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

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

Abstract

Statistical inference plays a critical role in modern scientific research, however, the dominant method for statistical inference in science, null hypothesis significance testing (NHST), is often misunderstood and misused, which leads to unreproducible findings. To address this issue, researchers propose to adopt the Bayes factor as an alternative to NHST. The Bayes factor is a principled Bayesian tool for model selection and hypothesis testing, and can be interpreted as the strength for both the null hypothesis H0 and the alternative hypothesis H1 based on the current data. Compared to NHST, the Bayes factor has the following advantages: it quantifies the evidence that the data provide for both the H0 and the H1, it is not “violently biased” against H0, it allows one to monitor the evidence as the data accumulate, and it does not depend on sampling plans. Importantly, the recently developed open software JASP makes the calculation of Bayes factor accessible for most researchers in psychology, as we demonstrated for the t-test. Given these advantages, adopting the Bayes factor will improve psychological researchers’ statistical inferences. Nevertheless, to make the analysis more reproducible, researchers should keep their data analysis transparent and open.

Abstract

Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.

Abstract

Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) has emerged as the most popular neuroimaging technique used to depict the biological microstructural properties of human brain white matter. However, like other MRI techniques, traditional DW-MRI data remains subject to head motion artifacts during scanning. For example, previous studies have indicated that, with traditional DW-MRI data, head motion artifacts significantly affect the evaluation of diffusion metrics. Actually, DW-MRI data scanned with higher sampling rate are important for accurately evaluating diffusion metrics because it allows for full-brain coverage through the acquisition of multiple slices simultaneously and more gradient directions. Here, we employed a publicly available multiband DW-MRI dataset to investigate the association between motion and diffusion metrics with the standard pipeline, tract-based spatial statistics (TBSS). The diffusion metrics used in this study included not only the commonly used metrics (i.e., FA and MD) in DW-MRI studies, but also newly proposed inter-voxel metric, local diffusion homogeneity (LDH). We found that the motion effects in FA and MD seems to be mitigated to some extent, but the effect on MD still exists. Furthermore, the effect in LDH is much more pronounced. These results indicate that researchers shall be cautious when conducting data analysis and interpretation. Finally, the motion-diffusion association is discussed.

Abstract

Magnetic resonance imaging (MRI) provides valuable data for understanding the human mind and brain disorders, but in-scanner head motion introduces systematic and spurious biases. For example, differences in MRI measures (e.g., network strength, white matter integrity) between patient and control groups may be due to the differences in their head motion. To determine whether head motion is an important variable in itself, or just simply a confounding variable, we explored individual differences in psychological traits that may predispose some people to move more than others during an MRI scan. In the first two studies, we demonstrated in both children (N  =  245) and adults (N  =  581) that head motion, estimated from resting-state functional MRI and diffusion tensor imaging, was reliably correlated with impulsivity scores. Further, the difference in head motion between children with attention deficit hyperactivity disorder (ADHD) and typically developing children was largely due to differences in impulsivity. Finally, in the third study, we confirmed the observation that the regression approach, which aims to deal with motion issues by regressing out motion in the group analysis, would underestimate the effect of interest. Taken together, the present findings provide empirical evidence that links in-scanner head motion to psychological traits.

Abstract

Background Although local features of brain morphology have been widely investigated in neuroscience, the inter-regional relations in brain morphology have rarely been investigated, especially not for individual participants. New method In this paper, we proposed a novel framework for investigating this relation based on an individual's magnetic resonance imaging (MRI) data. The key idea was to estimate the probability density function (PDF) of local morphological features within a brain region to provide a global description of this region. Then, the inter-regional relations were quantified by calculating the similarity of the PDFs for pairs of regions based on the Kullback–Leibler (KL) divergence. Results For illustration, we applied this approach to a pre-post intervention study to investigate the longitudinal changes in morphological relations after long-term sleep deprivation. The results suggest the potential application of this new method for studies on individual differences in brain structure. Comparison with existing methods The current method can be employed to estimate individual morphological relations between regions, which have been largely ignored by previous studies. Conclusions Our morphological relation metric, as a novel quantitative biomarker, can be used to investigate normal individual variability and even within-individual alterations/abnormalities in brain structure.

Abstract

Sleep loss can alter extrinsic, task-related functional MRI signals involved in attention, memory, and executive function. However, the effects of sleep loss on brain structure have not been well characterized. Recent studies with patients with sleep disorders and animal models have demonstrated reduction of regional brain structure in the hippocampus and thalamus. In this study, using T1-weighted MRI, we examined the change of regional gray matter volume in healthy adults after long-term total sleep deprivation (∼72 h). Regional volume changes were explored using voxel-based morphometry with a paired two-sample t-test. The results revealed significant loss of gray matter volume in the thalamus but not in the hippocampus. No overall decrease in whole brain gray matter volume was noted after sleep deprivation. As expected, sleep deprivation significantly reduced visual vigilance as assessed by the continuous performance test, and this decrease was correlated significantly with reduced regional gray matter volume in thalamic regions. This study provides the first evidence for sleep loss-related changes in gray matter in the healthy adult brain.