Publications

Abstract

Language is supported by a distributed network of brain regions with a particular contribution from the left hemisphere. A multi-level understanding of this network requires studying the genetic architecture of its functional connectivity and hemispheric asymmetry. We used resting state functional imaging data from 29,681 participants from the UK Biobank to measure functional connectivity between 18 left-hemisphere regions implicated in multimodal sentence-level processing, as well as their homotopic regions in the right-hemisphere, and interhemispheric connections. Multivariate genome-wide association analysis of this total network, based on common genetic variants (with population frequencies above 1%), identified 14 loci associated with network functional connectivity. Three of these loci were also associated with hemispheric differences of intrahemispheric connectivity. Polygenic dispositions to lower language-related abilities, dyslexia and left-handedness were associated with generally reduced leftward asymmetry of functional connectivity, but with some trait- and connection-specific exceptions. Exome-wide association analysis based on rare, protein-altering variants (frequencies < 1%) suggested 7 additional genes. These findings shed new light on the genetic contributions to language network connectivity and its asymmetry based on both common and rare genetic variants, and reveal genetic links to language-related traits and hemispheric dominance for hand preference.

Abstract

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1–18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Abstract

The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here we generated a new gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with inter-individual variation in structural connectivity between left-hemisphere frontal and temporal language cortex, and with predisposition to dyslexia. The axon guidance genes SLIT1 and SLIT2 were consistently implicated. These findings identify region-specific patterns of laminar gene expression as a feature of the brain’s language network.

Abstract

The human cerebral hemispheres show a left–right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4–13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.

Abstract

The coordinate system has been proposed as a fundamental and cross-culturally used spatial representation, through which people code location and direction information in the environment. Here we provided direct evidence demonstrating that daily experience with the cardinal coordinate system (i.e., east, west, north, and south) contributed to the representation of cognitive maps. Behaviorally, we found that individuals who relied more on the cardinal coordinate system for daily navigation made smaller errors in an indoor pointing task, suggesting that the cardinal coordinate system is an important element of cognitive maps. Neurally, the extent to which individuals relied on the cardinal coordinate system was positively correlated with the gray matter volume of the entorhinal cortex, suggesting that the entorhinal cortex may serve as the neuroanatomical basis of coordinate-based navigation (the entorhinal coordinate area, ECA). Further analyses on the resting-state functional connectivity revealed that the intrinsic interaction between the ECA and two hippocampal sub-regions, the subiculum and cornu ammonis, might be linked with the representation precision of cognitive maps. In sum, our study reveals an association between daily experience with the cardinal coordinate system and cognitive maps, and suggests that the ECA works in collaboration with hippocampal sub-regions to represent cognitive maps.

Abstract

Spatial navigation is a crucial ability for living. Previous animal studies have shown that the S100B gene is causally related to spatial navigation performance in mice. However, the genetic factors influencing human navigation and its neural substrates remain unclear. Here, we provided the first evidence that the S100B gene modulates neural processing of navigationally relevant scenes in humans. First, with a novel protocol, we demonstrated that the spatial pattern of S100B gene expression in postmortem brains was associated with brain activation pattern for spatial navigation in general, and for scene processing in particular. Further, in a large fMRI cohort of healthy adults of Han Chinese (N = 202), we found that S100B gene polymorphisms modulated scene selectivity in the retrosplenial cortex (RSC) and parahippocampal place area. Finally, the serum levels of S100B protein mediated the association between S100B gene polymorphism and scene selectivity in the RSC. Our study takes the first step toward understanding the neurogenetic mechanism of human spatial navigation and suggests a novel approach to discover candidate genes modulating cognitive functions.

Abstract

Spatial navigation is a crucial ability for living. Previous work has revealed multiple distributed brain regions associated with human navigation. However, little is known about how these regions work together as a network (referred to as navigation network) to support flexible navigation. In a novel protocol, we combined neuroimaging meta-analysis, and functional connectivity and behavioral data from the same subjects. Briefly, we first constructed the navigation network for each participant, by combining a large-scale neuroimaging meta-analysis (with the Neurosynth) and resting-state functional magnetic resonance imaging. Then, we investigated multiple topological properties of the navigation networks, including small-worldness, modularity, and highly connected hubs. Finally, we explored the behavioral relevance of these intrinsic properties in a large sample of healthy young adults (N = 190). We found that navigation networks showed small-world and modular organization at global level. More importantly, we found that increased small-worldness and modularity of the navigation network were associated with better navigation ability. Finally, we found that the right retrosplenial complex (RSC) acted as one of the hubs in the navigation network, and that higher betweenness of this region correlated with better navigation ability, suggesting a critical role of the RSC in modulating the navigation network in human brain. Our study takes one of the first steps toward understanding the underlying organization of the navigation network. Moreover, these findings suggest the potential applications of the novel approach to investigating functionally meaningful networks in human brain and their relations to the behavioral impairments in the aging and psychiatric patients.

Abstract

Spatial navigation is a crucial ability for living. Previous studies have shown that males are better at navigation than females, but little is known about the neural basis underlying the sex differences. In this study, we investigated whether cortical scene processing in three well-established scene-selective regions was sexually different, by examining sex differences in scene selectivity and its behavioral relevance to navigation. To do this, we used functional magnetic resonance imaging (fMRI) to scan the parahippocampal place area (PPA), retrosplenial complex (RSC), and occipital place area (OPA) in a large cohort of healthy young adults viewing navigationally relevant scenes (N = 202), and correlated their neural selectivity to scenes with their self-reported navigational ability. Behaviorally, we replicated the previous finding that males were better at navigation than females. Neurally, we found that the scene selectivity in the bilateral PPA, not in the RSC or OPA, was significantly higher in males than females. Such differences could not be explained by confounding factors including brain size and fMRI data quality. Importantly, males, not females, with stronger scene selectivity in the left PPA possessed better navigational ability. This brain-behavior association could not be accounted for by non-navigational abilities (i.e., intelligence and mental rotation ability). Overall, our study provides novel empirical evidence demonstrating sex differences in the brain activity, inviting further studies on sex differences in the neural network for spatial navigation.

Abstract

Scene-selective regions (SSRs), including the parahippocampal place area (PPA), retrosplenial cortex (RSC), and transverse occipital sulcus (TOS), are among the most widely characterized functional regions in the human brain. However, previous studies have mostly focused on the commonality within each SSR, providing little information on different aspects of their variability. In a large group of healthy adults (N = 202), we used functional magnetic resonance imaging to investigate different aspects of topographical and functional variability within SSRs, including interindividual, interhemispheric, and sex differences. First, the PPA, RSC, and TOS were delineated manually for each individual. We then demonstrated that SSRs showed substantial interindividual variability in both spatial topography and functional selectivity. We further identified consistent interhemispheric differences in the spatial topography of all three SSRs, but distinct interhemispheric differences in scene selectivity. Moreover, we found that all three SSRs showed stronger scene selectivity in men than in women. In summary, our work thoroughly characterized the interindividual, interhemispheric, and sex variability of the SSRs and invites future work on the origin and functional significance of these variabilities. Additionally, we constructed the first probabilistic atlases for the SSRs, which provide the detailed anatomical reference for further investigations of the scene network.