Brain Lateralization: A Comparative Perspective.

Comparative studies on brain asymmetry date back to the 19th century but then largely disappeared due to the assumption that lateralization is uniquely human. Since the reemergence of this field in the 1970s, we learned that left-right differences of brain and behavior exist throughout the animal kingdom and pay off in terms of sensory, cognitive, and motor efficiency. Ontogenetically, lateralization starts in many species with asymmetrical expression patterns of genes within the Nodal cascade that set up the scene for later complex interactions of genetic, environmental, and epigenetic factors. These take effect during different time points of ontogeny and create asymmetries of neural networks in diverse species. As a result, depending on task demands, left- or right-hemispheric loops of feedforward or feedback projections are then activated and can temporarily dominate a neural process. In addition, asymmetries of commissural transfer can shape lateralized processes in each hemisphere. It is still unclear if interhemispheric interactions depend on an inhibition/excitation dichotomy or instead adjust the contralateral temporal neural structure to delay the other hemisphere or synchronize with it during joint action. As outlined in our review, novel animal models and approaches could be established in the last decades, and they already produced a substantial increase of knowledge. Since there is practically no realm of human perception, cognition, emotion, or action that is not affected by our lateralized neural organization, insights from these comparative studies are crucial to understand the functions and pathologies of our asymmetric brain.

Rare variants and handedness: spotlight on TUBB4B.

Twin studies suggest that additive genetic effects account for about a quarter of the variance in handedness. Recently, Schijven et al. used exome-wide sequencing to provide evidence for a role of rare protein-coding variants in handedness. These included the gene encoding beta-tubulin, TUBB4B, suggesting that microtubules are relevant for handedness ontogenesis.

Handedness in schizophrenia and affective disorders: a large-scale cross-disorder study.

While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.

A Comparison of Hugging Frequency and Its Association with Momentary Mood Before and During COVID-19 Using Ecological Momentary Assessment.

The COVID-19 pandemic has necessitated a drastic decrease in human social interactions including social touch. One of the most prevalent forms of touch is hugging. Hugging has been demonstrated to benefit both physical and mental well-being. In the present study, we used an ecological momentary assessment approach to assess the relationship between hugging and momentary mood in two independent cohorts sampled prior or during the pandemic. We found that the frequency of hugging was significantly reduced during the pandemic. Using multilevel modeling, we found a significant positive association between momentary mood and daily hugs. This effect was moderated by the cohort, as individuals during the pandemic showed a stronger positive association compared to the cohort sampled prior to the pandemic. While we have to stress that our results are correlational in nature, they potentially indicate that social touch is more beneficial in times of social distancing.

Measuring paw preferences in dogs, cats and rats: Design requirements and innovations in methodology.

Studying behavioural lateralization in animals holds great potential for answering important questions in laterality research and clinical neuroscience. However, comparative research encounters challenges in reliability and validity, requiring new approaches and innovative designs to overcome. Although validated tests exist for some species, there is yet no standard test to compare lateralized manual behaviours between individuals, populations, and animal species. One of the main reasons is that different fine-motor abilities and postures must be considered for each species. Given that pawedness/handedness is a universal marker for behavioural lateralization across species, this article focuses on three commonly investigated species in laterality research: dogs, cats, and rats. We will present six apparatuses (two for dogs, three for cats, and one for rats) that enable an accurate assessment of paw preference. Design requirements and specifications such as zoometric fit for different body sizes and ages, reliability, robustness of the material, maintenance during and after testing, and animal welfare are extremely important when designing a new apparatus. Given that the study of behavioural lateralization yields crucial insights into animal welfare, laterality research, and clinical neuroscience, we aim to provide a solution to these challenges by presenting design requirements and innovations in methodology across species.

Structural architecture and brain network efficiency link polygenic scores to intelligence.

Intelligence is highly heritable. Genome-wide association studies (GWAS) have shown that thousands of alleles contribute to variation in intelligence with small effect sizes. Polygenic scores (PGS), which combine these effects into one genetic summary measure, are increasingly used to investigate polygenic effects in independent samples. Whereas PGS explain a considerable amount of variance in intelligence, it is largely unknown how brain structure and function mediate this relationship. Here, we show that individuals with higher PGS for educational attainment and intelligence had higher scores on cognitive tests, larger surface area, and more efficient fiber connectivity derived by graph theory. Fiber network efficiency as well as the surface of brain areas partly located in parieto-frontal regions were found to mediate the relationship between PGS and cognitive performance. These findings are a crucial step forward in decoding the neurogenetic underpinnings of intelligence, as they identify specific regional networks that link polygenic predisposition to intelligence.

Hand Preference in Stuttering: Meta-Analyses.

Reduced hemispheric asymmetries, as well as their behavioral manifestation in the form of atypical handedness (i.e., non-right, left-, or mixed-handedness), are linked to neurodevelopmental disorders, such as autism spectrum disorder, and several psychiatric disorders, such as schizophrenia. One neurodevelopmental disorder that is associated with reduced hemispheric asymmetries, but for which findings on behavioral laterality are conflicting, is stuttering. Here, we report a series of meta-analyses of studies that report handedness (assessed as hand preference) levels in individuals who stutter (otherwise healthy) compared to controls. For this purpose, articles were identified via a search in PubMed, Scopus, and PsycInfo (13 June 2023). On the basis of k = 52 identified studies totaling n = 2590 individuals who stutter and n = 17,148 controls, five random effects meta-analyses were conducted: four using the odds ratio [left-handers (forced choice); left-handers (extreme); mixed-handers; non-right-handers vs. total)] and one using the standardized difference in means as the effect size. We did not find evidence of a left (extreme)- or mixed-handedness difference or a difference in mean handedness scores, but evidence did emerge, when it came to left-handedness (forced-choice) and (inconclusively for) non-right-handedness. Risk-of-bias analysis was not deemed necessary in the context of these meta-analyses. Differences in hand skill or strength of handedness could not be assessed as no pertinent studies were located. Severity of stuttering could not be used s a moderator, as too few studies broke down their data according to severity. Our findings do not allow for firm conclusions to be drawn on whether stuttering is associated with reduced hemispheric asymmetries, at least when it comes to their behavioral manifestation.

Hemispheric asymmetries in mental disorders: evidence from rodent studies.

The brain is built with hemispheric asymmetries in structure and function to enable fast neuronal processing. In neuroimaging studies, several mental disorders have been associated with altered or attenuated hemispheric asymmetries. However, the exact mechanism linking asymmetries and disorders is not known. Here, studies in animal models of mental disorders render important insights into the etiology and neuronal alterations associated with both disorders and atypical asymmetry. In this review, the current literature of animal studies in rats and mice focusing on anxiety and fear, anhedonia and despair, addiction or substance misuse, neurodegenerative disorders as well as stress exposure, and atypical hemispheric asymmetries is summarized. Results indicate overall increased right-hemispheric neuronal activity and a left-sided behavioral bias associated with symptoms of anxiety, fear, anhedonia, behavioral despair as well as stress exposure. Addiction behavior is associated with right-sided bias and transgenic models of Alzheimer's disease indicate an asymmetrical accumulation of fibrillar plaques. Most studies focused on changes in the bilateral amygdala and frontal cortex. Across studies, two crucial factors influencing atypical asymmetries arose independently of the disorder modeled: sex and developmental age. In conclusion, animal models of mental disorders demonstrate atypical hemispheric asymmetries similar to findings in patients. Particularly, increased left-sided behavior and greater right-hemispheric activity were found across models applying stress-based paradigms. However, sex- and age-dependent effects on atypical hemispheric asymmetries are present that require further investigation. Animal models enable the analysis of hemispheric changes on the molecular level which may be most effective to detect early alterations.

Handedness and anxiety: a review.

Handedness is a core phenotype in clinical laterality research and several different disorders such as schizophrenia and autism spectrum disorders have been linked to a higher prevalence of non-right-handedness. Moreover, subclinical personality traits like schizotypy have been linked to a higher prevalence of non-right-handedness. The association with handedness is poorly understood for generalized anxiety disorder and specific phobias, as well as for state and trait anxiety and fear of specific stimuli in nonclinical samples. Therefore, we performed a narrative review of studies investigating handedness in anxiety disorders patients and studies that compared anxiety scores between different handedness groups. Unlike schizophrenia and autism spectrum disorders, there seems to be no strong association between anxiety disorders and handedness in adult patients, except for specific phobias. Studies often had small sample sizes and therefore a high risk to report spurious findings. Similar findings were reported in most non-clinical studies. Importantly, familial handedness affects phobia risk and antenatal maternal anxiety increased the probability of mixed-handedness. This suggests that a transgenerational, developmental perspective is essential to better understand the complex interrelations between handedness and anxiety. Familial and especially maternal handedness and anxiety disorders should be integrated into future studies on handedness and anxiety whenever possible.

Stress exposure, hand preference, and hand skill: A deep phenotyping approach.

ABSTRACTStress exposure and reactivity may show differential associations with handedness, but shallow phenotyping may influence the current knowledge. Importantly, different handedness measures do not necessarily show high correlations with each other and should not be used interchangeably as they may reflect different dimensions of laterality. Here, data on handedness from 599 participants in the population-based, longitudinal Dortmund Vital Study was used to determine various asymmetry indices. Hand preference was assessed with the Edinburgh Handedness Inventory (EHI) and the lateral preference inventory (LPI) measuring handedness, footedness, earedness, and eyedness. Hand performance was determined using the pegboard test. In addition, data on several dimensions of stress exposure and reactivity, including hair cortisol, and mental well-being was analysed to determine associations with handedness. All handedness measures correlated significantly with each other, with the strongest correlation between the EHI and the LPI handedness score. The EHI and LPI hand measures resulted in the highest effect sizes and most consistent correlations with stress or mental well-being. In contrast, the pegboard test only showed very little association with the stress and mental well-being measures. This highlights the importance of handedness phenotyping. Including preference measures is recommended to disentangle the link between handedness and mental health.

Handedness in ADHD: Meta-Analyses.

Meta-analyses have shown that several neurodevelopmental and psychiatric disorders, such as autism spectrum disorder and schizophrenia, are associated with a higher prevalence of atypical (left-, non-right-, or mixed-) handedness. One neurodevelopmental disorder for which this association is unclear is attention deficit hyperactivity disorder (ADHD). Here, some empirical studies have found evidence for a higher prevalence of atypical handedness in individuals with ADHD compared to neurotypical individuals. However, other studies failed to establish such an association. Therefore, meta-analytic integration is critical to estimate whether or not there is an association between handedness and ADHD. We report the results of three meta-analyses (left-, mixed-, and non-right-handedness) comparing handedness in individuals with ADHD to controls (typically developing individuals). The results show evidence of a trend towards elevated levels of atypical handedness when it comes to differences in left- and mixed-handedness (p = 0.09 and p = 0.07, respectively), but do show clear evidence of elevated levels of non-right-handedness between individuals with ADHD and controls (p = 0.02). These findings are discussed in the context of the hypothesis that ADHD is a disorder in which mostly right-hemispheric brain networks are affected. Since right-handedness represents a dominance of the left motor cortex for fine motor behavior, such as writing, as well as a left-hemispheric dominance for language functions, and about 90% of individuals are right-handers, this hypothesis might explain why there is not stronger evidence for an association of left-handedness with ADHD. We suggest that the mechanisms involved in the pathogenesis of ADHD might show an overlap with the mechanisms involved in handedness strength, but not handedness direction.

The Relationship Between Axon Density, Myelination, and Fractional Anisotropy in the Human Corpus Callosum.

The corpus callosum serves the functional integration and interaction between the two hemispheres. Many studies investigate callosal microstructure via diffusion tensor imaging (DTI) fractional anisotropy (FA) in geometrically parcellated segments. However, FA is influenced by several different microstructural properties such as myelination and axon density, hindering a neurobiological interpretation. This study explores the relationship between FA and more specific measures of microstructure within the corpus callosum in a sample of 271 healthy participants. DTI tractography was used to assess 11 callosal segments and gain estimates of FA. We quantified axon density and myelination via neurite orientation dispersion and density imaging (NODDI) to assess intra-neurite volume fraction and a multiecho gradient spin-echo sequence estimating myelin water fraction. The results indicate three common factors in the distribution of FA, myelin content and axon density, indicating potentially shared rules of topographical distribution. Moreover, the relationship between measures varied across the corpus callosum, suggesting that FA should not be interpreted uniformly. More specific magnetic resonance imaging-based quantification techniques, such as NODDI and multiecho myelin water imaging, may thus play a key role in future studies of clinical trials and individual differences.

Laterality 2020: entering the next decade.

In the 2010s, significant progress has been made in several key areas of laterality research, including neuroimaging, genetics and comparative research. In the present article, we discuss which trends are likely to shape laterality research in the 2020s. These include, but are not limited to: (1) Finding laterality-specific solutions to the replication crisis. (2) Integrating non-W.E.I.R.D. (Western, Educated, Industrialized, Rich, and Democratic) samples into laterality research to a larger extent. (3). Combining meta-analysis and large-scale databank studies to come to unbiased conclusions about true effects. (4) Understanding altered laterality in different psychiatric and neurodevelopmental disorders. (5) Exploring the relevance of laterality research for the treatment of psychiatric and neurodevelopmental disorders. (6) Investigating the molecular correlates of environmental factors that affect laterality. (7) Bridging the gap between laterality research in human subjects and non-human model species. (8) Utilizing "next-generation" neuroimaging in laterality research. (9) Integrating graph-theory and machine learning into laterality research. (10) Enhancing ecological validity in laterality research using mobile EEG and smartphone-based data collection. These trends will likely shape the next decade of laterality research by opening the way for novel questions, enhancing collaborations and boosting the reliability and validity of research findings in our field.

Laterality 2020: Response to the article commentaries.

In our recent opinion paper "Laterality 2020: entering the next decade", we highlighted trends that we thought are likely to shape laterality research in the 2020s. Our opinion paper inspired 11 commentaries by experts from several disciplines which discussed a wide range of topics complementing the 10 trends we identified in the opinion paper. In this reply, we summarize and discuss the 11 commentaries by clustering them into 3 different main topics. The topic that was covered by the largest number of commentaries was the role of comparative and evolutionary approaches in laterality research. Moreover, several comments focused on the ontogenesis of hemispheric asymmetries and the importance of reliability and validity in laterality research. Embracing the technical advances, research trends and controversies laid out in the commentaries will significantly improve our understanding of several of the core questions of laterality research.

Response inhibition to emotional faces is modulated by functional hemispheric asymmetries linked to handedness.

Effective response inhibition requires efficient bottom-up perceptual processing and effective top-down inhibitory control. To investigate the role of hemispheric asymmetries in these processes, 49 right- and 50 left-handers completed a tachistoscopic Go/Nogo task with positive and negative emotional faces while ERPs were recorded. Frontal resting state EEG asymmetry was assessed as a marker of individual differences in prefrontal inhibitory networks. Results supported a dependency of inhibitory processing on early lateralized processes. As expected, right-handers showed a stronger N170 over the right hemisphere, and better response inhibition when faces were projected to the right hemisphere. Left-handers showed a stronger N170 over the left hemisphere, and no behavioural asymmetry. Asymmetries in response inhibition were also valence-dependent, with better inhibition of responses to negative faces when projected to the right, and better inhibition of responses to positive faces when projected to the left hemisphere. Frontal asymmetry was not related to handedness, but did modulate response inhibition depending on valence. Consistent with the asymmetric inhibition model (Grimshaw & Carmel, 2014), greater right frontal activity was associated with better response inhibition to positive than to negative faces; subjects with greater left frontal activity showed an opposite trend. These findings highlight the interplay between bottom-up and top-down processes in explaining hemispheric asymmetries in response inhibition.

Asymmetries in social touch-motor and emotional biases on lateral preferences in embracing, cradling and kissing.

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.

How minimal variations in neuronal cytoskeletal integrity modulate cognitive control.

Until recently, investigating microscopic changes in the integrity of human brain matter has not been possible in vivo. It has hence remained unknown whether and how small non-pathological variations in cytoskeletal neuronal integrity affect human cognitive functioning. We investigated the role of neuronal cytoskeleton integrity for complex multicomponent behavior, which is relevant to real-life situations, as complex goals are often achieved by assembling a series of sub-tasks. For this, we quantified scaffolding proteins (i.e. neurofilament light; NF-L) using a single-molecule array (SIMOA), a new and uniquely ultra-sensitive method, and integrated this with behavioral and neurophysiological (EEG) data. For the first time, we showcase that slightest non-pathological variations in cytoskeletal integrity strongly modulate the efficiency of cognitive control processes. We show that the architecture and efficiency of theta-oscillations networks during cognitive control processes reflects a mechanism that establishes the relationship between neuronal cytoskeleton integrity and multicomponent behavior. Attentional selection processes do however not seem to play a role. The efficiency and network architecture of theta oscillations provides an important missing neural link that helps to explain how diffuse and seemingly miniscule variations in neuronal integrity may lead to reduced or even impaired cognitive functioning that is important for everyday activities.

Hemispheric asymmetries in cortical gray matter microstructure identified by neurite orientation dispersion and density imaging.

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.