Search

Background: Visual acuity (VA) significantly contributes to quality of life. Deficits are associated with reading difficulties (RD), which can have detrimental effects on education outcomes. In adults, it has been observed that vision defects such as myopia are associated with higher educational attainment (EA). This is almost certainly the result of gene-environment correlation (rGE) through pro-longed reading and screen time as well as time indoors. However, the cause/effect relationship of this pattern along developmental trajectories is not entirely clear. Methods: We examined associations between distance VA, socioeconomic status (SES), cognitive measures, and neurodevelopmental conditions in a longitudinal cohort of British children (ALSPAC, n = 6,807, M age = 11.8). We performed the first genome-wide association study (GWAS, n = 5,571) on VA and tested for genetic associations with relevant phenotypes using polygenic scores (PGS) and genetic correlation analyses. Results: VA was associated with higher SES and better cognitive performance on a range of tests including reading skill, while VA was reduced in individuals with RD compared to controls. We identify genetic associations at the NPLOC4 locus and highlight other genes involved in sensory function. In line with positive genetic correlations between VA and cognitive measures, EA PGS were positively associated with VA, while there was a less robust negative association with myopia PGS.Conclusions: Our results suggest that individuals with higher PGS for educational attainment, but not myopia, have increased VA in childhood. Better VA is associated with a range of positive outcomes, including cognitive abilities. In turn, environmental exposures linked to higher EA might have detrimental effects on vision offsetting the initial genetic advantage.

Meta-analysis is a commonly used tool to provide insight into effect estimates with high confidence due to the increase in power and resistance to sampling bias compared to individual studies. However, meta-analysis is not without flaws as bias from original research can easily carry over to the synthesized analysis. In the present study, we used non-parametric bootstrapping to address the issues of non-random sampling (i.e., the fact that meta-analyses aim to include all available data instead of random samples from the population), as well as large study bias in meta-analysis. We found that bootstrapping can be highly informative regarding (1) the robustness of effect estimates despite non-random sampling, (2) how the inclusion of additional datasets affects the effect estimate and its error, and (3) to identify influential datasets. We furthermore found that the standard deviation of the effect estimate decreases logarithmically with the addition of further datasets. Regarding large study bias, we found that (4) even in random-effects models, very large datasets have the potential to bias the data significantly. Using a bias adjustment method that replaces sample sizes of individual datasets by their square root radicand, we could account for the bias without losing a significant amount of information. We suggest that bootstrapping should be routinely used to estimate the robustness of effect estimates and assess large study bias in meta-analysis. To our knowledge, this is the first study to not only identify (and subsequently remove), but also to correct for influential studies.

Funding information: Deutsche Forschungsgemeinschaft, Grant/Award Number: SCHM 3530/1-1 (418445085); Royal Society, Grant/Award Number: UF150663; UK Medical Research Council and Wellcome, Grant/Award Number: 217065/Z/19/Z; Wellcome Trust, Grant/Award Number: 105621/Z/14/Z An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HTs) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWASs) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by external environmental factors. Here, we investigated HT and HTA in a children population cohort (ALSPAC, n = 6,743). Better hearing was associated with better cognitive performance and higher socioeconomic status. At the group level, HTA suggested a left ear advantage (mean = −0.28 dB) that was mainly driven by females. SNP heritability for HT and HTA was 0.13 and 0.02, respectively (n = 4,989). We found a modest negative genetic correlation between HT and reading ability. GWAS for HT (n = 5,344) did not yield significant hits but polygenic risk scores for higher educational attainment (EA, ß = −1,564.72, p = .008) and schizophrenia (ß = −241.14, p = .004) were associated with lower HT, that is, better hearing. In summary, we report new data supporting associations between hearing measures and cognitive abilities at the behavioral level. Genetic analysis suggests shared biological pathways between cognitive and sensory systems and provides evidence for a positive outcome of genetic risk for schizophrenia. Publisher PDF

The earliest form of social contact for a newborn is being cradled by its mother. This important behavior has been found to be lateralized to the left side by many, but not all empirical studies. Factors that have been suggested to modulate cradling asymmetry are handedness and sex. However, these factors have not been demonstrated consistently, possibly due to low sample sizes and inconsistent experimental paradigms. To address this issue, we used a meta-analytical approach to (1) quantify the widely reported leftward bias in human cradling and (2) identify moderating factors of the cradling bias such as handedness and sex. Across forty studies, we observed a leftward cradling bias showing that this effect is robust and replicable. Furthermore, we found that left-handers demonstrate a significantly less pronounced leftward bias compared to right-handers and that males are less lateralized compared to females. In conclusion, we could verify that parental handedness and sex contribute to a cradling population bias. Future studies examining genetic factors could illuminate the mechanism supporting a cradling bias.

Histological studies have reported microstructural hemispheric asymmetries in several cortical areas of the human brain, but reliable in vivo assessment methods have been lacking so far. Here, we used neurite orientation dispersion and density imaging (NODDI) to examine microstructural asymmetries in in vivo and determine if findings are in accordance with what has been reported in histological studies. We examined intra-neurite volume fraction (INVF), neurite orientation dispersion (ODI), and isotropic volume fraction (ISO) asymmetries in two independent samples of healthy adults (n = 269 and n = 251). Over both samples, we found greater left-hemispheric INVF in early auditory, inferior parietal and temporal-parietal-occipital areas. In contrast, we found greater right-hemispheric INVF in the fusiform and inferior temporal gyrus, reflecting what has been reported in histological studies. ODI was asymmetric towards the left hemisphere in frontal areas and towards the right hemisphere in early auditory areas. ISO showed less pronounced asymmetries. There were hardly any effects of sex or handedness on microstructural asymmetry as determined by NODDI. Taken together, these findings suggest substantial microstructural asymmetries in gray matter, making NODDI a promising marker for future genetic and behavioral studies on laterality.

The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and SP and JS will serve as guarantors for the analysis of the ALSPAC data presented in this paper. GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Support to the genetic analysis was provided by the St Andrews Bioinformatics Unit funded by the Wellcome Trust [grant 105621/Z/14/Z]. The Hong Kong sample was funded through a Collaborative Research Fund from the Hong Kong Special Administrative Region Research Grants Council (CUHK8/CRF/13G, and C4054-17WF). JS is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 418445085) and supported by the Wellcome Trust [Institutional Strategic Support fund, Grant number 204821/Z/16/Z]. SP is funded by the Royal Society (UF150663). Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n ≤ 5028 family trios) and SNP-based heritability (SNP-h2, n ≤ 5931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h2 for quantitative handedness and footedness was 0.21 and 0.23, respectively, which is higher than the SNP-h2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (0.45) compared to a binary measure for writing hand (0.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits. Publisher PDF

Alterations in functional brain lateralization, often indicated by an increased prevalence of left- and/or mixed-handedness, have been demonstrated in several psychiatric and neurodevelopmental disorders like schizophrenia or autism spectrum disorder. For depression, however, this relationship is largely unclear. While a few studies found evidence that handedness and depression are associated, both the effect size and the direction of this association remain elusive. Here, we collected data from 87 studies totaling 35,501 individuals to provide a precise estimate of differences in left-, mixed- and non-right-handedness between depressed and healthy samples and computed odds ratios (ORs) between these groups. Here, an OR > 1 signifies higher rates of atypical handedness in depressed compared to healthy samples. We found no differences in left- (OR = 1.04, 95% CI = [0.95, 1.15], p = .384), mixed- (OR = 1.64, 95% CI = [0.98, 2.74], p = .060) or non-right-handedness (OR = 1.05, 95% CI = [0.96, 1.15], p = .309) between the two groups. We could thus find no link between handedness and depression on the meta-analytical level.

The Acknowledgements section in this Article is incomplete. “This study was supported by the Deutsche Forschungsgemeinschaft through the Research Training Group “Situated Cognition” (GRK 2185/1). We acknowledge support by the DFG Open Access Funds of the Ruhr-Universität Bochum.” should read: “This study was supported by grants of the Deutsche Forschungsgemeinschaft (GU227/16-1; BE4045/26-1) as well as through the DFG Research Training Group “Situated Cognition” (GRK 2185/1). This study was also supported by the Ruhr University Bochum Cutting-Edge grant. We acknowledge support by the DFG Open Access Funds of the Ruhr-Universität Bochum.”. CA extern

This study was supported by grants of the Deutsche Forschungsgemeinschaft (GU227/16-1; BE4045/26-1) as well as through the DFG Research Training Group “Situated Cognition” (GRK 2185/1). This study was also supported by the Ruhr University Bochum Cutting-Edge grant. We acknowledge support by the DFG Open Access Funds of the Ruhr-Universität Bochum. Human language is dominantly processed in the left cerebral hemisphere in most of the population. While several studies have suggested that there are higher rates of atypical right-hemispheric language lateralization in left-/mixed-handers, an accurate estimate of this association from a large sample is still missing. In this study, we comprised data from 1,554 individuals sampled in three previous studies in which language lateralization measured via dichotic listening, handedness and footedness were assessed. Overall, we found a right ear advantage indicating typical left-hemispheric language lateralization in 82.1% of the participants. While we found significantly more left-handed individuals with atypical language lateralization on the categorical level, we only detected a very weak positive correlation between dichotic listening lateralization quotients (LQs) and handedness LQs using continuous measures. Here, only 0.4% of the variance in language lateralization were explained by handedness. We complemented these analyses with Bayesian statistics and found no evidence in favor of the hypothesis that language lateralization and handedness are related. Footedness LQs were not correlated with dichotic listening LQs, but individuals with atypical language lateralization also exhibited higher rates of atypical footedness on the categorical level. We also found differences in the extent of language lateralization between males and females with males exhibiting higher dichotic listening LQs indicating more left-hemispheric language processing. Overall, these findings indicate that the direct associations between language lateralization and motor asymmetries are much weaker than previously assumed with Bayesian correlation analyses even suggesting that they do not exist at all. Furthermore, sex differences seem to be present in language lateralization when the power of the study is adequate suggesting that endocrinological processes might influence this phenotype. Publisher PDF

An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HT) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWAS) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by environmental effects. We analysed HT and HTA in a children population cohort (ALSPAC, n = 6,743, 7.6 years). Better hearing was associated with more advanced cognitive skills and higher socioeconomic status (SES). Mean HTA was negative (−0.28 dB), suggesting a left ear advantage in children but mainly driven by females (−0.48 dB in females v -0.09 dB in males). We performed the first GWAS on HT in children and the very first GWAS on HTA (n = 5,344). Single marker trait association analysis did not yield significant hits. Polygenic risk score (PRS) analysis revealed associations of PRS for schizophrenia with HT, which remained significant after controlling for SES and cognitive skills, and of PRS for autism spectrum disorders (ASD) with HTA. Gene-based analysis for HTA reached genome-wide significance for MCM5, which is implicated in axon morphogenesis. This analysis also highlighted other genes associated with contralateral axon crossing. Some of these genes have previously been reported for ASD. These results further support the hypothesis that pathways distinguishing the left/right axis of the brain (i.e. commissural crossing) contribute to both different types of asymmetries (i.e. HTA) and neurodevelopmental disorders.

Funding: Deutsche Forschungsgemeinschaft (DFG) through the Research Training Group “Situated Cognition” (GRK 2185/1) and Grant number OC 127/9-1. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and S.P. and J.S. will serve as guarantors for the analysis of the ALSPAC data presented in this paper. J.S. is funded by the DFG (Project number: 418445085). S.P. is funded by the Royal Society. D.P.C. is funded by the Leverhulme Trust. Open Access funding was provided by Projekt DEAL. We acknowledge the support by the DFG Open Access Publication Funds of the Ruhr-Universität Bochum. Human lateral preferences, such as handedness and footedness, have interested researchers for decades due to their pronounced asymmetries at the population level. While there are good estimates on the prevalence of handedness in the population, there is no large-scale estimation on the prevalence of footedness. Furthermore, the relationship between footedness and handedness still remains elusive. Here, we conducted meta-analyses with four different classification systems for footedness on 145,135 individuals across 164 studies including new data from the ALSPAC cohort. The study aimed to determine a reliable point estimate of footedness, to study the association between footedness and handedness, and to investigate moderating factors influencing footedness. We showed that the prevalence of atypical footedness ranges between 12.10% using the most conservative criterion of left-footedness to 23.7% including all left- and mixed-footers as a single non-right category. As many as 60.1% of left-handers were left-footed whereas only 3.2% of right-handers were left-footed. Males were 4.1% more often non-right-footed compared to females. Individuals with psychiatric and neurodevelopmental disorders exhibited a higher prevalence of non-right-footedness. Furthermore, the presence of mixed-footedness was higher in children compared to adults and left-footedness was increased in athletes compared to the general population. Finally, we showed that footedness is only marginally influenced by cultural and social factors, which play a crucial role in the determination of handedness. Overall, this study provides new and useful reference data for laterality research. Furthermore, the data suggest that footedness is a valuable phenotype for the study of lateral motor biases, its underlying genetics and neurodevelopment. Publisher PDF

Frontal alpha EEG asymmetry, an indirect marker of asymmetries in relative frontal brain activity, are widely used in research on lateralization of emotional processing. While most authors focus on frontal electrode pairs (e.g., F3/F4 or F7/F8), several recent studies have indicated that EEG asymmetries can also be observed outside the frontal lobe and in frequency bands other than alpha. Because the focus of most EEG asymmetry research is on the correlations between asymmetry and other traits, much less is known about the distribution of patterns of asymmetry at the population level. To systematically assess these asymmetries in a representative sample, we determined EEG asymmetries across the head in the alpha, beta, delta and theta frequency bands in 235 healthy adults. We found significant asymmetries in all four frequency bands and across several brain areas, indicating that EEG asymmetries are not limited to frontal alpha. Asymmetries were not modulated by sex. They were modulated by direction of hand preference, with stronger right-handedness predicting greater right (relative to left) alpha power, or greater left (relative to right) activity. Taken together, the present results show that EEG asymmetries other than frontal alpha represent markers of asymmetric brain function that should be explored further.

Hemispheric asymmetries represent one of the major organizational principles in vertebrate neurobiology, but their molecular determinants are not well understood. For handedness, the most widely investigated form of hemispheric asymmetries in humans, single gene explanations have been the most popular ontogenetic model in the past. However, molecular genetic studies revealed only few specific genes that explain a small fraction of the phenotypic variance. In contrast, family studies indicated heritability of up to 0.66. It has been suggested that the lack of recognizable genetic heritability is partly accounted for by heritable epigenetic mechanisms. Based on recent neuroscientific findings highlighting the importance of epigenetic mechanisms for brain function and disease, we review recent findings describing non-genetic influences on handedness from conception to childhood. We aim to advance the idea that epigenetic regulation might be the mediating mechanism between environment and phenotype. Recent findings on molecular epigenetic mechanisms indicate that particular asymmetries in DNA methylation might affect asymmetric gene expression in the central nervous system that in turn mediates handedness. We propose that an integration of genes and environment is essential to fully comprehend the ontogenesis of handedness and other hemispheric asymmetries.

Handedness is a complex trait influenced by both genetic and non-genetic factors. Asymmetries of DNA methylation and gene expression in the developing foetus are thought to underlie its development. However, its molecular epigenetics are not well understood. We collected buccal cells from adult left- and right-handers (n = 60) to investigate whether epigenetic biomarkers of handedness can be identified in non-neuronal tissue. We associated DNA methylation in promoter regions of candidate genes with handedness direction. Results indicate that DNA methylation of genes asymmetrically expressed in the foetal brain or spinal cord might play a role within such a multifactorial model. Moreover, we provide tentative evidence that birth stress might be a factor that affects DNA methylation in NEUROD6, a gene that is asymmetrically expressed in foetal brains.

Handedness is one of the most prominent functional hemispheric asymmetries. Initially thought to be determined by a single gene, molecular genetic studies have shown that it is influenced by multiple genes. Recent research indicates that epigenetic regulation induces asymmetrical gene expression in the embryonic spinal cord, potentially leading to motor asymmetries. An integration of multiple genetic, epigenetic, and environmental factors is essential to fully comprehend handedness ontogenesis.

In human social interaction, affective touch plays an integral role to communicate intentions and emotions. Three of the most important forms of social touch are embracing, cradling and kissing. These behaviours have been demonstrated to be lateralized, but the underlying mechanisms are still not well understood. Both motor and emotive biases have been suggested to affect laterality of social touch. We aimed to systematically investigate how motor preferences and emotive biases influence the lateralization of embracing, cradling and kissing within the same sample. Participants performed all three forms of social touch in neutral, positive and negative emotional conditions. Like a previous study, we found a rightward bias for embracing that was modulated by both motor preferences and the emotional content of the situation. Kissing and cradling were not influenced by motor preferences. In general, a negative emotional connotation of the situation led to a reduction of lateral biases in social touch, independent of the individual direction.

Schizophrenia patients have a higher probability of altered structural and functional differences between the left and right hemisphere. Schizotypy as its nonclinical manifestation has been related to a higher incidence of non-right-handedness and atypical right-hemispheric language dominance. It has been suggested that genes involved in cilia function might link brain asymmetry and neurodevelopmental disorders. We assessed DNA methylation in the promoter regions of seven candidate genes involved in cilia function and psychiatric disorders from buccal cells and investigated their association with schizotypy and language lateralization in 60 healthy adults. Moreover, we determined microstructural properties of the planum temporale in a subsample of 52 subjects using neurite orientation dispersion and density imaging (NODDI). We found a significant association between schizotypy and DNA methylation in the AHI1 promoter region. Moreover, AHI1 DNA methylation significantly predicted language lateralization and asymmetry in estimated planum temporale neurite density. Finally, stronger leftward asymmetry in estimated neurite density was associated with a more pronounced right ear advantage (left hemisphere dominance) in the forced-right condition of the dichotic listening task, measuring attentional modulation of language lateralization. Our results are in line with a shared molecular basis of schizotypy and functional hemispheric asymmetries that is based on cilia function.

Silvia Paracchini is a Royal Society University Research Fellow. Judith Schmitz is a DFG fellow and received funding from the School of Medicine, University of St Andrews for this specific work. Across time and place, right hand preference has been the norm, but what is the precise prevalence of left- and right-handedness? Frequency of left-handedness has shaped and underpinned different fields of research, from cognitive neuroscience to human evolution, but reliable distributional estimates are still lacking. While hundreds of empirical studies have assessed handedness, a large-scale, comprehensive review of the prevalence of handedness and the factors that moderate it, is currently missing. Here, we report 5 meta-analyses on hand preference for different manual tasks and show that left-handedness prevalence lies between 9.3% (using the most stringent criterion of left-handedness) to 18.1% (using the most lenient criterion of nonright-handedness), with the best overall estimate being 10.6% (10.4% when excluding studies assessing elite athletes’ handedness). Handedness variability depends on (a) study characteristics, namely year of publication and ways to measure and classify handedness, and (b) participant characteristics, namely sex and ancestry. Our analysis identifies the role of moderators that require taking into account in future studies on handedness and hemispheric asymmetries. We argue that the same evolutionary mechanisms should apply across geographical regions to maintain the roughly 1:10 ratio, while cultural factors, such as pressure against left-hand use, moderate the magnitude of the prevalence of left-handedness. Although handedness appears as a straightforward trait, there is no universal agreement on how to assess it. Therefore, we urge researchers to fully report study and participant characteristics as well as the detailed procedure by which handedness was assessed and make raw data publicly available. Postprint

Previous studies showed that manipulating the speech production system influenced speech perception. This influence was mediated by task difficulty, listening conditions, and attention. In the present study we investigated the specificity of a somatosensory manipulation – a spoon over the tongue – in passive listening. We measured the mismatch negativity (MMN) while participants listened to vowels that differ in their articulation – the tongue height – and familiarity – native and unknown vowels. The same participants heard the vowels in a spoon and no-spoon block. The order of the blocks was counterbalanced across participants. Results showed no effect of the spoon. Instead, starting with the spoon enhanced the MMN amplitude. A second experiment showed the same MMN enhancement for starting with a somatosensory manipulation applied to a non-articulator – the hand. This result suggests that starting a study with a somatosensory manipulation raises attention to the task. This research was funded by grants from the European Commission Seventh Framework Programme (FP7/2007-2013): ERC grant agree¬ment number 323961 (UNDER CONTROL); Cooperation grant agreement num¬ber 613465 – (AThEME); the Spanish Ministerio de Economía y Competitividad (PSI2012 34071) and the Catalan Government (SGR 2014–1210) awarded to NSG. She also received the "ICREA Acadèmia" prize for excellence in research, funded by the Generalitat de Catalunya. BD received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement number 32867 and a postdoctoral fellowship from the Spanish Government (Juan de la Cierva fellowship JCI-2012-12678).

Handedness is the most investigated form of functional hemispheric asymmetries, but its neural correlates remain unclear. Functional imaging studies suggest differences between left- and right-handers in ipsilateral activation during unilateral hand movements, but do not allow for conclusions on the temporal dimension. In the Tapley and Bryden task, subjects have to draw as many dots as possible on a paper within 20 s using either the left or the right hand. We adapted the task for use during EEG in 36 left- and 36 right-handers. Subjects performed a visually guided response task with each trial consisting of eight motor responses. We investigated the lateralized readiness potential (LRP) at the first and last response of the sequence. Overall, increasing complexity of sequences was associated with earlier and less negative LRP peaks. For the last response, right-handers showed more negative LRP peak amplitudes than left-handers. The effect of handedness on LRP peak amplitude in the first response was modulated by task complexity with a more negative LRP peak amplitude in right-handers than left-handers in simple, but not in medium or complex trials. This effect might be due to more symmetrical processing in right-handers with increasing task complexity. These findings complement previous imaging studies and add a new perspective on the relationship between laterality and schizophrenia, associated with less pronounced LRPs and a higher prevalence of left-handedness.

Handedness and language lateralization are the most investigated phenotypes among functional hemispheric asymmetries, i.e. differences in function between the left and the right half of the human brain. Both phenotypes are left hemisphere-dominant, while investigations of the molecular factors underlying right hemisphere-dominant phenotypes are less prominent. In the classical line bisection task, healthy subjects typically show a leftward attentional bias due to a relative dominance of the right hemisphere for visuospatial attention. Based on findings of variations in dopamine-related genes affecting performance in the line bisection task, we first tested whether DNA methylation in non-neuronal tissue in the promoter regions of \(\it DBH\), \(\it SLC6A3\), and \(\it DRD2\) are associated with line bisection deviation. We replicated the typical behavioral pattern and found an effect of DNA methylation in the DBH promoter region on line bisection deviation in right-aligned trials. A second exploratory analysis indicated that an overall DNA methylation profile of genes involved in dopamine function predicts line bisection performance in right-aligned trials. Genetic variation in dopamine-related genes has been linked to attention deficit hyperactivity disorder (ADHD), a neurodevelopmental trait associated with rightward attentional bias. Overall, our findings point towards epigenetic markers for functional hemispheric asymmetries in non-neuronal tissue not only for left hemisphere-dominant, but also for right hemisphere-dominant phenotypes.

The ability to speak is a unique human capacity, but where is it located in our brains? This question is closely connected to the pioneering work of Pierre Paul Broca in the 1860s. Based on post-mortem observations of aphasic patients' brains, Broca located language production in the 3rd convolution of the left frontal lobe and thus reinitiated the localizationist view of brain functions. However, contemporary neuroscience has partially rejected this view in favor of a network-based perspective. This leads to the question, whether Broca's findings are still relevant today. In this mini-review, we discuss current and historical implications of Broca's work by focusing on his original contribution and contrasting it with contemporary knowledge. Borrowing from Broca's famous quote, our review shows that humans indeed "speak with the left hemisphere"- but Broca's area is not the sole "seat of articulatory language".

Social touch is an important aspect of human social interaction - across all cultures, humans engage in kissing, cradling and embracing. These behaviors are necessarily asymmetric, but the factors that determine their lateralization are not well-understood. Because the hands are often involved in social touch, motor preferences may give rise to asymmetric behavior. However, social touch often occurs in emotional contexts, suggesting that biases might be modulated by asymmetries in emotional processing. Social touch may therefore provide unique insights into lateralized brain networks that link emotion and action. Here, we review the literature on lateralization of cradling, kissing and embracing with respect to motor and emotive bias theories. Lateral biases in all three forms of social touch are influenced, but not fully determined by handedness. Thus, motor bias theory partly explains side biases in social touch. However, emotional context also affects side biases, most strongly for embracing. Taken together, literature analysis reveals that side biases in social touch are most likely determined by a combination of motor and emotive biases.

New findings identified the MORC1 gene as a link between early life stress and major depression. In this study, MORC1 methylation was investigated in 60 healthy human adults (30 women, 30 men) between 19 and 33 years of age. For analysis, DNA was isolated from buccal cells. The results show that DNA methylation in the MORC1 promoter region significantly correlates with the Beck Depression Inventory score in the examined non-clinical population. Sum score of birth complications, however, seems to correlate negatively with methylation. These findings further confirm that MORC1 is a stress sensitive gene and a possible biomarker for depression.

Language lateralization is one of the most prominent examples of functional hemispheric asymmetries. Previous studies indicate a significant contribution of factors not related to DNA sequence variation on the development of language lateralization, but the molecular processes underlying this relation are unclear. The Brandler-Paracchini model of hemispheric asymmetries assumes that genes involved in the establishment of ciliogenesis and bodily asymmetries also affect functional hemispheric asymmetries. Thus, genes implicated in this model represent a key target for epigenetic modulation of language lateralization. Here, we analyzed DNA methylation in the KIAA0319 (a gene involved in dyslexia and ciliogenesis) promoter region to investigate whether epigenetic markers of language lateralization can be identified in non-neuronal tissue. We found sex-specific effects of DNA methylation in single CpG sites on language lateralization in the forced-left (FL) and the forced-right (FR), but not on language lateralization in the non-forced (NF) condition of the dichotic listening task. These findings suggest that DNA methylation patterns in the KIAA0319 promoter region might be associated with cognitive control processes that are necessary to perform well in the forced-attention conditions. Furthermore, the assumption of an association between genes involved in ciliogenesis and the ontogenesis of functional hemispheric asymmetries is supported.

Hemispheric asymmetries are a major organizational principle in human emotion processing, but their interaction with prefrontal control processes is not well understood. To this end, we determined whether hemispheric differences in response inhibition depend on the emotional valence of the stimulus being inhibited. Participants completed a lateralised Go/Nogo task, in which Nogo stimuli were neutral or emotional (either positive or negative) images, while Go stimuli were scrambled versions of the same pictures. We recorded the N2 and P3 event-related potential (ERP) components, two common electrophysiological measures of response inhibition processes. Behaviourally, participants were more accurate in withholding responses to emotional than to neutral stimuli. Electrophysiologically, Nogo-P3 responses were greater for emotional than for neutral stimuli, an effect driven primarily by an enhanced response to positive images. Hemispheric asymmetries were also observed, with greater Nogo-P3 following left versus right visual field stimuli. However, the visual field effect did not interact with emotion. We therefore find no evidence that emotion-related asymmetries affect response inhibition processes.

Handedness is the most pronounced behavioral asymmetry in humans. Genome-wide association studies have largely failed to identify genetic loci associated with phenotypic variance in handedness, supporting the idea that the trait is determined by a multitude of small, possibly interacting genetic and non-genetic influences. However, these studies typically are not capable of detecting influences of rare mutations on handedness. Here, we used whole exome sequencing in a Turkish family with history of consanguinity and overrepresentation of left-handedness and performed quantitative trait analysis with handedness lateralization quotient as a phenotype. While rare variants on different loci showed significant association with the phenotype, none was functionally relevant for handedness. This finding was further confirmed by gene ontology group analysis. Taken together, our results add further evidence to the suggestion that there is no major gene or mutation that causes left-handedness.

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans. DOI: http://dx.doi.org/10.7554/eLife.22784.001

Vascular endothelial growth factor-A (VEGF-A) responsive effects mediated via the receptors fetal liver kinase-1 (flk-1) and fms-like tyrosine kinase (flt-1), are key processes of pulmonary vascular development. Flk-1 has been shown to be involved in early embryonic lung epithelial to endothelial crosstalk and branching morphogenesis. Recent reports suggested a role of VEGF-A in lung epithelial cell function. Based on these observations, we hypothesize that epithelial flk-1 has a unique function in pulmonary development. Thus, the aim of this study is to elucidate spatiotemporal expression of flk-1 during lung development with respect to the epithelial system. Embryonic lungs were screened for flk-1 messenger RNA and protein at daily intervals, including postnatal stages. From Embryonic Day (ED) 12.5 through ED 15.5, flk-1 expression was restricted to the early vascular primitive network, while from ED 16.5 on flk-1 was detectable in the epithelial system and persisted there postnatally. At postnatal stages, flk-1 expression was increasingly restricted to individual cells in the alveolar septa. Isolation and in vitro cultivation of alveolar epithelial cells confirmed flk-1 expression and showed VEGF secretion into the supernatant. To our knowledge, this is the first murine study characterizing epithelial flk-1 expression at different stages throughout lung organogenesis until birth and at postnatal stages. To confirm epithelial flk-1 expression, we performed reporter gene analysis of the flk-1 promoter in vivo. Investigations on transgenic mouse strains, containing either a complete or incomplete flk-1 promoter driving expression of the lacZ reporter gene, suggested differential flk-1 regulation in endothelial and epithelial cells.

Metastasis continues to be the major cause of morbidity and mortality in malignant melanoma. In our study, we explored whether inhibition of VEGFR-1 or VEGFR-2 signaling conveys distinct suppressive effects on B16 melanoma subcutaneous growth and metastasis formation. The inhibition of VEGFR-1 or -2 alone had no significant influence on both melanoma growth and metastasis formation. In contrast, simultaneous blockade of VEGFR-1 and -2 signaling strongly suppressed progression in both B16 tumor models. There was no expression of VEGFR-1 or -2 detectable on the B16 cells used, excluding the melanoma cells as direct therapeutic targets. Analyzing the contribution of progenitor-like cells during melanoma metastasis formation, we observed an enhanced proliferation and mobilization of VEGFR-1+ myeloid and VEGFR-2+ endothelial cells with progenitor potential by the induction of melanoma lung metastasis, which was not influenced by interference with VEGFR signaling. These results indicate that the antimetastatic effects exerted by combined inhibition of VEGFR-1 and -2 signaling were mediated via targeting cell populations other than progenitors only. Sole inhibition of VEGFR-1 signaling led to a strong reduction of the CD45-positive inflammatory infiltrate in the tumor tissue. However, the formation of lung metastasis was not affected, indicating that inhibition of the inflammatory response was not sufficient to efficiently block B16 melanoma metastasis development. Taken together, our data suggest that in the utilized B16 tumor models the blockade of both the inflammatory and the VEGFR-2-dependent angiogenic response are necessary to effectively inhibit solid tumor growth and formation of lung metastasis by B16 melanoma cells.

A large number of industrial manufacturers are forming alliances with partners throughout the supply chain with the focus on improving competitive position. These potential improvements may vary by the type of alliance being formed. In spite of this, little is known regarding what motivates a manufacturer to form an alliance at various channel positions (e.g. supplier versus customer alliances) and what the resultant performance outcomes are from these different types of alliances. This paper examines the importance manufacturers place on various motives based on the channel position of alliance. Further, the paper compares the objectives actually achieved across alliances with manufacturers and partners at different channel levels.

Establishing and maintaining successful alliances is an increasingly attractive, yet difficult strategic option for most firms in today's business environment. One component of the alliance process that has recently received considerable attention concerns the motivations of a firm and its potential partner to establish an alliance. This paper examines and compares alliance motives at three channel levels (manufacturer, distributor and logistical service supplier) and across three geographic trading regions (North America, Europe and the Pacific Basin). The managerial implications of the results are discussed with particular regard to developing and sustaining successful cooperative supply chain relationships.