Guy Vingerhoets

Handedness, the most pronounced human behavioural asymmetry, is a well-documented neurobiological phenomenon with significant implications for cognitive, motor, and social development (McManus, 200...

Hemispheric lateralization has been central to developmental dyslexia research for over a century, yet its role in the etiology of reading and language deficits remains elusive. While altered asymmetries have long been implicated, evidence is inconsistent, with limited consideration given to individual variability in lateralization patterns. This study investigated hemispheric lateralization in 35 adults with dyslexia and 35 matched controls using functional MRI across three language tasks: word generation, rhyming decision, and lexical decision. Laterality indices were calculated to comprehensively assess the strength, direction, and consistency of activation across global and regional task-specific brain areas. Significant group differences were not found in the absolute strength of lateralization for global measures or any regional measures, except in the fusiform gyrus, where people with dyslexia showed lower asymmetry. Directional asymmetry was similar across the two groups, except in the fusiform gyrus during the reading task, where dyslexic individuals showed a higher prevalence of right-hemisphere lateralization compared to controls. Interestingly, we found that dyslexic participants demonstrated greater inconsistency in regional lateralization during reading and rhyming tasks. Among individuals with dyslexia, those with inconsistent lateralization in the reading task had weaker fusiform lateralization, although fusiform lateralization strength itself did not predict reading outcomes. Our findings suggest that dyslexia is characterized by inconsistent, rather than universally weaker, lateralization patterns. Inconsistencies in task-related and regional lateralization may disrupt the efficiency of language networks, contributing to observed reading deficits. By highlighting the role of regional and task-specific inconsistencies, this study provides new insights into the neural mechanisms underlying dyslexia and underscores the importance of considering individual variability in hemispheric lateralization when investigating language disorders.

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

Although word production is considered a strongly left hemispheric lateralized function, its cerebral asymmetry varies among individuals. The most popular way of determining hemisphere dominance is to calculate a laterality index (LI) by comparing brain activity between the two hemispheres. Large LIs can readily be classified as left or right dominant, but there is no consensus on how to treat bilateral LIs indicating (near) symmetrical activity. The problem with interpreting very small LIs is perpetuated by a lack of reliability, stemming from the challenge of systematically investigating these uncommon cases (usually ≤ 10% of a sample). To address this gap, we performed two studies that investigated the reliability and across-methods generalizability of bilateral LIs obtained from functional transcranial Doppler sonography (fTCDS), an ultrasound-based approach that measures cerebral blood flow velocity. In Study 1, we compared reproducibility of bilateral LIs (n=35) and clearly lateralized LIs (n=32) during a letter verbal fluency fTCDS task across two sessions. While left-lateralized classifications were highly replicable (97% reproduced), poorer reproducibility was observed for bilateral classifications (51% reproduced). In fact, dichotomous left-right categorization yielded more reliable outcomes than assigning participants with bilateral LIs to a separate category (80% reproduced). Study 2 assessed whether small fTCDS asymmetry extended to other instruments for determining cerebral laterality (visual half field method and fMRI). Participants consistently classified as bilateral by fTCDS (n=18) also exhibited reduced group-level asymmetry in these other methods. Based on these results, we suggest that LIs reflect a combination of idiosyncratic cerebral asymmetry, state-dependent fluctuations, and measurement noise. Our findings also indicate that a subset of the population has a neural system for word production that is inherently weakly lateralized, although true hemispheric equivalence is likely extremely rare. Finally, we offer recommendations for classifying asymmetry in clinical and research contexts.

Situs inversus totalis (SIT), a rare condition involving the complete reversal of thoracic and abdominal organ placement, provides a unique model for investigating potential relationships between visceral and cerebral asymmetries. In this study, we examined whether white matter asymmetries are altered in a group of 21 SIT participants compared with 21 matched situs solitus (SO) controls. This sample represents the largest cohort of SIT individuals studied to date. Using fixel-based analysis, an advanced diffusion magnetic resonance imaging framework, we compared micro- and macrostructural white matter asymmetries across the whole brain between the two groups, specifically assessing fiber density and cross-section (FDC). Both groups showed extensive yet comparable patterns of white matter asymmetry, with no significant group differences. These asymmetry patterns were consistent with those reported in previous fixel-based studies. These results suggest that white matter lateralization is preserved despite complete visceral reversal. The observed divergence between brain and visceral asymmetry patterns suggests that symmetry breaking in visceral laterality relies on distinct mechanisms.

Previous research reported reversal of the prototypical brain torque in individuals with mirrored visceral topology (situs inversus totalis, SIT). Here, we investigate if typical asymmetry of the posterior intracranial venous system is also reversed in SIT and whether the direction and magnitude of this asymmetry is related to the direction and magnitude of the brain torque. Brain structural MRI images of 38 participants with SIT were compared with those of 38 matched control participants. Occipital and frontal petalia and bending were measured using a standardized procedure. In addition, representative sections of the left and right transverse sinuses were segmented, and their respective volumes determined. Participants with SIT showed general reversal of occipital and frontal petalia and occipital bending, as well as reversal of typical transverse sinus asymmetry. Transverse sinus volume was significantly correlated with several torque measures, such that the smaller transverse sinus was associated with a larger ipsilateral occipital petalia, contralateral occipital bending, and ipsilateral frontal bending. We propose an anatomical mechanism to explain occipital petalia and bending, and conclude that anatomical constraints imposed by the asymmetry of the posterior venous system provide and additional account to elucidate the formation of the human brain torque.

No two human brains are alike, and with the rise of precision medicine in neurology, we are seeing an increased emphasis on understanding the individual variability in brain structure and function that renders every brain unique. Functional and structural brain asymmetries are a fundamental principle of brain organization, and recent research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. In this Review, we provide an overview of brain asymmetries, variations in such asymmetries and their relevance in the clinical context. We review recent findings on brain asymmetries in neuropsychiatric and neurodevelopmental disorders, as well as in specific learning disabilities, with an emphasis on large-scale database studies and meta-analyses. We also highlight the relevance of asymmetries for disease symptom onset in neurodegenerative diseases and their implications for lateralized treatments, including brain stimulation. We conclude that alterations in brain asymmetry are not sufficiently specific to act as diagnostic biomarkers but can serve as meaningful symptom or treatment response biomarkers in certain contexts. On the basis of these insights, we provide several recommendations for neurological clinical practice.

Situs inversus totalis (SIT) is a rare congenital anomaly in which the arrangement of the visceral organs is completely left-right mirrored. A previous study by our lab suggests that SIT (N = 15) pairs with more heterogeneous asymmetrical brain organization and increased left-handedness. In addition, visceral reversal paired with poorer cognitive performance, especially when hemisphere organization was atypical. The current study sought to replicate these findings in a larger sample. We scanned 23 volunteers with SIT as well as an equal number of controls with usual organ arrangement, and determined their hemisphere dominance for two left hemisphere functions (language and manual praxis) and two right hemisphere functions (spatial attention and face recognition). Effects of situs inversus etiology were explored by pooling data from the original cohort with the replication sample. Our results reveal the expected population dominance for each of the cognitive functions in SIT, albeit they were less pronounced – but not significantly so – compared to controls. Unusual patterns of hemispheric crowding and mirror-reversal of functional brain organization was observed more often in SIT (48%) than in the controls (30%), but this difference also did not reach statistical significance. However, left-handedness was found to be significantly more common in SIT (24%) than in the overall population (10.6%). Finally, cognitive ability was not associated with organ situs or hemisphere organization. Taken together, our data adds to the growing evidence that the determinants of visceral and neural asymmetries are largely independent from one another and that complete situs inversus does not co-occur with an obligatory transposition of the brain’s functional architecture. There nevertheless might be instances in which (genetic) factors simultaneously cause complete visceral reversal and atypical brain laterality, particularly in asyndromal cases of situs inversus.