Sex differences in the functional network underpinnings of psychotic-like experiences in children.

Psychotic-like experiences (PLEs) include a range of sub-threshold symptoms that resemble aspects of psychosis but do not necessarily indicate the presence of psychiatric illness. These experiences are highly prevalent in youth and are associated with developmental disruptions across social, academic, and emotional domains. While not all youth who report PLEs develop psychosis, many develop other psychiatric illnesses during adolescence and adulthood. As such, PLEs are theorized to represent early markers of poor mental health. Here, we characterized the similarities and differences in the neurobiological underpinnings of childhood PLEs across the sexes using a large sample from the ABCD Study (n=5,260), revealing sex-specific associations between functional networks connectivity and PLEs. We find that although the networks associated with PLEs overlap to some extent across the sexes, there are also crucial differences. In females, PLEs are associated with dispersed cortical and non-cortical connections, whereas in males, they are primarily associated with functional connections within limbic, temporal parietal, somato/motor, and visual networks. These results suggest that early transdiagnostic markers of psychopathology may be distinct across the sexes, further emphasizing the need to consider sex in psychiatric research as well as clinical practice.

A multidimensional investigation of sleep and biopsychosocialprofiles with associated neural signatures.

Sleep is essential for optimal functioning and health. Interconnected to multiple biological, psychological and socio-environmental factors (i.e., biopsychosocial factors), the multidimensional nature of sleep is rarely capitalized on in research. Here, we deployed a data-driven approach to identify sleep-biopsychosocial profiles that linked self-reported sleep patterns to inter-individual variability in health, cognition, and lifestyle factors in 770 healthy young adults. We uncovered five profiles, including two profiles reflecting general psychopathology associated with either reports of general poor sleep or an absence of sleep complaints (i.e., sleep resilience) respectively. The three other profiles were driven by sedative-hypnotics-use and social satisfaction, sleep duration and cognitive performance, and sleep disturbance linked to cognition and mental health. Furthermore, identified sleep-biopsychosocial profiles displayed unique patterns of brain network organization. In particular, somatomotor network connectivity alterations were involved in the relationships between sleep and biopsychosocial factors. These profiles can potentially untangle the interplay between individuals' variability in sleep, health, cognition and lifestyle - equipping research and clinical settings to better support individual's well-being.

Gradients of Brain Organization: Smooth Sailing from Methods Development to User Community.

Multimodal neuroimaging grants a powerful in vivo window into the structure and function of the human brain. Recent methodological and conceptual advances have enabled investigations of the interplay between large-scale spatial trends - or gradients - in brain structure and function, offering a framework to unify principles of brain organization across multiple scales. Strong community enthusiasm for these techniques has been instrumental in their widespread adoption and implementation to answer key questions in neuroscience. Following a brief review of current literature on this framework, this perspective paper will highlight how pragmatic steps aiming to make gradient methods more accessible to the community propelled these techniques to the forefront of neuroscientific inquiry. More specifically, we will emphasize how interest for gradient methods was catalyzed by data sharing, open-source software development, as well as the organization of dedicated workshops led by a diverse team of early career researchers. To this end, we argue that the growing excitement for brain gradients is the result of coordinated and consistent efforts to build an inclusive community and can serve as a case in point for future innovations and conceptual advances in neuroinformatics. We close this perspective paper by discussing challenges for the continuous refinement of neuroscientific theory, methodological innovation, and real-world translation to maintain our collective progress towards integrated models of brain organization.

In-vivo whole-cortex marker of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth.

A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I ratio remains unknown. Here we non-invasively estimate a putative marker of whole-cortex E/I ratio by fitting a large-scale biophysically-plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our model generates realistic brain dynamics in the Human Connectome Project. Next, we show that the estimated E/I ratio marker is sensitive to the GABA-agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced E/I changes are spatially consistent with positron emission tomography measurement of benzodiazepine receptor density. We then investigate the relationship between the E/I ratio marker and neurodevelopment. We find that the E/I ratio marker declines heterogeneously across the cerebral cortex during youth, with the greatest reduction occurring in sensorimotor systems relative to association systems. Importantly, among children with the same chronological age, a lower E/I ratio marker (especially in association cortex) is linked to better cognitive performance. This result is replicated across North American (8.2 to 23.0 years old) and Asian (7.2 to 7.9 years old) cohorts, suggesting that a more mature E/I ratio indexes improved cognition during normative development. Overall, our findings open the door to studying how disrupted E/I trajectories may lead to cognitive dysfunction in psychopathology that emerges during youth.

A multidimensional investigation of sleep and biopsychosocial profiles with associated neural signatures.

Sleep is essential for optimal functioning and health. Interconnected to multiple biological, psychological and socio-environmental factors (i.e., biopsychosocial factors), the multidimensional nature of sleep is rarely capitalized on in research. Here, we deployed a data-driven approach to identify sleep-biopsychosocial profiles that linked self-reported sleep patterns to inter-individual variability in health, cognition, and lifestyle factors in 770 healthy young adults. We uncovered five profiles, including two profiles reflecting general psychopathology associated with either reports of general poor sleep or an absence of sleep complaints (i.e., sleep resilience) respectively. The three other profiles were driven by sedative-hypnotics-use and social satisfaction, sleep duration and cognitive performance, and sleep disturbance linked to cognition and mental health. Furthermore, identified sleep-biopsychosocial profiles displayed unique patterns of brain network organization. In particular, somatomotor network connectivity alterations were involved in the relationships between sleep and biopsychosocial factors. These profiles can potentially untangle the interplay between individuals' variability in sleep, health, cognition and lifestyle - equipping research and clinical settings to better support individual's well-being.

Organization of the Human Cerebral Cortex Estimated Within Individuals: Networks, Global Topography, and Function.

The cerebral cortex is populated by specialized regions that are organized into networks. Here we estimated networks from functional MRI (fMRI) data in intensively sampled participants. The procedure was developed in two participants (scanned 31 times) and then prospectively applied to 15 participants (scanned 8-11 times). Analysis of the networks revealed a global organization. Locally organized first-order sensory and motor networks were surrounded by spatially adjacent second-order networks that linked to distant regions. Third-order networks possessed regions distributed widely throughout association cortex. Regions of distinct third-order networks displayed side-by-side juxtapositions with a pattern that repeated across multiple cortical zones. We refer to these as Supra-Areal Association Megaclusters (SAAMs). Within each SAAM, two candidate control regions were adjacent to three separate domain-specialized regions. Response properties were explored with task data. The somatomotor and visual networks responded to body movements and visual stimulation, respectively. Second-order networks responded to transients in an oddball detection task, consistent with a role in orienting to salient events. The third-order networks, including distinct regions within each SAAM, showed two levels of functional specialization. Regions linked to candidate control networks responded to working memory load across multiple stimulus domains. The remaining regions dissociated across language, social, and spatial / episodic processing domains. These results suggest progressively higher-order networks nest outwards from primary sensory and motor cortices. Within the apex zones of association cortex, there is specialization that repeatedly divides domain-flexible from domain-specialized regions. We discuss implications of these findings including how repeating organizational motifs may emerge during development.

MRI economics: Balancing sample size and scan duration in brain wide association studies.

A pervasive dilemma in neuroimaging is whether to prioritize sample size or scan duration given fixed resources. Here, we systematically investigate this trade-off in the context of brain-wide association studies (BWAS) using resting-state functional magnetic resonance imaging (fMRI). We find that total scan duration (sample size × scan duration per participant) robustly explains individual-level phenotypic prediction accuracy via a logarithmic model, suggesting that sample size and scan duration are broadly interchangeable. The returns of scan duration eventually diminish relative to sample size, which we explain with principled theoretical derivations. When accounting for fixed costs associated with each participant (e.g., recruitment, non-imaging measures), we find that prediction accuracy in small-scale BWAS might benefit from much longer scan durations (>50 min) than typically assumed. Most existing large-scale studies might also have benefited from smaller sample sizes with longer scan durations. Both logarithmic and theoretical models of the relationships among sample size, scan duration and prediction accuracy explain well-predicted phenotypes better than poorly-predicted phenotypes. The logarithmic and theoretical models are also undermined by individual differences in brain states. These results replicate across phenotypic domains (e.g., cognition and mental health) from two large-scale datasets with different algorithms and metrics. Overall, our study emphasizes the importance of scan time, which is ignored in standard power calculations. Standard power calculations inevitably maximize sample size at the expense of scan duration. The resulting prediction accuracies are likely lower than would be produced with alternate designs, thus impeding scientific discovery. Our empirically informed reference is available for future study design: WEB_APPLICATION_LINK.

Macroscale intrinsic dynamics are associated with microcircuit function in focal and generalized epilepsies.

Epilepsies are a group of neurological disorders characterized by abnormal spontaneous brain activity, involving multiscale changes in brain functional organizations. However, it is not clear to what extent the epilepsy-related perturbations of spontaneous brain activity affect macroscale intrinsic dynamics and microcircuit organizations, that supports their pathological relevance. We collect a sample of patients with temporal lobe epilepsy (TLE) and genetic generalized epilepsy with tonic-clonic seizure (GTCS), as well as healthy controls. We extract massive temporal features of fMRI BOLD time-series to characterize macroscale intrinsic dynamics, and simulate microcircuit neuronal dynamics used a large-scale biological model. Here we show whether macroscale intrinsic dynamics and microcircuit dysfunction are differed in epilepsies, and how these changes are linked. Differences in macroscale gradient of time-series features are prominent in the primary network and default mode network in TLE and GTCS. Biophysical simulations indicate reduced recurrent connection within somatomotor microcircuits in both subtypes, and even more reduced in GTCS. We further demonstrate strong spatial correlations between differences in the gradient of macroscale intrinsic dynamics and microcircuit dysfunction in epilepsies. These results emphasize the impact of abnormal neuronal activity on primary network and high-order networks, suggesting a systematic abnormality of brain hierarchical organization.

Translating phenotypic prediction models from big to small anatomical MRI data using meta-matching.

Individualized phenotypic prediction based on structural MRI is an important goal in neuroscience. Prediction performance increases with larger samples, but small-scale datasets with fewer than 200 participants are often unavoidable. We have previously proposed a "meta-matching" framework to translate models trained from large datasets to improve the prediction of new unseen phenotypes in small collection efforts. Meta-matching exploits correlations between phenotypes, yielding large improvement over classical machine learning when applied to prediction models using resting-state functional connectivity as input features. Here, we adapt the two best performing meta-matching variants ("meta-matching finetune" and "meta-matching stacking") from our previous study to work with T1-weighted MRI data by changing the base neural network architecture to a 3D convolution neural network. We compare the two meta-matching variants with elastic net and classical transfer learning using the UK Biobank (N = 36,461), Human Connectome Project Young Adults (HCP-YA) dataset (N = 1,017) and HCP-Aging dataset (N = 656). We find that meta-matching outperforms elastic net and classical transfer learning by a large margin, both when translating models within the same dataset, as well as translating models across datasets with different MRI scanners, acquisition protocols and demographics. For example, when translating a UK Biobank model to 100 HCP-YA participants, meta-matching finetune yielded a 136% improvement in variance explained over transfer learning, with an average absolute gain of 2.6% (minimum = -0.9%, maximum = 17.6%) across 35 phenotypes. Overall, our results highlight the versatility of the meta-matching framework.

DeepResBat: deep residual batch harmonization accounting for covariate distribution differences.

Pooling MRI data from multiple datasets requires harmonization to reduce undesired inter-site variabilities, while preserving effects of biological variables (or covariates). The popular harmonization approach ComBat uses a mixed effect regression framework that explicitly accounts for covariate distribution differences across datasets. There is also significant interest in developing harmonization approaches based on deep neural networks (DNNs), such as conditional variational autoencoder (cVAE). However, current DNN approaches do not explicitly account for covariate distribution differences across datasets. Here, we provide mathematical results, suggesting that not accounting for covariates can lead to suboptimal harmonization outcomes. We propose two DNN-based harmonization approaches that explicitly account for covariate distribution differences across datasets: covariate VAE (coVAE) and DeepResBat. The coVAE approach is a natural extension of cVAE by concatenating covariates and site information with site- and covariate-invariant latent representations. DeepResBat adopts a residual framework inspired by ComBat. DeepResBat first removes the effects of covariates with nonlinear regression trees, followed by eliminating site differences with cVAE. Finally, covariate effects are added back to the harmonized residuals. Using three datasets from three different continents with a total of 2787 participants and 10085 anatomical T1 scans, we find that DeepResBat and coVAE outperformed ComBat, CovBat and cVAE in terms of removing dataset differences, while enhancing biological effects of interest. However, coVAE hallucinates spurious associations between anatomical MRI and covariates even when no association exists. Therefore, future studies proposing DNN-based harmonization approaches should be aware of this false positive pitfall. Overall, our results suggest that DeepResBat is an effective deep learning alternative to ComBat.

Multilayer meta-matching: translating phenotypic prediction models from multiple datasets to small data.

Resting-state functional connectivity (RSFC) is widely used to predict phenotypic traits in individuals. Large sample sizes can significantly improve prediction accuracies. However, for studies of certain clinical populations or focused neuroscience inquiries, small-scale datasets often remain a necessity. We have previously proposed a "meta-matching" approach to translate prediction models from large datasets to predict new phenotypes in small datasets. We demonstrated large improvement of meta-matching over classical kernel ridge regression (KRR) when translating models from a single source dataset (UK Biobank) to the Human Connectome Project Young Adults (HCP-YA) dataset. In the current study, we propose two meta-matching variants ("meta-matching with dataset stacking" and "multilayer meta-matching") to translate models from multiple source datasets across disparate sample sizes to predict new phenotypes in small target datasets. We evaluate both approaches by translating models trained from five source datasets (with sample sizes ranging from 862 participants to 36,834 participants) to predict phenotypes in the HCP-YA and HCP-Aging datasets. We find that multilayer meta-matching modestly outperforms meta-matching with dataset stacking. Both meta-matching variants perform better than the original "meta-matching with stacking" approach trained only on the UK Biobank. All meta-matching variants outperform classical KRR and transfer learning by a large margin. In fact, KRR is better than classical transfer learning when less than 50 participants are available for finetuning, suggesting the difficulty of classical transfer learning in the very small sample regime. The multilayer meta-matching model is publicly available at GITHUB_LINK.

Functional brain networks are associated with both sex and gender in children.

Sex and gender are associated with human behavior throughout the lifespan and across health and disease, but whether they are associated with similar or distinct neural phenotypes is unknown. Here, we demonstrate that, in children, sex and gender are uniquely reflected in the intrinsic functional connectivity of the brain. Unimodal networks are more strongly associated with sex while heteromodal networks are more strongly associated with gender. These results suggest sex and gender are irreducible to one another not only in society but also in biology.

Controversies and progress on standardization of large-scale brain network nomenclature.

Progress in scientific disciplines is accompanied by standardization of terminology. Network neuroscience, at the level of macroscale organization of the brain, is beginning to confront the challenges associated with developing a taxonomy of its fundamental explanatory constructs. The Workgroup for HArmonized Taxonomy of NETworks (WHATNET) was formed in 2020 as an Organization for Human Brain Mapping (OHBM)-endorsed best practices committee to provide recommendations on points of consensus, identify open questions, and highlight areas of ongoing debate in the service of moving the field toward standardized reporting of network neuroscience results. The committee conducted a survey to catalog current practices in large-scale brain network nomenclature. A few well-known network names (e.g., default mode network) dominated responses to the survey, and a number of illuminating points of disagreement emerged. We summarize survey results and provide initial considerations and recommendations from the workgroup. This perspective piece includes a selective review of challenges to this enterprise, including (1) network scale, resolution, and hierarchies; (2) interindividual variability of networks; (3) dynamics and nonstationarity of networks; (4) consideration of network affiliations of subcortical structures; and (5) consideration of multimodal information. We close with minimal reporting guidelines for the cognitive and network neuroscience communities to adopt.

The arrow of time of brain signals in cognition: Potential intriguing role of parts of the default mode network.

A promising idea in human cognitive neuroscience is that the default mode network (DMN) is responsible for coordinating the recruitment and scheduling of networks for computing and solving task-specific cognitive problems. This is supported by evidence showing that the physical and functional distance of DMN regions is maximally removed from sensorimotor regions containing environment-driven neural activity directly linked to perception and action, which would allow the DMN to orchestrate complex cognition from the top of the hierarchy. However, discovering the functional hierarchy of brain dynamics requires finding the best way to measure interactions between brain regions. In contrast to previous methods measuring the hierarchical flow of information using, for example, transfer entropy, here we used a thermodynamics-inspired, deep learning based Temporal Evolution NETwork (TENET) framework to assess the asymmetry in the flow of events, 'arrow of time', in human brain signals. This provides an alternative way of quantifying hierarchy, given that the arrow of time measures the directionality of information flow that leads to a breaking of the balance of the underlying hierarchy. In turn, the arrow of time is a measure of nonreversibility and thus nonequilibrium in brain dynamics. When applied to large-scale Human Connectome Project (HCP) neuroimaging data from close to a thousand participants, the TENET framework suggests that the DMN plays a significant role in orchestrating the hierarchy, that is, levels of nonreversibility, which changes between the resting state and when performing seven different cognitive tasks. Furthermore, this quantification of the hierarchy of the resting state is significantly different in health compared to neuropsychiatric disorders. Overall, the present thermodynamics-based machine-learning framework provides vital new insights into the fundamental tenets of brain dynamics for orchestrating the interactions between cognition and brain in complex environments.

Nocturnal Blood Pressure Estimation from Sleep Plethysmography Using Machine Learning.

BACKGROUND: Elevated nocturnal blood pressure (BP) is a risk factor for cardiovascular disease (CVD) and mortality. Cuffless BP assessment aided by machine learning could be a desirable alternative to traditional cuff-based methods for monitoring BP during sleep. We describe a machine-learning-based algorithm for predicting nocturnal BP using single-channel fingertip plethysmography (PPG) in healthy adults. METHODS: Sixty-eight healthy adults with no apparent sleep or CVD (53% male), with a median (IQR) age of 29 (23-46 years), underwent overnight polysomnography (PSG) with fingertip PPG and ambulatory blood pressure monitoring (ABPM). Features based on pulse morphology were extracted from the PPG waveforms. Random forest models were used to predict night-time systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: Our model achieved the highest out-of-sample performance with a window length of 7 s across window lengths explored (60 s, 30 s, 15 s, 7 s, and 3 s). The mean absolute error (MAE ± STD) was 5.72 ± 4.51 mmHg for SBP and 4.52 ± 3.60 mmHg for DBP. Similarly, the root mean square error (RMSE ± STD) was 6.47 ± 1.88 mmHg for SBP and 4.62 ± 1.17 mmHg for DBP. The mean correlation coefficient between measured and predicted values was 0.87 for SBP and 0.86 for DBP. Based on Shapley additive explanation (SHAP) values, the most important PPG waveform feature was the stiffness index, a marker that reflects the change in arterial stiffness. CONCLUSION: Our results highlight the potential of machine learning-based nocturnal BP prediction using single-channel fingertip PPG in healthy adults. The accuracy of the predictions demonstrated that our cuffless method was able to capture the dynamic and complex relationship between PPG waveform characteristics and BP during sleep, which may provide a scalable, convenient, economical, and non-invasive means to continuously monitor blood pressure.

Within-Individual Organization of the Human Cerebral Cortex: Networks, Global Topography, and Function.

The human cerebral cortex is populated by specialized regions that are organized into networks. Here we estimated networks using a Multi-Session Hierarchical Bayesian Model (MS-HBM) applied to intensively sampled within-individual functional MRI (fMRI) data. The network estimation procedure was initially developed and tested in two participants (each scanned 31 times) and then prospectively applied to 15 new participants (each scanned 8 to 11 times). Detailed analysis of the networks revealed a global organization. Locally organized first-order sensory and motor networks were surrounded by spatially adjacent second-order networks that also linked to distant regions. Third-order networks each possessed regions distributed widely throughout association cortex. Moreover, regions of distinct third-order networks displayed side-by-side juxtapositions with a pattern that repeated similarly across multiple cortical zones. We refer to these as Supra-Areal Association Megaclusters (SAAMs). Within each SAAM, two candidate control regions were typically adjacent to three separate domain-specialized regions. Independent task data were analyzed to explore functional response properties. The somatomotor and visual first-order networks responded to body movements and visual stimulation, respectively. A subset of the second-order networks responded to transients in an oddball detection task, consistent with a role in orienting to salient or novel events. The third-order networks, including distinct regions within each SAAM, showed two levels of functional specialization. Regions linked to candidate control networks responded to working memory load across multiple stimulus domains. The remaining regions within each SAAM did not track working memory load but rather dissociated across language, social, and spatial / episodic processing domains. These results support a model of the cerebral cortex in which progressively higher-order networks nest outwards from primary sensory and motor cortices. Within the apex zones of association cortex there is specialization of large-scale networks that divides domain-flexible from domain-specialized regions repeatedly across parietal, temporal, and prefrontal cortices. We discuss implications of these findings including how repeating organizational motifs may emerge during development.

A critical period plasticity framework for the sensorimotor-association axis of cortical neurodevelopment.

To understand human brain development it is necessary to describe not only the spatiotemporal patterns of neurodevelopment but also the neurobiological mechanisms that underlie them. Human neuroimaging studies have provided evidence for a hierarchical sensorimotor-to-association (S-A) axis of cortical neurodevelopment. Understanding the biological mechanisms that underlie this program of development using traditional neuroimaging approaches has been challenging. Animal models have been used to identify periods of enhanced experience-dependent plasticity - 'critical periods' - that progress along cortical hierarchies and are governed by a conserved set of neurobiological mechanisms that promote and then restrict plasticity. In this review we hypothesize that the S-A axis of cortical development in humans is partly driven by the cascading maturation of critical period plasticity mechanisms. We then describe how recent advances in in vivo neuroimaging approaches provide a promising path toward testing this hypothesis by linking signals derived from non-invasive imaging to critical period mechanisms.

The impact of regional heterogeneity in whole-brain dynamics in the presence of oscillations.

Large variability exists across brain regions in health and disease, considering their cellular and molecular composition, connectivity, and function. Large-scale whole-brain models comprising coupled brain regions provide insights into the underlying dynamics that shape complex patterns of spontaneous brain activity. In particular, biophysically grounded mean-field whole-brain models in the asynchronous regime were used to demonstrate the dynamical consequences of including regional variability. Nevertheless, the role of heterogeneities when brain dynamics are supported by synchronous oscillating state, which is a ubiquitous phenomenon in brain, remains poorly understood. Here, we implemented two models capable of presenting oscillatory behavior with different levels of abstraction: a phenomenological Stuart-Landau model and an exact mean-field model. The fit of these models informed by structural- to functional-weighted MRI signal (T1w/T2w) allowed us to explore the implication of the inclusion of heterogeneities for modeling resting-state fMRI recordings from healthy participants. We found that disease-specific regional functional heterogeneity imposed dynamical consequences within the oscillatory regime in fMRI recordings from neurodegeneration with specific impacts on brain atrophy/structure (Alzheimer's patients). Overall, we found that models with oscillations perform better when structural and functional regional heterogeneities are considered, showing that phenomenological and biophysical models behave similarly at the brink of the Hopf bifurcation.

Distinct brain network features predict internalizing and externalizing traits in children and adults.

Internalizing and externalizing traits are two distinct classes of behaviors in psychiatry. However, whether shared or unique brain network features predict internalizing and externalizing behaviors in children and adults remain poorly understood. Using a sample of 2262 children from the Adolescent Brain Cognitive Development (ABCD) study and 752 adults from the Human Connectome Project (HCP), we show that network features predicting internalizing and externalizing behavior are, at least in part, dissociable in children, but not in adults. In ABCD children, traits within internalizing and externalizing behavioral categories are predicted by more similar network features concatenated across task and resting states than those between different categories. We did not observe this pattern in HCP adults. Distinct network features predict internalizing and externalizing behaviors in ABCD children and HCP adults. These data reveal shared and unique brain network features accounting for individual variation within broad internalizing and externalizing categories across developmental stages.

Language network lateralization is reflected throughout the macroscale functional organization of cortex.

Hemispheric specialization is a fundamental feature of human brain organization. However, it is not yet clear to what extent the lateralization of specific cognitive processes may be evident throughout the broad functional architecture of cortex. While the majority of people exhibit left-hemispheric language dominance, a substantial minority of the population shows reverse lateralization. Using twin and family data from the Human Connectome Project, we provide evidence that atypical language dominance is associated with global shifts in cortical organization. Individuals with atypical language organization exhibit corresponding hemispheric differences in the macroscale functional gradients that situate discrete large-scale networks along a continuous spectrum, extending from unimodal through association territories. Analyses reveal that both language lateralization and gradient asymmetries are, in part, driven by genetic factors. These findings pave the way for a deeper understanding of the origins and relationships linking population-level variability in hemispheric specialization and global properties of cortical organization.