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

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

Bruchs Membrane Opening Area Measurement in Healthy Nepalese Eyes.

BACKGROUND: Bruch's membrane opening area is the circular area around the disc of Bruch's membrane, which is devoid of Bruch's membrane and can be assessed by capturing the retinal imaging system by Spectral-domain optical coherence tomography. BMOA can be a new landmark in analyzing the glaucomatous optic nerve head, myopic optic disc, optic neuropathy and uveitic disc edema. This is the first study from South Asia to evaluate the normal Bruch's membrane opening area among Nepalese eyes. METHODS: This hospital-based, cross-sectional, quantitative, observational study cross-sectional study was conducted in a tertiary eye care hospital in Nepal. Healthy immunocompetent Nepalese participants of both genders and different age groups were enrolled. The mean average Bruch's membrane opening area of each eyes, the difference in Bruch's membrane opening area between the two eyes and the gender of varying age groups were analyzed. RESULTS: Around 162 eyes (81 participants) were analyzed. The mean age was 56.69±17.5years. The mean average Bruch's membrane opening area of the right and left eye was 2.53±0.58 mm2 and 2.50 ±0.58 mm2. There was no significant difference in the Bruch's membrane opening area in either eye in both genders of any age group. CONCLUSION: The Bruch's membrane opening area does not differ significantly according to the laterality, gender and age group in Nepalese eyes.

Training in Cortically Blinded Fields Appears to Confer Patient-Specific Benefit Against Retinal Thinning.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Effect of breathing conditions on relationships between impairment, breathing laterality and coordination symmetry in elite para swimmers.

The aim was to investigate the effect of breathing conditions and swimming pace on the relationships between the impairment, the breathing laterality and motor coordination symmetry in elite front crawl Para swimmers. Fifteen elite Para swimmers with unilateral physical impairment or with visual impairment and unilateral breathing preference performed eight 25 m using four breathing conditions (every three strokes, every two strokes on preferred and non-preferred breathing side and apnea) at slow and fast paces in a randomized order. Multicamera video system and five sensors have been used to assess arm and leg stroke phases and to compute symmetry of arm coordination (SIIdC) and of leg kick rate (SIKR). Our findings emphasized motor coordination asymmetry whatever the breathing conditions and swimming paces, highlighting the influence of impairment. Multinomial logistic regression exhibited a high probability for motor coordination asymmetry (SIIdC and SIKR) to be present in categories of Para swimmers with impairment and breathing laterality on the same side, suggesting the joined effect of unilateral impairment and unilateral breathing. Moreover, unilateral physical impairment and breathing laterality could also occur on different sides and generate motor coordination asymmetry on different sides and different levels (arms vs. legs). Finally, visual impairment seems amplify the effect of unilateral breathing on motor coordination asymmetry.

Cross-hemispheric communication: Insights on lateralized brain functions.

On the surface, the two hemispheres of vertebrate brains look almost perfectly symmetrical, but several motor, sensory, and cognitive systems show a deeply lateralized organization. Importantly, the two hemispheres are connected by various commissures, white matter tracts that cross the brain's midline and enable cross-hemispheric communication. Cross-hemispheric communication has been suggested to play an important role in the emergence of lateralized brain functions. Here, we review current advances in understanding cross-hemispheric communication that have been made using modern neuroscientific tools in rodents and other model species, such as genetic labeling, large-scale recordings of neuronal activity, spatiotemporally precise perturbation, and quantitative behavior analyses. These findings suggest that the emergence of lateralized brain functions cannot be fully explained by largely static factors such as genetic variation and differences in structural brain asymmetries. In addition, learning-dependent asymmetric interactions between the left and right hemispheres shape lateralized brain functions.

Associations between handedness and brain functional connectivity patterns in children.

Handedness develops early in life, but the structural and functional brain connectivity patterns associated with it remains unknown. Here we investigate associations between handedness and the asymmetry of brain connectivity in 9- to 10-years old children from the Adolescent Brain Cognitive Development (ABCD) study. Compared to right-handers, left-handers had increased global functional connectivity density in the left-hand motor area and decreased it in the right-hand motor area. A connectivity-based index of handedness provided a sharper differentiation between right- and left-handers. The laterality of hand-motor connectivity varied as a function of handedness in unimodal sensorimotor cortices, heteromodal areas, and cerebellum (P < 0.001) and reproduced across all regions of interest in Discovery and Replication subsamples. Here we show a strong association between handedness and the laterality of the functional connectivity patterns in the absence of differences in structural connectivity, brain morphometrics, and cortical myelin between left, right, and mixed handed children.

Hemispheric asymmetry of hand and tool perception in left- and right-handers with known language dominance.

Regions in the brain that are selective for images of hands and tools have been suggested to be lateralised to the left hemisphere of right-handed individuals. In left-handers, many functions related to tool use or tool pantomime may also depend more on the left hemisphere. This result seems surprising, given that the dominant hand of these individuals is controlled by the right hemisphere. One explanation is that the left hemisphere is dominant for speech and language in the majority of left-handers, suggesting a supraordinate control system for complex motor sequencing that is required for skilled tool use, as well as for speech. In the present study, we examine if this left-hemispheric specialisation extends to perception of hands and tools in left- and right-handed individuals. We, crucially, also include a group of left-handers with right-hemispheric language dominance to examine their asymmetry biases. The results suggest that tools lateralise to the left hemisphere in most right-handed individuals with left-hemispheric language dominance. Tools also lateralise to the language dominant hemisphere in right-hemispheric language dominant left-handers, but the result for left-hemispheric language dominant left-handers are more varied, and no clear bias towards one hemisphere is found. Hands did not show a group-level asymmetry pattern in any of the groups. These results suggest a more complex picture regarding hemispheric overlap of hand and tool representations, and that visual appearance of tools may be driven in part by both language dominance and the hemisphere which controls the motor-dominant hand.

The line bisection bias as a deficit of proportional reasoning - evidence from number line estimation in neglect.

This study aimed to investigate whether neurological patients presenting with a bias in line bisection show specific problems in bisecting a line into two equal parts or their line bisection bias rather reflects a special case of a deficit in proportional reasoning more generally. In the latter case, the bias should also be observed for segmentations into thirds or quarters. To address this question, six neglect patients with a line bisection bias were administered additional tasks involving horizontal lines (e.g., segmentation into thirds and quarters, number line estimation, etc.). Their performance was compared to five neglect patients without a line bisection bias, 10 patients with right hemispheric lesions without neglect, and 32 healthy controls. Most interestingly, results indicated that neglect patients with a line bisection bias also overestimated segments on the left of the line (e.g., one third, one quarter) when dissecting lines into parts smaller than halves. In contrast, such segmentation biases were more nuanced when the required line segmentation was framed as a number line estimation task with either fractions or whole numbers. Taken together, this suggests a generalization of line bisection bias towards a segmentation or proportional processing bias, which is congruent with attentional weighting accounts of line bisection/neglect. As such, patients with a line bisection bias do not seem to have specific problems bisecting a line, but seem to suffer from a more general deficit processing proportions.

Disengagement of attention with spatial neglect: A systematic review of behavioral and anatomical findings.

The present review examined the consequences of focal brain injury on spatial attention studied with cueing paradigms, with a particular focus on the disengagement deficit, which refers to the abnormal slowing of reactions following an ipsilesional cue. Our review supports the established notion that the disengagement deficit is a functional marker of spatial neglect and is particularly pronounced when elicited by peripheral cues. Recent research has revealed that this deficit critically depends on cues that have task-relevant characteristics or are associated with negative reinforcement. Attentional capture by task-relevant cues is contingent on damage to the right temporo-parietal junction (TPJ) and is modulated by functional connections between the TPJ and the right insular cortex. Furthermore, damage to the dorsal premotor or prefrontal cortex (dPMC/dPFC) reduces the effect of task-relevant cues. These findings support an interactive model of the disengagement deficit, involving the right TPJ, the insula, and the dPMC/dPFC. These interconnected regions play a crucial role in regulating and adapting spatial attention to changing intrinsic values of stimuli in the environment.

Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Effects of shoe collar height and limb dominance on landing knee biomechanics in female collegiate volleyball players.

Volleyball-specific footwear with higher collar heights (a mid-cut shoe) are worn to restrict ankle motion. Reduced ankle dorsiflexion has been associated with increased frontal plane motion and injury risk at the knee. With the high frequency of unilateral landings in volleyball, the purpose of this study was to determine the effect of volleyball-specific shoes and limb dominance on knee landing mechanics in collegiate volleyball players. It was hypothesized that participants would exhibit smaller sagittal plane and greater frontal plane knee joint mechanics in mid-cut and dominant limb and that vertical and posterior directed ground reaction forces would be greater wearing mid-cut, yet similar between limbs. Seventeen female volleyball players performed unilateral landings on each limb in mid-cut and low-top volleyball shoes. For shoe main effects, smaller peak dorsiflexion angle and internal peak plantarflexion moment and greater peak medial ground reaction force were found in the mid-cut but with no impact on knee mechanics. For limb main effects, the internal peak knee abduction moment was greater in the dominant limb. Greater peak lateral ground reaction force was found in the interaction between the non-dominant limb and low-top. Further research is warranted to better understand shoe and limb impact in volleyball players.

App-Mohedo®: A mobile app for the management of chronic pelvic pain. A design and development study.

BACKGROUND: Chronic Pelvic Pain (CPP) has been described as a public health priority worldwide, and it is among the most prevalent and costly healthcare problems. Graded motor imagery (GMI) is a therapeutic tool that has been successfully used to improve pain in several chronic conditions. GMI therapy is divided into three stages: laterality training (LRJT, Left Right Judgement Task), imagined movements, and mirror therapy. No tool that allows working with LRJT in pelvic floor has been developed to date. OBJECTIVE: This research aims to describe the process followed for the development of a highly usable, multi-language and multi-platform mobile application using GMI with LRJT to improve the treatment of patients with CPP. In addition, this will require achieving two other goals: firstly, to generate 550 pelvic floor images and, subsequently, to carry out an empirical study to objectively classify them into different difficulty levels of. This will allow the app to properly organize and plan the different therapy sessions to be followed by each patient. METHODOLOGY: For the design, evaluation and development of the app, an open methodology of user-centered design (MPIu + a) was applied. Furthermore, to classify and establish the pelvic floor images of the app in different difficulty levels, an observational, cross-sectional study was conducted with 132 volunteers through non-probabilistic sampling. RESULTS: On one hand, applying MPIu+a, a total of 5 phases were required to generate an easy-to-use mobile application. On the other hand, the 550 pelvic floor images were classified into 3 difficulty levels (based on the percentage of correct answers and response time used by the participants in the classification process of each image): Level 1 (191 images with Accuracy = 100 % and RT = [0-2.5] seconds); Level 2 (208 images with Accuracy = 75-100 % and RT = [2.5-5] seconds); and Level 3 (151 images with Accuracy = 50-75 % and RT > 5 s). CONCLUSION: App-Mohedo® is the first multi-platform, multi-language and easy-to-use mobile application that, through GMI with LRJT, and with an adequate bank of images classified into three levels of difficulty, can be used as a complementary therapeutic tool in the treatment of patients with CPP. This work can also serve as an example, model or guide when applying a user-centered methodology, as MPIu + a, to the development of other apps, especially in the field of health.

triact package for R: analyzing the lying behavior of cows from accelerometer data.

Accelerometers are sensors proven to be useful to analyze the lying behavior of cows. For reasons of algorithm transparency and control, researchers often prefer to use their own data analysis scripts rather than proprietary software. We developed the triact R package that assists animal scientists in analyzing the lying behavior of cows from raw data recorded with a triaxial accelerometer (manufacturer agnostic) attached to a hind leg. In a user-friendly workflow, triact allows the determination of common measures for lying behavior including total lying duration, the number of lying bouts, and the mean duration of lying bouts. Further capabilities are the description of lying laterality and the calculation of proxies for the level of physical activity of the cow. In this publication we describe the functionality of triact and the rationales behind the implemented algorithms. The triact R package is developed as an open-source project and freely available via the CRAN repository.

Comparison of migraine with left- versus right-sided headache: A cross-sectional study.

OBJECTIVE: The goal of this study was to clarify whether clinical differences exist between patients with migraine who experience headache that is typically left-sided ("left-migraine") versus right-sided ("right-migraine") during attacks. BACKGROUND: Migraine has been associated with unilateral headache for millennia and remains a supportive trait for the clinical diagnosis of migraine of the International Classification of Headache Disorders. It is currently unknown why headache in migraine is commonly unilateral, and whether headache-sidedness is associated with other clinical features. METHODS: This is a cross-sectional study comparing left- versus right-migraine using all available intake questionnaires of new patients evaluated at an academic tertiary headache center over a 20-year period. Eligibility was based on patient written responses indicating the typical location of headache during attacks. In our analyses, the side of headache (left or right) was the predictor variable. The outcomes included various migraine characteristics and psychiatric comorbidities. RESULTS: We identified 6527 patients with migraine, of which 340 met study eligibility criteria. Of these, 48.8% (166/340) had left migraine, and 51.2% (174/340) had right migraine. When comparing patients with left- versus right-migraine, patients with left migraine experienced 3.6 fewer headache-free days (95% confidence interval [CI] 1.3-5.9; p = 0.002) and 2.4 more severe headache days (95% CI 0.8-4.1; p = 0.004) in the previous 4 weeks. No significant differences in age, sex, handedness, migraine characteristics, or psychiatric comorbidities were identified between the two groups. CONCLUSIONS: Patients with migraine with typically left-sided headache during attacks reported a higher burden of headache frequency and severity than those with typically right-sided headache during attacks. These findings may have implications for our understanding of migraine pathophysiology, treatment, and clinical trial design.

Functional Integration of the Subregions of the Primary Motor Cortex: The Impact of Handedness and Hemispheric Lateralization.

OBJECTIVE: Cytoarchitectonic mapping has revealed distinct subregions within Broadmann area 4 (BA 4) - BA 4a and BA 4p - with varying functional roles across tasks. We investigate their functional connectivity using resting-state functional magnetic resonance imaging (rsfMRI) to explore bilateral differences and the impact of handedness on connectivity within major brain networks. METHODS: This retrospective study involved 54 left- and right-handed subjects. We employed regions-to-regions-network rsfMRI analysis to examine the Cytoarchitectonic mapping of BA 4a and BA 4p functional connectivity with eight major brain networks. RESULTS: Our findings reveal differential connectivity patterns in both right-handed and left-handed subjects: Both right-handed subjects' BA 4a and BA 4p subregions exhibit connections to sensorimotor, dorsal attention, frontoparietal, and anterior cerebellar networks. Notably, BA 4a shows unique connectivity to the posterior cerebellum, lateral visual networks, and select salience regions. Similar connectivity patterns are observed in left-handed subjects, with BA 4a linked to sensorimotor, dorsal attention, frontoparietal, and anterior cerebellar networks. However, BA 4a in left-handed subjects shows distinct connectivity only to the posterior cerebellum. In both groups, the right portion of BA 4 demonstrates heightened connectivity compared to the left portion within each subregion. CONCLUSION: Our study uncovers complex patterns of functional connectivity within BA 4a and BA 4p, influenced by handedness. These findings emphasize the importance of considering hemisphere-specific and handedness-related factors in functional connectivity analyses, with potential implications for understanding brain organization in health and neurodegenerative diseases.

Modeling the association between functional connectivity and lateralization with the activity flow framework.

The human brain is localized and distributed. On the one hand, each cognitive function tends to involve one hemisphere more than the other, also known as the principle of lateralization. On the other hand, interactions among brain regions in the form of functional connectivity (FC) are indispensable for intact function. Recent years have seen growing interest in the association between lateralization and FC. However, FC metrics vary from spurious correlation to causal associations. If lateralization manifests local processing and causal network interactions, more causally valid FC metrics should predict lateralization index (LI) better than FC based on simple correlations. The present study directly investigates this hypothesis within the activity flow framework to compare the association between lateralization and four brain connectivity metrics: correlation-based FC, multiple-regression FC, partial-correlation FC, and combinedFC. We propose two modeling approaches: the one-step approach, which models the relationship between LI and FC directly, and the two-step approach, which predicts the brain activation and calculates the LI. Our results indicated that multiple-regression FC, partial-correlation FC, and combinedFC could significantly improve the model prediction compared to correlation-based FC, which was consistent in a spatial working memory task (typically right-lateralized) and a language task (typically left-lateralized). The one-step and two-step approach yielded similar conclusions. In addition, the finding was replicated in a clinical sample of schizophrenia (SZ), bipolar disorder (BP), and attention deficit hyperactivity disorder (ADHD). The present study suggests that the causal interactions among brain regions help shape the lateralization pattern.

Transcranial magnetic stimulation on the right dorsal attention network modulates the center-surround profile of the attentional focus.

Psychophysical observations indicate that the spatial profile of visuospatial attention includes a central enhancement around the attentional focus, encircled by a narrow zone of reduced excitability in the immediate surround. This inhibitory ring optimally amplifies relevant target information, likely stemming from top-down frontoparietal recurrent activity modulating early visual cortex activations. However, the mechanisms through which neural suppression gives rise to the surrounding attenuation and any potential hemispheric specialization remain unclear. We used transcranial magnetic stimulation to evaluate the role of two regions of the dorsal attention network in the center-surround profile: the frontal eye field and the intraparietal sulcus. Participants performed a psychophysical task that mapped the entire spatial attentional profile, while transcranial magnetic stimulation was delivered either to intraparietal sulcus or frontal eye field on the right (Experiment 1) and left (Experiment 2) hemisphere. Results showed that stimulation of right frontal eye field and right intraparietal sulcus significantly changed the center-surround profile, by widening the inhibitory ring around the attentional focus. The stimulation on the left frontal eye field, but not left intraparietal sulcus, induced a general decrease in performance but did not alter the center-surround profile. Results point to a pivotal role of the right dorsal attention network in orchestrating inhibitory spatial mechanisms required to limit interference by surrounding distractors.

Assessment of language lateralization in epilepsy patients using the super-selective Wada test.

BACKGROUND: The classical Wada test (cWada), performed by injecting a short-acting anesthetic through the intracarotid route, helps determine language dominance. In the cWada, adverse effects are observed in 10-30% of trials, hindering accurate assessments. In this study, we assessed the effectiveness of the super-selective Wada test (ssWada), a more selective approach for anesthetic infusion into the middle cerebral artery (MCA). METHODS: We retrospectively examined the data of 17 patients with epilepsy who underwent ssWada via anesthetic injection into one M1 segment of the MCA and at least one contralateral trial. RESULTS: The ssWada identified 12 patients with left language dominance, 3 with right language dominance, and 2 with bilateral language distribution. Nine trials on the language dominant side resulted in global aphasia for patients with left- or right language dominance. Of the 13 trials conducted on the non-dominant language side, 12 revealed intact language function and one resulted in confusion. Among these, the outcomes of global aphasia or no language impairment were confirmed in the contralateral trials. Among the 22 trials of unilateral M1 injections in patients with unilateral language dominance, 21 (95.5%) showed either global aphasia or no language impairment, indicating language dominance. CONCLUSIONS: The ssWada yields clear results, with a high rate of over 90% in determining the language dominant hemisphere with few side effects.

Roles of Handedness and Hemispheric Lateralization: Implications for Rehabilitation of the Central and Peripheral Nervous Systems: A Rapid Review.

IMPORTANCE: Handedness and motor asymmetry are important features of occupational performance. With an increased understanding of the basic neural mechanisms surrounding handedness, clinicians will be better able to implement targeted, evidence-based neurorehabilitation interventions to promote functional independence. OBJECTIVE: To review the basic neural mechanisms behind handedness and their implications for central and peripheral nervous system injury. DATA SOURCES: Relevant published literature obtained via MEDLINE. FINDINGS: Handedness, along with performance asymmetries observed between the dominant and nondominant hands, may be due to hemispheric specializations for motor control. These specializations contribute to predictable motor control deficits that are dependent on which hemisphere or limb has been affected. Clinical practice recommendations for occupational therapists and other rehabilitation specialists are presented. CONCLUSIONS AND RELEVANCE: It is vital that occupational therapists and other rehabilitation specialists consider handedness and hemispheric lateralization during evaluation and treatment. With an increased understanding of the basic neural mechanisms surrounding handedness, clinicians will be better able to implement targeted, evidence-based neurorehabilitation interventions to promote functional independence. Plain-Language Summary: The goal of this narrative review is to increase clinicians' understanding of the basic neural mechanisms related to handedness (the tendency to select one hand over the other for specific tasks) and their implications for central and peripheral nervous system injury and rehabilitation. An enhanced understanding of these mechanisms may allow clinicians to better tailor neurorehabilitation interventions to address motor deficits and promote functional independence.