Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7—mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

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Left-handedness and its genetic influences are associated with structural asymmetries mapped across the cerebral cortex in 31,864 individuals

10.1101/2021.07.16.452594 ◽

2021 ◽

Author(s):

Zhiqiang Sha ◽

Antonietta Pepe ◽

Dick Schijven ◽

Amaia Carrion Castillo ◽

James M. Roe ◽

...

Keyword(s):

Cerebral Cortex ◽

Surface Area ◽

Image Data ◽

Hand Preference ◽

Occipital Cortex ◽

Imaging Data ◽

Left Handedness ◽

Genome Wide ◽

Cortical Regions ◽

Related Proteins

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We re-sampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers and right-handers showed average differences of surface area asymmetry within fusiform, anterior insular, anterior-middle-cingulate and precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2 and NME7 - the latter is mutated in left-right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas non-heritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

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The genetic architecture of the human cerebral cortex

Science ◽

10.1126/science.aay6690 ◽

2020 ◽

Vol 367 (6484) ◽

pp. eaay6690 ◽

Cited By ~ 46

Author(s):

Katrina L. Grasby ◽

Neda Jahanshad ◽

Jodie N. Painter ◽

Lucía Colodro-Conde ◽

Janita Bralten ◽

...

Keyword(s):

Cerebral Cortex ◽

Surface Area ◽

Meta Analysis ◽

Brain Magnetic Resonance Imaging ◽

Regulatory Elements ◽

Total Surface Area ◽

Imaging Data ◽

Cortical Structure ◽

A Genome ◽

Significant Enrichment

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

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Planar cell polarity pathway and development of the human visual cortex

10.1101/404558 ◽

2018 ◽

Cited By ~ 1

Author(s):

Jean Shin ◽

Shaojie Ma ◽

Edith Hofer ◽

Yash Patel ◽

Gennady V. Roshchupkin ◽

...

Keyword(s):

Cerebral Cortex ◽

Visual Cortex ◽

Cytochrome Oxidase ◽

Surface Area ◽

Cell Polarity ◽

Cortical Thickness ◽

Planar Cell Polarity ◽

Chromosome 17 ◽

Intracranial Volume ◽

Cortical Regions

AbstractThe radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 23,800 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (global) component was associated mainly with loci on chromosome 17 (9.5e-32 ≤ p ≤ 2.8e-10), including those detected previously as linked with intracranial volume and/or general cognitive function. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=2.4e-34). DAAM1 is a key component in the planar-cell-polarity signaling pathway. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that, in concert with thalamocortical input to cortical subplate, DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

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Human Handedness: Genetics, Microtubules, Neuropsychiatric Diseases and Brain Language Areas

10.1101/454660 ◽

2018 ◽

Cited By ~ 1

Author(s):

A. Wiberg ◽

G. Douaud ◽

M. Ng ◽

Y. Al Omran ◽

F. Alfaro-Almagro ◽

...

Keyword(s):

Imaging Study ◽

Brain Regions ◽

Uk Biobank ◽

Left Handedness ◽

Genome Wide ◽

Neuropsychiatric Diseases ◽

Additional Locus ◽

Language Areas ◽

Related Proteins ◽

The Brain

AbstractBackgroundThe skew in distribution of handedness is a uniquely human trait, and has fascinated researchers for centuries. The heritability of handedness is estimated at 25%, but defining genetic variants contributing to this trait has so far proved elusive.MethodsWe performed GWAS of self-reported handedness in UK Biobank, a prospective cohort study of ∼500,000 individuals. Furthermore, we investigated correlations between our associated SNPs and brain imaging-derived phenotypes (IDPs) from >9,000 individuals in UK Biobank, as well as between self-reported handedness and IDPs.ResultsOur association study of 38,322 left-handers vs 356,567 right-handers (excluding ambidextrous participants) revealed three genome-wide significant loci (rs199512, 17q21.31, p=4.1x10−9; rs45608532, 22q11.22, p=1.4x10−8; rs13017199, 2q34, p=3.3x10−8). In the imaging study, we found strong associations between rs199512 and diffusion MRI measures mainly in white matter tracts connecting language-related brain regions (p<2.0x10−6). Direct investigation between handedness and IDPs revealed numerous associations with functional connectivity between the same language-related areas of the brain. A second GWAS of non-right handers (n=44,631) vs right-handers (n=356,567) revealed an additional locus: rs3094128, 6p21.33, p=2.9x10−8. Three of the four associated loci (2q34, 17q21.31, 6p21.33) contain genes that encode microtubule-related proteins that are highly expressed in the brain: MAP2, MAPT and TUBB. These genes are strongly implicated in the pathogenesis of diseases that are known to affect an excess of left-handed people, including schizophrenia.ConclusionsThis is the first GWAS to identify genome-wide significant loci for human handedness in the general population, and the genes at these loci have biological plausibility in contributing to neurodevelopmental lateralization of brain organisation, which appears to predispose both to left-handedness and to certain neurodegenerative and psychiatric diseases.

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Human Cerebral Cortex: Localization, Parcellation, and Morphometry with Magnetic Resonance Imaging

Journal of Cognitive Neuroscience ◽

10.1162/jocn.1992.4.4.352 ◽

1992 ◽

Vol 4 (4) ◽

pp. 352-374 ◽

Cited By ~ 271

Author(s):

J. Rademacher ◽

A. M. Galaburda ◽

D. N. Kennedy ◽

P. A. Filipek ◽

V. S. Caviness

Keyword(s):

Cerebral Cortex ◽

Magnetic Resonance ◽

Functional Anatomy ◽

Image Data ◽

Magnetic Resonance Images ◽

Surface Anatomy ◽

Interindividual Variations ◽

Primary Image ◽

Computational Reconstruction ◽

Cortical Regions

We describe a system of parcellation of the human brain that is based on the functional anatomy of the cerebral cortex and that is applied to the analysis of magnetic resonance images. This system is designed to support investigations of hemispheric asymmetries and quantitative lesion localization studies in cognitive neuroscience. The system of cortical subdivision is a neural systems oriented model that approximates subdivisions supported by previous architectonic and functional analyses. It is based primarily on boundaries determined by "limiting fissures." It is completed by a set of coronal planes, keyed to visible anatomic landmarks, which "close" the borders of the parcellation subdivisions. The method depends on computational reconstruction of the primary image data in multiple planes so as to allow the observed pattern of limiting fissures in a given brain to be digitized. In this presentation, the method is applied in order to define the surface anatomy of the cerebral hemispheres in a normal subject. Volumetric measurements of individual cortical regions are compared as hemispheric percentiles to areal perceniiles derived from the analysis of Jouandet et al. (1989), a conceptually related though methodologically different approach. We specifically address the approach to the study of interhemispheric differences and interindividual variations in cortical anatomy.

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Complete flatmounting of the macaque cerebral cortex

Visual Neuroscience ◽

10.1017/s0952523803206088 ◽

2003 ◽

Vol 20 (6) ◽

pp. 663-686 ◽

Cited By ~ 39

Author(s):

LAWRENCE C. SINCICH ◽

DANIEL L. ADAMS ◽

JONATHAN C. HORTON

Keyword(s):

Cerebral Cortex ◽

Surface Area ◽

Close Correlation ◽

Macaque Monkey ◽

Cholera Toxin B Subunit ◽

Primate Model ◽

Cortical Input ◽

Brain Surface ◽

Area V2 ◽

Cortical Regions

The elaborate folding of the brain surface has posed a practical impediment to investigators engaged in mapping the areas of the cerebral cortex. This obstacle has been overcome partially by the development of methods to erase the sulci and gyri by physically flattening the cortex prior to sectioning. In this study, we have prepared a step-by-step atlas of the flatmounting process for the entire cerebral cortex in the macaque monkey. The cortex was dissected from the white matter, unfolded, and flattened in a single piece of tissue by making three relieving cuts. The flatmount was sectioned at 60–75 μm and processed for cytochrome oxidase (CO) or myelin. From animal to animal there was nearly a twofold variation in the surface area of individual cortical regions, and of the whole cortex. In each specimen, a close correlation was found between V1 surface area (mean = 1343 mm2), V2 surface area (mean = 1012 mm2), hippocampal area (mean = 181 mm2), and total cerebral cortex area (mean = 10,430 mm2). The complete pattern of CO stripes in area V2 was labeled clearly in several cases; the number of cycles of thick-pale-thin-pale stripes ranged from 26 to 34. Characteristic patterns of strong CO activity were encountered in areas V3, MT, auditory and somatosensory cortex. In some animals we made injections of a retrograde tracer, gold-conjugated cholera toxin B subunit, into area V2 to identify all sources of cortical input. In addition to previously described inputs, we identified three new regions in the occipitotemporal region that project to V2. Flatmounting the cerebral cortex is a simple, efficient method that can be used routinely for mapping areas and connections in the macaque brain, the most widely used primate model of the human brain.

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Discrimination of the hierarchical structure of cortical layers in 2-photon microscopy data by combined unsupervised and supervised machine learning

10.1101/427955 ◽

2018 ◽

Author(s):

Dong Li ◽

Melissa Zavaglia ◽

Guangyu Wang ◽

Yi Hu ◽

Hong Xie ◽

...

Keyword(s):

Machine Learning ◽

Cerebral Cortex ◽

High Resolution ◽

Functional Organization ◽

Image Data ◽

Hierarchical Organization ◽

Training Data ◽

Supervised Machine Learning ◽

Imaging Data ◽

Laminar Organization

AbstractThe laminar organization of the cerebral cortex is a fundamental characteristic of the brain, with essential implications for cortical function. Due to the rapidly growing amount of high-resolution brain imaging data, a great demand arises for automated and flexible methods for discriminating the laminar texture of the cortex. Here, we propose a combined approach of unsupervised and supervised machine learning to discriminate the hierarchical cortical laminar organization in high-resolution 2-photon microscopic neural image data without observer bias, that is, without the prerequisite of manually labeled training data. For local cortical foci, we modify an unsupervised clustering approach to identify and represent the laminar cortical structure. Subsequently, supervised machine learning is applied to transfer the resulting layer labels across different locations and image data, to ensure the existence of a consistent layer label system. By using neurobiologically meaningful features, the discrimination results are shown to be consistent with the layer classification of the classical Brodmann scheme, and provide additional insight into the structure of the cerebral cortex and its hierarchical organization. Thus, our work paves a new way for studying the anatomical organization of the cerebral cortex, and potentially its functional organization.

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Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

Nature Communications ◽

10.1038/s41467-021-22234-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Thomas A. Johnson ◽

Ville Paakinaho ◽

Sohyoung Kim ◽

Gordon L. Hager ◽

Diego M. Presman

Keyword(s):

Receptor Binding ◽

Site Response ◽

Physiological Role ◽

Binding Potential ◽

Open Chromatin ◽

Imaging Data ◽

Response Elements ◽

Genome Wide ◽

Genomic Studies

AbstractA widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.

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ESR white paper: blockchain and medical imaging

Insights into Imaging ◽

10.1186/s13244-021-01029-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

◽

Elmar Kotter ◽

Luis Marti-Bonmati ◽

Adrian P. Brady ◽

Nandita M. Desouza

Keyword(s):

Medical Imaging ◽

Image Data ◽

Distributed Database ◽

Relevant Information ◽

White Paper ◽

Imaging Data ◽

Data Set ◽

Blockchain Technology ◽

Potential Applications ◽

Basic Technology

AbstractBlockchain can be thought of as a distributed database allowing tracing of the origin of data, and who has manipulated a given data set in the past. Medical applications of blockchain technology are emerging. Blockchain has many potential applications in medical imaging, typically making use of the tracking of radiological or clinical data. Clinical applications of blockchain technology include the documentation of the contribution of different “authors” including AI algorithms to multipart reports, the documentation of the use of AI algorithms towards the diagnosis, the possibility to enhance the accessibility of relevant information in electronic medical records, and a better control of users over their personal health records. Applications of blockchain in research include a better traceability of image data within clinical trials, a better traceability of the contributions of image and annotation data for the training of AI algorithms, thus enhancing privacy and fairness, and potentially make imaging data for AI available in larger quantities. Blockchain also allows for dynamic consenting and has the potential to empower patients and giving them a better control who has accessed their health data. There are also many potential applications of blockchain technology for administrative purposes, like keeping track of learning achievements or the surveillance of medical devices. This article gives a brief introduction in the basic technology and terminology of blockchain technology and concentrates on the potential applications of blockchain in medical imaging.

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Handedness in Children with Autism Spectrum Disorders

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.2189 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S214-S214 ◽

Cited By ~ 1

Author(s):

L. Kobylinska ◽

C.G. Anghel ◽

I. Mihailescu ◽

F. Rad ◽

I. Dobrescu

Keyword(s):

Autism Spectrum Disorders ◽

Training Programs ◽

Hand Preference ◽

Children With Autism ◽

Autism Spectrum ◽

Left Handedness ◽

Children With Asd ◽

Hand Laterality ◽

Spectrum Disorders ◽

Competing Interest

Children with autism spectrum disorders (ASD) have a less definitive hand preference for certain actions as opposed to neurotypical children. Moreover, left-handedness in children with ASD has been associated with more echolalia. The objective was to conduct a screening of potential risk and associated features for autism spectrum disorders, among which the hand preference of the child. The current aim is to compare the perceived handedness of children with autism spectrum disorders with that of children with other psychiatric pathologies.MethodsEight hundred and forty-two parents completed our risk and associated features screening questionnaire. Out of these, 494 answered the question regarding handedness (209 had children diagnosed with ASD). This asked the parents to state how they perceived their child's handedness. An ADOS assessment has been conducted for 170 of the children whose parents were included in the study, based on clinical relevance for the case. The data were analysed using Excel and SPSS 22.0. For the comparisons, Chi2 and the Kruskal–Wallis test were used.ResultsChildren with ASD had more left-handedness (χ2(2) = 12.54, P = 0.002). There were no differences between boys and girls in terms of perceived handedness in any of the groups. There were no differences in the ADOS scores according to the perceived hand laterality (χ2(2) = 0.58, P = 0.74).ConclusionRightward-asymmetry in regions of corpus callosum has been reported to correlate with symptoms severity in ASD. The finding of different perceived handedness in children with ASD versus children with other psychiatric pathologies is useful for designing appropriate, individualized training programs for motor therapy.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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