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.

Polygenic risk score for bipolar disorder associates with divergent thinking and brain structures in the prefrontal cortex.

It has been hypothesized that a higher genetic risk of bipolar disorder (BD) is associated with greater creativity. Given the clinical importance of bipolar disorder and the importance of creativity to human society and cultural development, it is essential to reveal their associations and the neural basis of the genetic risk of bipolar disorder to gain insight into its etiology. However, despite the previous demonstration of the associations of polygenic risk score (PRS) of BD and creative jobs, the associations of BD-PRS and creativity measured by the divergent thinking (CMDT) and regional gray matter volume (rGMV) as well as regional white matter volume (rWMV) have not been investigated. Using psychological analyses and whole-brain voxel-by-voxel analyses, we examined these potential associations in 1558 young, typically developing adult students. After adjusting for confounding variables and multiple comparisons, a greater BD-PRS was associated with a greater total CMDT fluency score, and a significant relationship was found in fluency subscores. A greater BD-PRS was also associated with lower total mood disturbance. Neuroimaging analyses revealed that the BD-PRS was associated with greater rGMV in the right inferior frontal gyrus, which is a consistently affected area in BD, as well as a greater rWMV in the left middle frontal gyrus, which has been suggested to play a central role in the increased creativity associated with the risk of BD with creativity. These findings suggest a relationship between the genetic risk of BD and CMDT and prefrontal cortical structures among young educated individuals.

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.

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.

Effects of Time-Compressed Speech Training on Multiple Functional and Structural Neural Mechanisms Involving the Left Superior Temporal Gyrus.

Time-compressed speech is an artificial form of rapidly presented speech. Training with time-compressed speech (TCSSL) in a second language leads to adaptation toward TCSSL. Here, we newly investigated the effects of 4 weeks of training with TCSSL on diverse cognitive functions and neural systems using the fractional amplitude of spontaneous low-frequency fluctuations (fALFF), resting-state functional connectivity (RSFC) with the left superior temporal gyrus (STG), fractional anisotropy (FA), and regional gray matter volume (rGMV) of young adults by magnetic resonance imaging. There were no significant differences in change of performance of measures of cognitive functions or second language skills after training with TCSSL compared with that of the active control group. However, compared with the active control group, training with TCSSL was associated with increased fALFF, RSFC, and FA and decreased rGMV involving areas in the left STG. These results lacked evidence of a far transfer effect of time-compressed speech training on a wide range of cognitive functions and second language skills in young adults. However, these results demonstrated effects of time-compressed speech training on gray and white matter structures as well as on resting-state intrinsic activity and connectivity involving the left STG, which plays a key role in listening comprehension.

Neural bases of the adaptive mechanisms associated with reciprocal partner choice.

In our society, partner choice is often reciprocal and, therefore, compromising one's choice may be adaptive depending on one's own market price. To reveal the neural mechanisms underlying this adaptive process, functional magnetic resonance imaging (fMRI) was performed on 27 male subjects during virtual partner choice tasks involving a dance-partner choice or a part-time job choice. Following the evaluation of a rival, the subjects chose a partner either in the face of competition with a rival (reciprocal choice condition) or during no competition (nonreciprocal condition). Irrespective of the type of partner choice situation, the posterior cingulate cortex (PCC) and right temporoparietal junction (TPJ) were specifically activated during reciprocal partner choice. The PCC was also activated during the evaluation of a rival relative to the self, which indicates the involvement of this region in the processing of one's own market price. Activation in the right TPJ was related to the individual tendency to avoid choosing a higher-value candidate when the rival-value was high in the reciprocal choice condition, which indicates that this region plays a role in market-adaptive strategy. Taken together with extant anatomical knowledge, the two-component neurobiological structure underlying the adaptive mechanism of partner choice identified in this study seems to represent the hierarchical evolution of the human socio-cognitive system.

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.

Interpersonal frontopolar neural synchronization in group communication: An exploration toward fNIRS hyperscanning of natural interactions.

Research of interpersonal neural synchronization (INS) using functional near-infrared spectroscopy (fNIRS) hyperscanning is an expanding nascent field. This field still requires the accumulation of findings and establishment of analytic standards. In this study, we therefore intend to extend fNIRS-based INS research in three directions: (1) verifying the enhancement of frontopolar INS by natural and unstructured verbal communication involving more than two individuals; (2) examining timescale dependence of the INS modulation; and (3) evaluating the effects of artifact reduction methods in capturing INS. We conducted an fNIRS hyperscanning study while 12 groups of four subjects were engaged in cooperative verbal communication. Corresponding to the three objectives, our analyses of the data (1) confirmed communication-enhanced frontopolar INS, as expected from the region's roles in social communication; (2) revealed the timescale dependency in the INS modulation, suggesting the merit of evaluating INS in fine timescale bins; and (3) determined that removal of the skin blood flow component engenders substantial improvement in sensitivity to communication-enhanced INS and segregation from artifactual synchronization, and that caution for artifact reduction preprocessing is needed to avoid excessive removal of the neural fluctuation component. Accordingly, this study provides a prospective technical basis for future hyperscanning studies during daily communicative activities.

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).

Neuroanatomical correlates of the sense of control: Gray and white matter volumes associated with an internal locus of control.

A belief that effort is rewarded can develop incentive, achievement motivation, and self-efficacy. Individuals with such a belief attribute causes of events to themselves, not to external, uncontrollable factors, and are thus said to have an internal locus of control. An internal locus of control is a positive personality trait and has been thoroughly studied in applied psychology, but has not been widely examined in neuroscience. In the present study, correlations between locus of control assessment scores and brain volumes were examined in 777 healthy young adults using magnetic resonance imaging. A whole-brain multiple regression analysis with corrections for the effects of age, gender, and intelligence was conducted. Voxel-based morphometry analyses revealed that gray matter volumes in the anterior cingulate cortex, striatum, and anterior insula positively correlated with higher scores, which indicate an internal LOC. In addition, white matter volumes in the striatum showed significant correlations with an internal locus of control. These results suggest that cognitive, socioemotional, self-regulatory, and reward systems might be associated with internal control orientation. The finding of greater volumes in several brain regions in individuals with a stronger internal locus of control indicates that there is a neuroanatomical basis for the belief that one's efforts are rewarded.

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.

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.

The neural bases underlying social risk perception in purchase decisions.

Social considerations significantly influence daily purchase decisions, and the perception of social risk (i.e., the anticipated disapproval of others) is crucial in dissuading consumers from making purchases. However, the neural basis for consumers' perception of social risk remains undiscovered, and this novel study clarifies the relevant neural processes. A total of 26 volunteers were scanned while they evaluated purchase intention of products (purchase intention task) and their anticipation of others' disapproval for possessing a product (social risk task), using functional magnetic resonance imaging (fMRI). The fMRI data from the purchase intention task was used to identify the brain region associated with perception of social risk during purchase decision making by using subjective social risk ratings for a parametric modulation analysis. Furthermore, we aimed to explore if there was a difference between participants' purchase decisions and their explicit evaluations of social risk, with reference to the neural activity associated with social risk perception. For this, subjective social risk ratings were used for a parametric modulation analysis on fMRI data from the social risk task. Analysis of the purchase intention task revealed a significant positive correlation between ratings of social risk and activity in the anterior insula, an area of the brain that is known as part of the emotion-related network. Analysis of the social risk task revealed a significant positive correlation between ratings of social risk and activity in the temporal parietal junction and the medial prefrontal cortex, which are known as theory-of-mind regions. Our results suggest that the anterior insula processes consumers' social risk implicitly to prompt consumers not to buy socially unacceptable products, whereas ToM-related regions process such risk explicitly in considering the anticipated disapproval of others. These findings may prove helpful in understanding the mental processes involved in purchase decisions.

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.

Resting state functional connectivity associated with trait emotional intelligence.

Previous neuroimaging studies have suggested that trait emotional intelligence (TEI) is associated with components of the neural network involved in social cognition (SCN) and somatic marker circuitry (SMC). Our study is the first to investigate the association of TEI with resting-state functional connectivity (RSFC) between the key nodes of SCN and SMC [medial prefromtal cortex (mPFC) and bilateral anterior insula (AI), respectively] and other brain regions. We found that (a) the intrapersonal factor of TEI was negatively correlated with RSFC between mPFC and the anterior part of the right dorsolateral prefrontal cortex (DLPFC), (b) the TEI interpersonal factor score was positively correlated with RSFC between mPFC and the lingual gyrus, and (c) total TEI was positively correlated with RSFC between mPFC and the precuneus as well as (d) between the left AI and the middle part of the right DLPFC. Taken together with previous study findings, our findings can be comprehensively understood as neural mechanisms of SCN and SMC components are associated with TEI. In particular, the fluent interaction between SCN's two key nodes (mPFC and precuneus/PCC) [as well as between DMN's two key nodes] is suggested to be crucial for total TEI. Our study also indicated that (a) a clear functional separation between the two key nodes of the two major intrinsic networks, DMN and the task-positive network (mPFC and DLPFC), is important for higher intrapersonal TEI, (b) brain interactions involving vision-related areas (lingual gyrus) and the key node of SCN (mPFC) are important for interpersonal TEI, and (c) control of DLPFC over the key node of SMC (AI) is important for total TEI.

Accelerated preprocessing of large numbers of brain images by parallel computing on supercomputers.

"Preprocessing" is the first step required in brain image analysis that improves the overall quality and reliability of the results. However, it is computationally demanding and time-consuming, particularly to handle and parcellate complicatedly folded cortical ribbons of the human brain. In this study, we aimed to shorten the analysis time for data preprocessing of 1410 brain images simultaneously on one of the world's highest-performing supercomputers, "Fugaku." The FreeSurfer was used as a benchmark preprocessing software for cortical surface reconstruction. All the brain images were processed simultaneously and successfully analyzed in a calculation time of 17.33 h. This result indicates that using a supercomputer for brain image preprocessing allows big data analysis to be completed shortly and flexibly, thus suggesting the possibility of supercomputers being used for expanding large data analysis and parameter optimization of preprocessing in the future.