neuroimaging studies of feelings of guilt. We hypothesized that the neural networks for guilty feelings are widespread and include the insula, inferior parietal lobule (IPL), amygdala, subgenual cingulate cortex (SCC), and ventromedial prefrontal cortex (vmPFC), which are essential for cognitions of guilt. We investigated the association between regional gray matter density (rGMD) and feelings of guilt in 764 healthy young students (422 males, 342 females; 20.7 ± 1.8 years) using magnetic resonance imaging and the guilty feeling scale (GFS) for the younger generation which comprises interpersonal situation (IPS) and rule-breaking situation (RBS) scores. Both the IPS and RBS were negatively related to the rGMD in the right posterior insula (PI). The IPS scores were negatively correlated with rGMD in the left anterior insula (AI), right IPL, and vmPFC using small volume correction. A post hoc analysis performed on the significant clusters identified through these analyses revealed that rGMD activity in the right IPL showed a significant negative association with the empathy quotient. These findings at the whole-brain level are the widespread comprehensive neural network regions for guilty feelings. Interestingly, the novel finding in this study is that the PI was implicated as a common region for feelings of guilt with interaction between the IPS and RBS. Additionally, the neural networks including the IPL were associated with empathy and with regions implicated in moral reasoning (AI and vmPFC), and punishment (AI).

Degree centrality and fractional amplitude of low-frequency oscillations associated with Stroop interference.

Stroop paradigms are commonly used as an index of attention deficits and a tool for investigating functions of the frontal lobes and other associated structures. Here we investigated the correlation between resting-state functional magnetic imaging (fMRI) measures [degree centrality (DC)/fractional amplitude of low frequency fluctuations (fALFFs)] and Stroop interference. We examined this relationship in the brains of 958 healthy young adults. DC reflects the number of instantaneous functional connections between a region and the rest of the brain within the entire connectivity matrix of the brain (connectome), and thus how much of the node influences the entire brain areas, while fALFF is an indicator of the intensity of regional brain spontaneous activity. Reduced Stroop interference was associated with larger DC in the left lateral prefrontal cortex, left IFJ, and left inferior parietal lobule as well as larger fALFF in the areas of the dorsal attention network and the precuneus. These findings suggest that Stroop performance is reflected in resting state functional properties of these areas and the network. In addition, default brain activity of the dorsal attention network and precuneus as well as higher cognitive processes represented there, and default stronger global influence of the areas critical in executive functioning underlie better Stroop performance.

Regional gray matter density is associated with morningness-eveningness: Evidence from voxel-based morphometry.

Diurnal preference (morningness-eveningness) is known to be associated with several individual characteristics that are important in the fields of sociology, education, and psychiatry. Despite this importance, the anatomical correlates of individual differences in morningness-eveningness are unknown, and these were investigated in the present study. We used voxel-based morphometry and a questionnaire to determine individual morningness-eveningness and its association with brain structures in 432 healthy men and 344 healthy women (age, 20.7±1.8years). We demonstrated that morningness (less eveningness) was associated with (a) lower regional gray matter density (rGMD) in the precuneus and adjacent areas, (b) lower rGMD in the left posterior parietal cortex and adjacent areas, and (c) higher rGMD in the bilateral orbitofrontal cortex. Further, our exploratory analyses revealed that (d) higher rGMD in hypothalamic areas around the bilateral suprachiasmatic nuclei were associated with morningness. These findings demonstrate that variations in morningness-eveningness reflect the GM structures of focal regions across the cortex, and suggest a structural basis for individual morningness-eveningness and its association with a wide range of psychological variables distributed across different GM areas of the brain.

Cognitive and neural correlates of the 5-repeat allele of the dopamine D4 receptor gene in a population lacking the 7-repeat allele.

The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of attention deficit hyperactivity disorder (ADHD) and substantially exists in Asian populations, which have a lower ADHD prevalence. In this study, we investigated the effect of this allele on microstructural properties of the brain and on its functional activity during externally directed attention-demanding tasks and creative performance in the 765 Asian subjects. For this purpose, we employed diffusion tensor imaging, N-back functional magnetic resonance imaging paradigms, and a test to measure creativity by divergent thinking. The 5-repeat allele was significantly associated with increased originality in the creative performance, increased mean diffusivity (the measure of how the tissue includes water molecules instead of neural and vessel components) in the widespread gray and white matter areas of extensive areas, particularly those where DRD4 is expressed, and reduced task-induced deactivation in the areas that are deactivated during the tasks in the course of both the attention-demanding working memory task and simple sensorimotor task. The observed neural characteristics of 5-repeat allele carriers may lead to an increased risk of ADHD and behavioral deficits. Furthermore, the increased originality of creative thinking observed in the 5-repeat allele carriers may support the notion of the side of adaptivity of the widespread risk allele of psychiatric diseases.

The structure of the amygdala associates with human sexual permissiveness: evidence from voxel-based morphometry.

Sexual behavior is a critical function of human procreation. Despite previous studies that investigated the neural mechanisms of basic human physiological sexual functions, the neural mechanisms that underlie individual differences in human sexual permissiveness remain unknown. We used voxel-based morphometry and a questionnaire (scale for sexual attitudes) to measure sexual permissiveness to investigate the gray matter and white matter structural correlates of sexual permissiveness. Sexual permissiveness was negatively correlated with regional gray matter density of the structures involving the right amygdala and surrounding areas, and positively correlated with regional white matter density of the white matter area that spread around the left amygdala to the hypothalamus area. There were no gender-specific relationships in the neural correlates of our findings. These findings suggest that structural variations in regions that play key roles in the basic physiological aspects of human sexuality underlie individual complex sexual attitudes in social life.

Mean diffusivity of globus pallidus associated with verbal creativity measured by divergent thinking and creativity-related temperaments in young healthy adults.

Recent investigations revealed mean diffusivity (MD) in gray matter and white matter areas is correlated with individual cognitive differences in healthy subjects and show unique properties and sensitivity that other neuroimaging tools donot have. In this study, we tested the hypothesis that the MD in the dopaminergic system is associated with individual differences in verbal creativity measured by divergent thinking (VCDT) and novelty seeking based on prior studies suggesting associations between these and dopaminergic functions. We examined this issue in a large sample of right-handed healthy young adults. We used analyses of MD and a psychological measure of VCDT, as well as personality measures of the Temperament and Character Inventory (TCI). Our results revealed associations between higher VCDT and lower MD in the bilateral globus pallidus. Furthermore, not only higher novelty seeking, but also lower harm avoidance, higher self-directedness, and higher self-transcendence were robustly associated with lower MD in the right globus pallidus, whereas higher persistence was associated with lower MD in the left globus pallidus. These personality variables were also associated with VCDT. The globus pallidus receives the dopaminergic input from the substantia nigra and plays a key role in motivation which is critically linked to dopamine. These results suggested the MD in the globus pallidus, underlie the association between VCDT and multiple personalities in TCI including novelty seeking.

Increased posterior hippocampal volumes in children with lower increase in body mass index: a 3-year longitudinal MRI study.

People are generally lean during childhood and show more variability in body sizes and shapes later in life. Cortical development generally correlates with body growth. However, in children cortical growth may be impaired with oversized body growth. Inverse correlations between body mass index (BMI) and brain volumes suggest that lean bodies may be associated with increased cortical volume. To clarify the positive effects of a lean body on a child's cortical development, we used MRI to measure brain structures longitudinally in 107 children and adolescents aged 5-16 years. The relationships between changes in BMI and cortical volumes during 3 years of development were investigated, while controlling for age, gender and intracranial volume changes. Voxel-based morphometry analyses revealed that an increase in the volume of the right posterior medial temporal lobe ­ including the hippocampus and parahippocampal gyrus ­ was associated with lower BMI increases. No correlations were observed between higher BMI increases and cortical volumes. Our results suggest that keeping a lean body ­ or not getting fat ­ during childhood can induce an increase in regional cortical volume rather than impair growth. This is the first longitudinal study showing positive effects of a lean body on cortical development in children.

Association between resting-state functional connectivity and empathizing/systemizing.

Empathizing is the drive to identify the mental status of other individuals and respond to it with an appropriate emotion; systemizing is the drive to analyze a system. Previously, we have shown that structures associated with the default mode network (DMN) and external attention system (EAS) are associated with empathizing and systemizing, respectively. Here we investigated the association between resting-state functional connectivity (RSFC) and empathizing/systemizing in 248 healthy young adults. We considered the medial prefrontal cortex (mPFC) and bilateral dorsolateral prefrontal cortices (DLPFCs), which are key nodes of DMN and EAS, as seed regions, and investigated correlations across subjects between individual empathizing/systemizing and RSFC between each seed region and other brain regions. We found that higher empathizing was associated with larger RSFC between the mPFC and areas in (a) the dorsal anterior cingulate cortex (dACC), (b) precuneus, and (c) left superior temporal sulcus (STS). Furthermore, there was an interaction effect between sex and systemizing on RSFC between the left DLPFC and dACC: males showed positive correlations between this RSFC and systemizing, whereas females showed the opposite tendency. Thus, empathizing was associated with increased positive functional coupling with the key node and other nodes of DMN, as well as the area associated with feeling another's pain. Systemizing was associated with increased positive functional coupling between the key nodes of EAS in males. These findings provide further support for the concept of an association between DMN/EAS and empathizing/systemizing.