Biology subjects

Francks, C.

Publications and source records attributed to Francks, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Population-wide variation in connectopic organization of cerebral language hubs

The uniquely human capacity for language is supported by a distributed brain network with cerebral cortical hubs in the left inferior frontal gyrus (LIFG) and left superior temporal sulcus (LSTS). Individual differences in the graded spatial organization of function across these regions may provide sensitive phenotypes for behavioural and genetic association analyses, to better understand the biological underpinnings of language. In 41,437 UK Biobank participants we applied connectopic mapping to the LIFG and LSTS. This approach maps spatial changes across a region in terms of connectivity with the rest of the brain, based on resting state functional imaging. On average, we found that Brodmann Area (BA) 44, BA 45 and the posterior LSTS were strongly connected to the superior and inferior parietal lobe and the dorsal attention and frontoparietal networks, whereas BA 47 and the medial LSTS were strongly connected to superior frontal areas BA 8B and BA 9, and the default mode network more broadly. However, there was extensive population-wide variation in these graded connectopic patterns, which significantly mediated the effects of polygenic scores for reading ability and educational attainment on performance on a vocabulary task. Furthermore we identified 3 genomic loci displaying multivariate association patterns with these connectopic maps, one of which coincides with a long non-coding RNA, LINC01165, with potential relevance in human evolution. Overall, connectopic mapping produced fewer significant genetic association findings and lower heritability (range from 0.3 to 9.4%) than previous parcel-based approaches for mapping language network connectivity. These observations suggest higher genetic complexity and/or prominent roles for environmental or random developmental effects on these connectopic maps.

neuroscience↗

bioRxiv2025

Integrating brain structure and function for the neurobiology and genetics of language

Brain structure and function have largely been studied separately in relation to the neurobiology and genetics of language. Here we used linked independent component analysis to integrate language network functional connectivity with brain volumetric and white matter structure in 32,677 UK Biobank participants, followed by analysis of behavioural, neurobiological and genetic correlates of the derived multimodal structure-function imaging components. Stronger functional connectivity between brain language areas was associated with increased volume of parts of the cerebellum and motor cortex, together with smaller ventricles and sensory parietal and occipital areas. The brain structure-function language components mediated an association between vocabulary level and polygenic scores for reading ability. We report 18 genomic loci associated with brain structure-function language components. Single-nucleotide polymorphism (SNP)-based heritability estimates for these components were 23-30%, and there was significant enrichment of heritability in primate-conserved genomic loci and fetal brain human-gained enhancer elements. This study revealed that structural correlates of functional language network connectivity extend well beyond previously defined language areas of the brain, and highlights the value of multimodal brain phenotyping for human neurogenetic discovery.

neuroscience↗

bioRxiv2025

Structural and functional brain asymmetry in relation to heterogeneous causes of situs inversus totalis

Various aspects of brain organization differ between the left and right hemispheres. Clues to the developmental origins of these asymmetries may be gained through associations with situs inversus totalis (SIT), a rare condition in which visceral organs are reversed on the left-right axis. In the largest previous brain imaging analyses of SIT (38 cases, 38 controls from Belgium), typical functional asymmetries such as left-hemisphere language dominance were mostly unaltered, but various aspects of asymmetrical cerebral structure - petalia, bending, and posterior venous anatomy - were often reversed in this condition. SIT can be a monogenic trait that arises from rare genetic variants, usually affecting motile cilia which help to create the embryonic left-right body axis. However, most SIT cases do not have obvious genetic causes and may arise from environmental or random effects during embryogenesis. We sequenced the genomes of 23 SIT cases and 23 controls from the Belgian brain imaging dataset and pooled with prior data from 15 cases and 15 controls. We aimed to discover whether there are altered brain asymmetries in SIT cases with disruptive DNA variants in ciliary genes, or in other types of genes, as compared to genetically unsolved cases. In total, 19 cases had likely causal variants affecting ciliary function, while 19 cases remained genetically unsolved. Functional and structural brain asymmetries were not significantly different in genetically solved versus unsolved SIT cases. Therefore, functional brain asymmetries seem largely independent of known mechanisms of visceral situs formation, while structural brain torque is altered in SIT regardless of the presence or absence of overt genetic causes.

neuroscience↗

bioRxiv2025

Perfect imperfections: seeking molecular and cellular asymmetries in the mouse brain

Although perfect symmetry is a mathematical ideal, many Bilateria exhibit left-right asymmetries of body, brain and behavior that are adaptive 1-3. In the human brain, various aspects of cognition are lateralized, including language 4 and handedness 5, which rely on left hemisphere dominance in most people. Brain hemispheric specialization can support parallel processing, neural efficiency, and action selection 3,6, while atypical structural or functional asymmetries are often found in neuropsychiatric disorders 7-10. Mice may be useful models for studying brain asymmetry because they show hemispheric differences of structure 11,12 and neurophysiology 13, but the extent to which molecular and cellular differences are involved remains unknown. We applied spatial transcriptomics with single molecule resolution to coronal sections from 31 adult mouse brains, to assess left-right differences of gene expression and cell types. Sections were chosen to capture the hippocampus and auditory cortex, as these two regions have shown the most prior evidence for functional asymmetry 13-15. In the hippocampus, Crhr1 (Corticotropin-Releasing Hormone Receptor 1) was more highly expressed in the pyramidal layers of CA1, CA3 and the dentate gyrus of the left hemisphere compared to the right. In the auditory cortex, three principal components capturing transcriptomic variation showed hemispheric differences, including prominent contributions from genes that have shown associations with human brain asymmetry. Overall cellular density and cell type proportions generally showed no significant hemispheric differences, with Car3 cortical excitatory neurons showing the most laterality. The transcriptional left-right differences that we found may relate to functional asymmetries for learning, memory and hearing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/675542v1_ufig1.gif" ALT="Figure 1"> View larger version (119K): org.highwire.dtl.DTLVardef@1530502org.highwire.dtl.DTLVardef@16dd244org.highwire.dtl.DTLVardef@107950corg.highwire.dtl.DTLVardef@ca52a3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMolecular and cellular basis of functional brain asymmetry is barely known C_LIO_LISpatial transcriptomics with cellular resolution applied to mouse brain coronal sections C_LIO_LIGenes implicated in human brain asymmetry showed hemispheric differences in mice C_LIO_LINo hemispheric differences of cell type abundances C_LI

neuroscience↗

bioRxiv2025

Functional characterization of pathogenic SATB2 missense variants identifies distinct effects on chromatin binding and transcriptional activity

SATB2-associated syndrome is an autosomal dominant neurodevelopmental syndrome caused by genetic alterations in the transcription factor SATB2. The associated phenotype is variable, and genotype-phenotype correlation studies have not yet been able to explain differences in severity and symptoms across affected individuals. While haploinsufficiency is the most often described disease mechanism, with the majority of variants consisting of whole- or partial-gene deletions and protein truncating variants with predicted loss-of-function, approximately one-third of affected individuals carry a SATB2 missense variant with an unknown effect. In this study, we sought to functionally characterize these missense variants to uncover associated pathogenic mechanisms. We combined a set of human cell-based experiments to screen 31 etiological SATB2 missense variants for effects on nuclear localization, global chromatin binding, and transcriptional activity. Our data indicate partial loss-of-function effects for most of the studied missense variants, but identify at least eight variants with increased SATB2 function showing a combination (or subset) of features that include stronger co-localization with DNA, decreased nuclear protein mobility suggesting increased overall chromatin binding, and maintained or increased transcriptional activity. These results demonstrate that phenotypes associated with variants in SATB2 may have distinct underlying disease mechanisms, and the data could provide a resource for future studies investigating disease variability and potential therapies for this condition.

genetics↗

bioRxiv2025

Spatial and single-nucleus transcriptomic profile of a chimpanzee frontal pole

Chimpanzees, our closest living relatives, share a vast amount of our genetic code, with the majority of differences found in non-coding regions of the genome. Functional and gene regulatory differences drive phenotypic divergence, including the distinctive brain anatomy of humans compared to chimpanzees and other apes. However, little is known about species differences in gene expression, and how they relate to the evolution of neuroanatomy and cognition. This is primarily due to the limited availability of great ape brain samples and challenges in comparative spatial transcriptomic studies. Here, we present the first spatial transcriptomic data from a chimpanzee brain based on post mortem tissue from an adult female, who was euthanised due to poor health. We focus on the frontal pole, a brain region that has undergone significant evolutionary changes in size and organisation since the last common ancestor of humans and chimpanzees, and is considered critical for cognitive evolution. We examined the gene expression profiles and cell-type composition of the frontal pole on the left hemisphere, including both neuronal and non-neuronal cell types across cortical layers and white matter. By integrating our spatial transcriptomic data with a publicly available single-nucleus transcriptomic dataset of the chimpanzee dorsolateral prefrontal cortex, we mapped the spatial distribution of 29 chimpanzee brain cell types. This study represents a first step towards characterisation of spatial gene regulatory differences between the brains of non-human great apes and humans. Significance statementRecent advances in spatial transcriptomics technologies provided important insights into the spatial organisation of gene expression and cell types in human and mouse brains, yet applications in non-model organisms remain limited. Here, we present the first-ever spatial transcriptomics dataset from a chimpanzee brain. We demonstrate i) the applicability of a widely used spatial transcriptomics technique to chimpanzee brain samples freshly frozen in isopentane, and ii) an end-to-end pipeline for generating good-quality spatial transcriptomics data from chimpanzee brains. Our work paves the way for future comparative spatial transcriptomics studies across human and non-human primate brains, and marks a step toward applying spatial omics methods to great ape brains.

evolutionary biology↗

bioRxiv2024

Global brain asymmetry and its variations in aging and related diseases

Functional lateralization is a cardinal feature of human brain, and deviations from typical lateralization are observed in various brain disorders. Although this phenomenon has been widely acknowledged in the field of human neuroscience, decades of research have shown that it is a challenge to bridge the gap between (a)typically lateralized functions and hemispheric differences in structure (termed structural asymmetry). To address this important question, the present study employed the state-of-the-art machine learning techniques to investigate the brain structural asymmetry and its associations with cognitive functions, aging, and aging-related diseases, by integrating large-scale datasets. Our proposed multivariate approach revealed previously unknown and substantial structural differences between the left and right hemispheres, and established the associations between the global brain asymmetry and lateralized functions including hand motor and emotion processing. Furthermore, at the population level we mapped the aging trajectories of the global brain asymmetry, and unveiled significant diagnosis-specific variations in patients with Alzheimers disease and Parkinsons disease, and individuals carrying a relevant genetic risk for atypical brain aging (i.e., APOE4 carriers). These results demonstrated left-hemisphere-linked changes in aging, which has challenged the traditional "right hemi-aging" model, and offered a promising approach for assessing brain aging and related diseases. Overall, our study with a novel approach presents one of the largest-scale investigation of global brain asymmetry, and takes an important step forward in understanding the intricate interplay between structural asymmetry, lateralized functions, and brain aging in health and disease. Significance statementFunctional lateralization is fundamental to the human brain, with deviations linked to various brain disorders. Bridging the gap between functional lateralization and structural asymmetry has been a long-standing challenge. Using advanced machine learning and large-scale datasets, this study introduced a multivariate global brain asymmetry approach and revealed previously unidentified structural differences between the brain hemispheres, correlating these with cognitive functions, aging, and diseases like Alzheimers and Parkinsons. Contrary to the traditional "right hemi-aging" model, we found left-hemisphere-linked aging changes. This work provides new insights into brain asymmetry, lateralized functions, and aging, offering a promising approach for assessing brain health and disease. Classifications: Biological Sciences (Psychological and Cognitive Sciences);

neuroscience↗

bioRxiv2024

No phenotypic consequences of archaic hominin alleles in present-day humans

Advances in paleo-genetics allowed the identification of protein-coding changes arising on the lineage leading to Homo sapiens, by comparing genomes of present-day and archaic hominins. Experimental validation of the potential impact of such changes has so far been restricted to functional assays and model organisms. Large-scale biobanking now makes it possible to identify present-day carriers of archaic alleles and to directly assess phenotypic consequences in living adults. We queried exomes of half a million people in the UK Biobank at 37 genomic positions with supposedly fixed human-specific protein-coding changes. This yielded 103 carriers at 17 positions, with variable allele counts across ancestries. Contrasting carriers and non-carriers of an exemplary archaic allele in SSH2, we observed no deviation from the norm in a range of health, psychological, and cognitive traits. We also identified 62 archaic-allele carriers for a TKTL1 missense change, previously shown to have large effects on cortical neurogenesis in brain organoids and animal models. Carriers did not show differences in relevant anatomical brain measures, and a substantial proportion had college/university degrees. This work offers an empirical demonstration of how large-scale biobank investigations of living adults can transform our understanding of human evolution. The findings challenge the notion of fixed human-specific genomic changes, highlight that individual interrogation of relevant sites is unlikely to yield major insights into the emergence of complex human traits, and emphasise the importance of including diverse ancestries when investigating origins of our species.

genetics↗

bioRxiv2024

Imaging genomics reveals genetic architecture of the globular human braincase

Compared with our fossil ancestors and Neandertal kin, modern humans have evolved a distinctive skull shape, with a rounder braincase and more delicate face. Competing explanations for this rounder skull have either linked it to changes in brain organisation, or seen it as a by-product of gracilization (evolution of thinner and lighter skeletal anatomy). Here, we combined palaeoanthropological data from hominin fossils and imaging genomics data from living humans to gain insight into evolutionary and developmental mechanisms shaping this uniquely modern human phenotype. We analysed endocranial globularity from magnetic resonance imaging (MRI) brain scans and genetic data of more than 33,000 adults. We discovered 28 genomic loci significantly associated with endocranial globularity. There was genetic overlap with the brains ventricular system, white matter microstructure, and sulcal morphology, and with multivariate genetic analyses of reading/language skills, but not with general cognition. The associated genes exhibited enriched expression in the brain during prenatal development and early childhood. The connection to the ventricular system hints at a role for cerebrospinal fluid pressure in shaping the endocranium during development. Genes linked to endocranial globularity also showed enhanced expression in the cardiovascular and female reproductive systems. This finding suggests co-evolutionary pathways whereby changes impacting factors such as energy needs, pregnancy, or fertility concurrently shape the brain and its structure.

genetics↗

bioRxiv2024

The neocortical infrastructure for language involves region-specific patterns of laminar gene expression

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 brains language network.

genetics↗

bioRxiv2023

The universe is asymmetric, the mouse brain too.

Hemispheric brain asymmetry is a basic organizational principle of the human brain and has been implicated in various psychiatric conditions, including autism spectrum disorder. Brain asymmetry is not a uniquely human feature and is observed in other species such as the mouse. Yet, asymmetry patterns are generally nuanced, and substantial sample sizes are required to detect these patterns. In this pre-registered study, we use a mouse dataset from the Province of Ontario Neurodevelopmental Network, which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse. Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain, such as larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole, opposite to what has been shown in humans. This suggests the existence of species-specific traits. Further clustering analysis identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. Our study shows potential for the use of mouse models in studying the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.

neuroscience↗

bioRxiv2023

Exome-wide analysis implicates rare protein-altering variants in human handedness

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examined whether left-handedness is also influenced by rare coding variants (frequencies [≤] 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals (UK Biobank). The beta-tubulin gene TUBB4B showed exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers (0.076%) than right-handers (0.028%). The TUBB4B variants were mostly heterozygous missense changes, but included two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 showed evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study revealed a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

genetics↗

bioRxiv2022

Genetic architecture of the white matter connectome of the human brain

White matter tracts form the structural basis of large-scale functional networks in the human brain. We applied brain-wide tractography to diffusion images from 30,810 adult participants (UK Biobank), and found significant heritability for 90 regional connectivity measures and 851 tract-wise connectivity measures. Multivariate genome-wide association analyses identified 355 independently associated lead SNPs across the genome, of which 77% had not been previously associated with human brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia and neurons. We used the multivariate association profiles of lead SNPs to identify 26 genomic loci implicated in structural connectivity between core regions of the left-hemisphere language network, and also identified 6 loci associated with hemispheric left-right asymmetry of structural connectivity. Polygenic scores for schizophrenia, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, left-handedness, Alzheimers disease, amyotrophic lateral sclerosis, and epilepsy showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to the structural connectome of the human brain in the general adult population, highlighting links with polygenic disposition to brain disorders and behavioural traits. One sentence summaryVariability in white matter fiber tracts of the human brain is associated with hundreds of newly discovered genomic loci that especially implicate stem, neural and glial cells during prenatal development, and is also associated with polygenic dispositions to various brain disorders and behavioural traits.

neuroscience↗

bioRxiv2021

Left-handedness and its genetic influences are associated with structural asymmetries mapped across 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 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.

neuroscience↗

bioRxiv2021

Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores (PRS) for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. PRS for the two disorders were positively correlated (r=0.08, p=7.13x10-50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each PRS was associated with multivariate brain asymmetry after adjusting for sex, ASD PRS r=0.03, p=2.17x10-9, schizophrenia PRS r=0.04, p=2.61x10-11, but the multivariate patterns were mostly distinct for the two PRS, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both PRS were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risk for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.

neuroscience↗

bioRxiv2020

Relations between hemispheric asymmetries of grey matter and auditory processing of spoken syllables in 281 healthy adults

Most people have a right-ear advantage for the perception of spoken syllables, consistent with left hemisphere dominance for speech processing. However, there is considerable variation, with some people showing left-ear advantage. The extent to which this variation is reflected in brain structure remains unclear. We tested for relations between hemispheric asymmetries of auditory processing and of grey matter in 281 adults, using dichotic listening and voxel-based morphometry. This was the largest study of this issue to date. Per-voxel asymmetry indexes were derived for each participant following registration of brain magnetic resonance images to a template that was symmetrized. The asymmetry index derived from dichotic listening was related to grey matter asymmetry in clusters of voxels corresponding to the amygdala and cerebellum lobule VI. There was also a smaller, non-significant cluster in the posterior superior temporal gyrus, a region of auditory cortex. These findings contribute to the mapping of asymmetrical structure-function links in the human brain, and suggest that subcortical structures should be investigated in relation to hemispheric dominance for speech processing, in addition to auditory cortex.

neuroscience↗

bioRxiv2020

The genetic architecture of structural left-right asymmetry of the human brain

Left-right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and can be altered in cognitive and psychiatric disorders1-8. No mechanism has yet been identified for establishing the human brains left-right axis9. We performed multivariate genome-wide association scanning (mvGWAS) of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci affecting different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left-right axis determination in other organs of invertebrates and frogs10-12. Genetic variants affecting brain asymmetry overlapped with those influencing autism, educational attainment and schizophrenia.

neuroscience↗

bioRxiv2020

Analysis of structural brain asymmetries in Attention-Deficit/Hyperactivity Disorder in 39 datasets

ObjectiveSome studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here we performed the largest-ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. MethodsWe analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,978 people with ADHD and unaffected 1,917 controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modelling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. ResultsThere was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.4, P=0.019). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.4, P=0.007) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohens d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. ConclusionPrior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

neuroscience↗