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Background Alterations in the hippocampus and prefrontal cortex (PFC) have frequently been reported in depressed patients. These parameters might prove to be a consistent finding in depression. In addition, peripheral DNA methylation of the MORC1 gene promoter showed stable associations with depression across independent samples. However, the question arises whether MORC1, supposedly acting as transcription factor, might also be involved in neurobiological alterations accompanying depression. This study further analyses the role of MORC1 in depression by investigating a potential correlation between peripheral MORC1 DNA methylation and neuronal structural properties previously associated with depression in humans. Methods Beck Depression Inventory (BDI) was assessed in 52 healthy participants. DNA was extracted from buccal cells and MORC1 methylation correlated with micro- and macrostructural properties derived from magnetic resonance imaging (MRI) and neurite orientation dispersion and density imaging (NODDI) in the hippocampus and medial prefrontal cortex (mPFC). Results MORC1 methylation was associated with volume reduction and neurite orientation dispersion and density markers in the hippocampus and mPFC. BDI was positively associated with neurite orientation dispersion and density markers in the hippocampus. Limitations The study was conducted in a small sample of healthy participants with subclinical depressive symptoms. Peripheral tissue was analyzed. Conclusion We found significant negative associations between peripheral MORC1 methylation and macro- and microstructural markers in the hippocampus and mPFC. Thus, MORC1 might be involved in neurobiological properties. Studies investigating neuronal methylation patterns of MORC1 are needed to support this hypothesis.
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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 diferent classifcation 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 infuencing 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 nonright 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 leftfootedness was increased in athletes compared to the general population. Finally, we showed that footedness is only marginally infuenced 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.
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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 signifcantly 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 diferences 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 fndings 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 diferences seem to be present in language lateralization when the power of the study is adequate suggesting that endocrinological processes might infuence this phenotype.
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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.
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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.
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The Edinburgh Handedness Inventory (EHI) and the Waterloo Footedness Questionnaire (WFQ) are two of the most widely used questionnaires to assess lateralized everyday behavior in human participants. However, it is unclear to what extent the specific behavior assessed in these questionnaires elicit lateralized neural activity when performed in real-life situations. To illuminate this unresolved issue, we assessed EEG alpha and beta asymmetries during real-life performance of the behaviors assessed in the EHI and WFQ using a mobile EEG system. This methodology provides high ecological validity for studying neural correlates of motor behavior under more naturalistic conditions. Our results indicate that behavioral performance of items of both the EHI and WFQ differentiate between left- and right-handers and left- and right-footers on the neural level, especially in the alpha frequency band. These results were unaffected by movement parameters. Furthermore, we could demonstrate that neural activity elicited specifically during left-sided task performance provides predictive power for the EHI or WFQ score of the participants. Overall, our results show that these prominent questionnaires not only distinguish between different motor preferences on the behavioral level, but also on the neurophysiological level. Furthermore, we could show that mobile EEG systems are a powerful tool to investigate motor asymmetries in ecologically valid situations outside of the laboratory setting. Future research should focus on other lateralized behavioral phenotypes in real-life settings to provide more insights into lateralized motor functions.
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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.
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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.
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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.
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The brain is one of the most prominent examples for structural and functional differences between the left and right half of the body. For handedness and language lateralization, the most widely investigated behavioral phenotypes, only a small fraction of phenotypic variance has been explained by molecular genetic studies. Due to environmental factors presumably also playing a role in their ontogenesis and based on first molecular evidence, it has been suggested that functional hemispheric asymmetries are partly under epigenetic control. This review article aims to elucidate the molecular factors underlying hemispheric asymmetries and their association with inner organ asymmetries. While we previously suggested that epigenetic mechanisms might partly account for the missing heritability of handedness, this article extends this idea by suggesting possible alternatives for transgenerational transmission of epigenetic states that do not require germ line epigenetic transmission. This is in line with a multifactorial model of hemispheric asymmetries, integrating genetic, environmental, and epigenetic influencing factors in their ontogenesis.
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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 DBH , SLC6A3 , and 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.
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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.
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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.
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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".
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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.
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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.
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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.
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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.
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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.
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Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes.
