Hemispheric specialization is a fundamental aspect of human brain organization. While left-hemispheric dominance for language is common, atypical right-hemispheric dominance exists in a significant minority. This study aimed to determine the extent to which this lateralization impacts the overall functional organization of the cortex. Previous research has established the existence of functional gradients across the cortex, organizing networks along a spectrum from unimodal to association areas. The study hypothesized that atypical language dominance would be reflected in global shifts in these cortical gradients, extending beyond the language network itself. Understanding this relationship is crucial for understanding the origins and consequences of hemispheric specialization, and its potential implications for various neurological and psychiatric conditions. The study's importance lies in bridging the gap between localized cognitive functions and the overall architecture of the brain, potentially offering insights into neurodevelopmental disorders where atypical lateralization is observed.

The study builds upon extensive research on language lateralization, tracing back to post-mortem studies of aphasia patients that identified key language regions in the left hemisphere (Broca's and Wernicke's areas). In vivo imaging studies and data-driven network parcellation have further supported the left-lateralized language network. However, the literature also acknowledges the existence of atypical language organization, which is not fixed across development and varies across individuals, being more prevalent in left-handed individuals. The mechanisms underlying this variability remain largely unknown. Concurrently, research has uncovered macroscale functional gradients within the cortex, reflecting the spatial arrangement of areal parcels along continuous spectra from unimodal to association areas. These gradients are consistent across various measures of brain organization, including function, anatomy, and gene expression. Previous work has shown hemispheric differences in the organization of these gradients. This study leverages these findings to investigate the relationship between language lateralization and global cortical organization.

The study utilized data from the Human Connectome Project (HCP), specifically resting-state fMRI (rs-fMRI) and task-based fMRI data (Story-Math contrast) from 995 participants. Language lateralization was assessed using SENSAAS, a higher-order language atlas, employing five functional metrics: network and hub-level asymmetries during the language task, and resting-state measures of language network strength (sum and asymmetry) and inter-hemispheric connectivity. Hierarchical clustering was used to classify participants into three groups: strong typical (left-lateralized), mild typical, and atypical (right-lateralized). Diffusion map embedding was applied to resting-state data to extract functional gradients reflecting the dominant patterns of connectivity within each hemisphere. The first three gradients, explaining 57% of total variance, were analyzed. For each participant, gradient asymmetry values were calculated as the difference between left and right hemisphere values, averaged across network parcels. Analyses of covariance were used to examine the relationship between language lateralization and gradient asymmetries, controlling for age, sex, handedness, and intracranial volume. Finally, heritability analyses were conducted using twin and family data to investigate the genetic influence on both language lateralization and gradient asymmetries. SOLAR software was used for this analysis, controlling for the same covariates as in the previous analyses.

The study identified three groups of participants based on language lateralization: strong typical (left-lateralized, n=480), mild typical (n=433), and atypical (right-lateralized, n=82, ~8% of the sample). Atypical individuals exhibited significant rightward lateralization in task-based and resting-state measures. Analysis of functional gradients revealed that atypical language lateralization was associated with global shifts in cortical organization, specifically within association cortex networks, but not unimodal networks across three primary gradients. These alterations in hemispheric dominance predominantly stemmed from increases in gradient values within the right hemisphere for most affected networks. Heritability analysis showed that both language lateralization (h²=11.2%, p=0.038) and gradient asymmetries (G1: 14.4%, p=0.007; G2: 2.0%, p=0.36; G3: 24.0%, p<10⁻⁶) were partially heritable. Heritability was significantly higher in heteromodal association cortices than in unimodal networks.

The findings demonstrate a strong link between atypical language lateralization and widespread alterations in cortical functional organization, primarily affecting association cortex networks. This supports the notion that language lateralization is not an isolated phenomenon but rather a reflection of a broader pattern of hemispheric asymmetry. The heritability of both language lateralization and gradient asymmetries suggests a genetic basis for this organization, potentially influenced by developmental processes that bias fundamental aspects of brain lateralization. The preferential impact on association cortices is consistent with the evolutionary expansion of these areas in primates and the significance of these regions in higher-order cognitive functions. The results highlight the complex interplay between localized cognitive functions and the global organization of the brain.

This study provides compelling evidence that atypical language network organization is reflected in global changes in cortical functional gradients, particularly within association cortices. The partial heritability of both language lateralization and these gradient asymmetries suggests a genetic contribution to this phenomenon. This research advances our understanding of the relationship between localized hemispheric specialization and the overall topographic organization of the brain, emphasizing the interconnectedness of different brain functions and their developmental trajectories. Future studies should investigate the precise developmental mechanisms underlying these relationships and explore the implications of atypical lateralization for various cognitive processes and neuropsychiatric conditions.

The cross-sectional nature of the study limits the ability to track developmental changes in language lateralization and its impact on cortical organization. The use of only one language comprehension task in the HCP database might limit the generalizability of the findings. Further research is needed to establish the causal relationships between language lateralization and broader patterns of cortical organization, and to explore the clinical implications of these findings for individuals with aphasia or other neurological conditions.