Functional network modules overlap and are linked to interindividual connectome differences during human brain development.

The modular structure of functional connectomes in the human brain undergoes substantial reorganization during development. However, previous studies have implicitly assumed that each region participates in one single module, ignoring the potential spatial overlap between modules. How the overlapping functional modules develop and whether this development is related to gray and white matter features remain unknown. Using longitudinal multimodal structural, functional, and diffusion MRI data from 305 children (aged 6 to 14 years), we investigated the maturation of overlapping modules of functional networks and further revealed their structural associations. An edge-centric network model was used to identify the overlapping modules, and the nodal overlap in module affiliations was quantified using the entropy measure. We showed a regionally heterogeneous spatial topography of the overlapping extent of brain nodes in module affiliations in children, with higher entropy (i.e., more module involvement) in the ventral attention, somatomotor, and subcortical regions and lower entropy (i.e., less module involvement) in the visual and default-mode regions. The overlapping modules developed in a linear, spatially dissociable manner, with decreased entropy (i.e., decreased module involvement) in the dorsomedial prefrontal cortex, ventral prefrontal cortex, and putamen and increased entropy (i.e., increased module involvement) in the parietal lobules and lateral prefrontal cortex. The overlapping modular patterns captured individual brain maturity as characterized by chronological age and were predicted by integrating gray matter morphology and white matter microstructural properties. Our findings highlight the maturation of overlapping functional modules and their structural substrates, thereby advancing our understanding of the principles of connectome development.

Interference of default mode on attention networks in adults with attention-deficit/hyperactivity disorder and its association with genetic variants and treatment outcomes.

AIMS: Altered brain functional connectivity has been proposed as the neurobiological underpinnings of attention-deficit/hyperactivity disorder (ADHD), and the default mode interference hypothesis is one of the most popular neuropsychological models. Here, we explored whether this hypothesis is supported in adults with ADHD and the association with high-risk genetic variants and treatment outcomes. METHODS: Voxel-based whole-brain connectome analysis was conducted on resting-state functional MRI data from 84 adults with ADHD and 89 healthy controls to identify functional connectivity substrates corresponding to ADHD-related alterations. The candidate genetic variants and 12-week cognitive behavioral therapy data were leveraged from the same population to assess these associations. RESULTS: We detected breakdowns of functional connectivity in the precuneus and left middle temporal gyrus in adults with ADHD, with exact contributions from decreased connectivity within the default mode, dorsal and ventral attention networks, as well as increased connectivity among them with the middle temporal gyrus serving as a crucial 'bridge'. Additionally, significant associations between the altered functional connectivity and genetic variants in both MAOA and MAOB were detected. Treatment restored brain function, with the amelioration of connectivity of the middle temporal gyrus, accompanied by improvements in ADHD core symptoms. CONCLUSIONS: These findings support the interference of default mode on attention in adults with ADHD and its association with genetic risk variants and clinical management, providing insights into the underlying pathogenesis of ADHD and potential biomarkers for treatment evaluation.

Development of segregation and integration of functional connectomes during the first 1,000 days.

The first 1,000 days of human life lay the foundation for brain development and later cognitive growth. However, the developmental rules of the functional connectome during this critical period remain unclear. Using high-resolution, longitudinal, task-free functional magnetic resonance imaging data from 930 scans of 665 infants aged 28 postmenstrual weeks to 3 years, we report the early maturational process of connectome segregation and integration. We show the dominant development of local connections alongside a few global connections, the shift of brain hubs from primary regions to high-order association cortices, the developmental divergence of network segregation and integration along the anterior-posterior axis, the prediction of neurocognitive outcomes, and their associations with gene expression signatures of microstructural development and neuronal metabolic pathways. These findings advance our understanding of the principles of connectome remodeling during early life and its neurobiological underpinnings and have implications for studying typical and atypical development.

Development of neonatal connectome dynamics and its prediction for cognitive and language outcomes at age 2.

The functional brain connectome is highly dynamic over time. However, how brain connectome dynamics evolves during the third trimester of pregnancy and is associated with later cognitive growth remains unknown. Here, we use resting-state functional Magnetic Resonance Imaging (MRI) data from 39 newborns aged 32 to 42 postmenstrual weeks to investigate the maturation process of connectome dynamics and its role in predicting neurocognitive outcomes at 2 years of age. Neonatal brain dynamics is assessed using a multilayer network model. Network dynamics decreases globally but increases in both modularity and diversity with development. Regionally, module switching decreases with development primarily in the lateral precentral gyrus, medial temporal lobe, and subcortical areas, with a higher growth rate in primary regions than in association regions. Support vector regression reveals that neonatal connectome dynamics is predictive of individual cognitive and language abilities at 2  years of age. Our findings highlight network-level neural substrates underlying early cognitive development.

Structural connectome architecture shapes the maturation of cortical morphology from childhood to adolescence.

Cortical thinning is an important hallmark of the maturation of brain morphology during childhood and adolescence. However, the connectome-based wiring mechanism that underlies cortical maturation remains unclear. Here, we show cortical thinning patterns primarily located in the lateral frontal and parietal heteromodal nodes during childhood and adolescence, which are structurally constrained by white matter network architecture and are particularly represented using a network-based diffusion model. Furthermore, connectome-based constraints are regionally heterogeneous, with the largest constraints residing in frontoparietal nodes, and are associated with gene expression signatures of microstructural neurodevelopmental events. These results are highly reproducible in another independent dataset. These findings advance our understanding of network-level mechanisms and the associated genetic basis that underlies the maturational process of cortical morphology during childhood and adolescence.

Functional connectome through the human life span.

The functional connectome of the human brain represents the fundamental network architecture of functional interdependence in brain activity, but its normative growth trajectory across the life course remains unknown. Here, we aggregate the largest, quality-controlled multimodal neuroimaging dataset from 119 global sites, including 33,809 task-free fMRI and structural MRI scans from 32,328 individuals ranging in age from 32 postmenstrual weeks to 80 years. Lifespan growth charts of the connectome are quantified at the whole cortex, system, and regional levels using generalized additive models for location, scale, and shape. We report critical inflection points in the non-linear growth trajectories of the whole-brain functional connectome, particularly peaking in the fourth decade of life. Having established the first fine-grained, lifespan-spanning suite of system-level brain atlases, we generate person-specific parcellation maps and further show distinct maturation timelines for functional segregation within different subsystems. We identify a spatiotemporal gradient axis that governs the life-course growth of regional connectivity, transitioning from primary sensory cortices to higher-order association regions. Using the connectome-based normative model, we demonstrate substantial individual heterogeneities at the network level in patients with autism spectrum disorder and patients with major depressive disorder. Our findings shed light on the life-course evolution of the functional connectome and serve as a normative reference for quantifying individual variation in patients with neurological and psychiatric disorders.

Leading basic modes of spontaneous activity drive individual functional connectivity organization in the resting human brain.

Spontaneous activity of the human brain provides a window to explore intrinsic principles of functional organization. However, most studies have focused on interregional functional connectivity. The principles underlying rich repertoires of instantaneous activity remain largely unknown. We apply a recently proposed eigen-microstate analysis to three resting-state functional MRI datasets to identify basic modes that represent fundamental activity patterns that coexist over time. We identify five leading basic modes that dominate activity fluctuations. Each mode exhibits a distinct functional system-dependent coactivation pattern and corresponds to specific cognitive profiles. In particular, the spatial pattern of the first leading basis mode shows the separation of activity between the default-mode and primary and attention regions. Based on theoretical modelling, we further reconstruct individual functional connectivity as the weighted superposition of coactivation patterns corresponding to these leading basic modes. Moreover, these leading basic modes capture sleep deprivation-induced changes in brain activity and interregional connectivity, primarily involving the default-mode and task-positive regions. Our findings reveal a dominant set of basic modes of spontaneous activity that reflect multiplexed interregional coordination and drive conventional functional connectivity, furthering the understanding of the functional significance of spontaneous brain activity.

Frequency-resolved connectome alterations in major depressive disorder: A multisite resting fMRI study.

BACKGROUND: Functional connectome studies have revealed widespread connectivity alterations in major depressive disorder (MDD). However, the low frequency bandpass filtering (0.01-0.08 Hz or 0.01-0.1 Hz) in most studies have impeded our understanding on whether and how these alterations are affected by frequency of interest. METHODS: Here, we performed frequency-resolved (0.01-0.06 Hz, 0.06-0.16 Hz and 0.16-0.24 Hz) connectome analyses using a large-sample resting-state functional MRI dataset of 1002 MDD patients and 924 healthy controls from seven independent centers. RESULTS: We reported significant frequency-dependent connectome alterations in MDD in left inferior parietal, inferior temporal, precentral, and fusiform cortices and bilateral precuneus. These frequency-dependent connectome alterations are mainly derived by abnormalities of medium- and long-distance connections and are brain network-dependent. Moreover, the connectome alteration of left precuneus in high frequency band (0.16-0.24 Hz) is significantly associated with illness duration. LIMITATIONS: Multisite harmonization model only removed linear site effects. Neurobiological underpinning of alterations in higher frequency (0.16-0.24 Hz) should be further examined by combining fMRI data with respiration, heartbeat and blood flow recordings in future studies. CONCLUSIONS: These results highlight the frequency-dependency of connectome alterations in MDD and the benefit of examining connectome alteration in MDD under a wider frequency band.

Different computational relations in language are captured by distinct brain systems.

A critical way for humans to acquire information is through language, yet whether and how language experience drives specific neural semantic representations is still poorly understood. We considered statistical properties captured by 3 different computational principles of language (simple co-occurrence, network-(graph)-topological relations, and neural-network-vector-embedding relations) and tested the extent to which they can explain the neural patterns of semantic representations, measured by 2 functional magnetic resonance imaging experiments that shared common semantic processes. Distinct graph-topological word relations, and not simple co-occurrence or neural-network-vector-embedding relations, had unique explanatory power for the neural patterns in the anterior temporal lobe (capturing graph-common-neighbors), inferior frontal gyrus, and posterior middle/inferior temporal gyrus (capturing graph-shortest-path). These results were relatively specific to language: they were not explained by sensory-motor similarities and the same computational relations of visual objects (based on visual image database) showed effects in the visual cortex in the picture naming experiment. That is, different topological properties within language and the same topological computations (common-neighbors) for language and visual inputs are captured by different brain regions. These findings reveal the specific neural semantic representations along graph-topological properties of language, highlighting the information type-specific and statistical property-specific manner of semantic representations in the human brain.

3D-MASNet: 3D mixed-scale asymmetric convolutional segmentation network for 6-month-old infant brain MR images.

Precise segmentation of infant brain magnetic resonance (MR) images into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) are essential for studying neuroanatomical hallmarks of early brain development. However, for 6-month-old infants, the extremely low-intensity contrast caused by inherent myelination hinders accurate tissue segmentation. Existing convolutional neural networks (CNNs) based segmentation models for this task generally employ single-scale symmetric convolutions, which are inefficient for encoding the isointense tissue boundaries in baby brain images. Here, we propose a 3D mixed-scale asymmetric convolutional segmentation network (3D-MASNet) framework for brain MR images of 6-month-old infants. We replaced the traditional convolutional layer of an existing to-be-trained network with a 3D mixed-scale convolution block consisting of asymmetric kernels (MixACB) during the training phase and then equivalently converted it into the original network. Five canonical CNN segmentation models were evaluated using both T1- and T2-weighted images of 23 6-month-old infants from iSeg-2019 datasets, which contained manual labels as ground truth. MixACB significantly enhanced the average accuracy of all five models and obtained the most considerable improvement in the fully convolutional network model (CC-3D-FCN) and the highest performance in the Dense U-Net model. This approach further obtained Dice coefficient accuracies of 0.931, 0.912, and 0.961 in GM, WM, and CSF, respectively, ranking first among 30 teams on the validation dataset of the iSeg-2019 Grand Challenge. Thus, the proposed 3D-MASNet can improve the accuracy of existing CNNs-based segmentation models as a plug-and-play solution that offers a promising technique for future infant brain MRI studies.

Development of functional connectome gradients during childhood and adolescence.

Connectome mapping studies have documented a principal primary-to-transmodal gradient in the adult brain network, capturing a functional spectrum that ranges from perception and action to abstract cognition. However, how this gradient pattern develops and whether its development is linked to cognitive growth, topological reorganization, and gene expression profiles remain largely unknown. Using longitudinal resting-state functional magnetic resonance imaging data from 305 children (aged 6-14 years), we describe substantial changes in the primary-to-transmodal gradient between childhood and adolescence, including emergence as the principal gradient, expansion of global topography, and focal tuning in primary and default-mode regions. These gradient changes are mediated by developmental changes in network integration and segregation, and are associated with abstract processing functions such as working memory and expression levels of calcium ion regulated exocytosis and synaptic transmission-related genes. Our findings have implications for understanding connectome maturation principles in normal development and developmental disorders.

Meta-connectomic analysis maps consistent, reproducible, and transcriptionally relevant functional connectome hubs in the human brain.

Human brain connectomes include sets of densely connected hub regions. However, the consistency and reproducibility of functional connectome hubs have not been established to date and the genetic signatures underlying robust hubs remain unknown. Here, we conduct a worldwide harmonized meta-connectomic analysis by pooling resting-state functional MRI data of 5212 healthy young adults across 61 independent cohorts. We identify highly consistent and reproducible connectome hubs in heteromodal and unimodal regions both across cohorts and across individuals, with the greatest effects observed in lateral parietal cortex. These hubs show heterogeneous connectivity profiles and are critical for both intra- and inter-network communications. Using post-mortem transcriptome datasets, we show that as compared to non-hubs, connectome hubs have a spatiotemporally distinctive transcriptomic pattern dominated by genes involved in the neuropeptide signaling pathway, neurodevelopmental processes, and metabolic processes. These results highlight the robustness of macroscopic connectome hubs and their potential cellular and molecular underpinnings, which markedly furthers our understanding of how connectome hubs emerge in development, support complex cognition in health, and are involved in disease.

Structural insight into the individual variability architecture of the functional brain connectome.

Human cognition and behaviors depend upon the brain's functional connectomes, which vary remarkably across individuals. However, whether and how the functional connectome individual variability architecture is structurally constrained remains largely unknown. Using tractography- and morphometry-based network models, we observed the spatial convergence of structural and functional connectome individual variability, with higher variability in heteromodal association regions and lower variability in primary regions. We demonstrated that functional variability is significantly predicted by a unifying structural variability pattern and that this prediction follows a primary-to-heteromodal hierarchical axis, with higher accuracy in primary regions and lower accuracy in heteromodal regions. We further decomposed group-level connectome variability patterns into individual unique contributions and uncovered the structural-functional correspondence that is associated with individual cognitive traits. These results advance our understanding of the structural basis of individual functional variability and suggest the importance of integrating multimodal connectome signatures for individual differences in cognition and behaviors.

Alterations in Connectome Dynamics in Autism Spectrum Disorder: A Harmonized Mega- and Meta-analysis Study Using the Autism Brain Imaging Data Exchange Dataset.

BACKGROUND: Neuroimaging studies have reported functional connectome aberrancies in autism spectrum disorder (ASD). However, the time-varying patterns of connectome topology in individuals with ASD and the connection between these patterns and gene expression profiles remain unknown. METHODS: To investigate case-control differences in dynamic connectome topology, we conducted mega- and meta-analyses of resting-state functional magnetic resonance imaging data of 939 participants (440 patients with ASD and 499 healthy control subjects, all males) from 18 independent sites, selected from the Autism Brain Imaging Data Exchange (ABIDE) dataset. Functional data were preprocessed and analyzed using harmonized protocols, and brain module dynamics was assessed using a multilayer network model. We further leveraged postmortem brain-wide gene expression data to identify transcriptomic signatures associated with ASD-related alterations in brain dynamics. RESULTS: Compared with healthy control participants, individuals with ASD exhibited a higher global mean and lower standard deviation of whole-brain module dynamics, indicating an unstable and less regionally differentiated pattern. More specifically, individuals with ASD showed higher module switching, primarily in the medial prefrontal cortex, posterior cingulate gyrus, and angular gyrus, and lower switching in the visual regions. These alterations in brain dynamics were predictive of social impairments in individuals with ASD and were linked with expression profiles of genes primarily involved in the regulation of neurotransmitter transport and secretion as well as with previously identified autism-related genes. CONCLUSIONS: This study is the first to identify consistent alterations in brain network dynamics in ASD and the transcriptomic signatures related to those alterations, furthering insights into the biological basis behind this disorder.

Frequency-Resolved Connectome Hubs and Their Test-Retest Reliability in the Resting Human Brain.

Functional hubs with disproportionately extensive connectivities play a crucial role in global information integration in human brain networks. However, most resting-state functional magnetic resonance imaging (R-fMRI) studies have identified functional hubs by examining spontaneous fluctuations of the blood oxygen level-dependent signal within a typical low-frequency band (e.g., 0.01-0.08 Hz or 0.01-0.1 Hz). Little is known about how the spatial distributions of functional hubs depend on frequency bands of interest. Here, we used repeatedly measured R-fMRI data from 53 healthy young adults and a degree centrality analysis to identify voxelwise frequency-resolved functional hubs and further examined their test-retest reliability across two sessions. We showed that a wide-range frequency band (0.01-0.24 Hz) accessible with a typical sampling rate (fsample = 0.5 Hz) could be classified into three frequency bands with distinct patterns, namely, low-frequency (LF, 0.01-0.06 Hz), middle-frequency (MF, 0.06-0.16 Hz), and high-frequency (HF, 0.16-0.24 Hz) bands. The functional hubs were mainly located in the medial and lateral frontal and parietal cortices in the LF band, and in the medial prefrontal cortex, superior temporal gyrus, parahippocampal gyrus, amygdala, and several cerebellar regions in the MF and HF bands. These hub regions exhibited fair to good test-retest reliability, regardless of the frequency band. The presence of the three frequency bands was well replicated using an independent R-fMRI dataset from 45 healthy young adults. Our findings demonstrate reliable frequency-resolved functional connectivity hubs in three categories, thus providing insights into the frequency-specific connectome organization in healthy and disordered brains.

Progressive Stabilization of Brain Network Dynamics during Childhood and Adolescence.

Functional brain networks require dynamic reconfiguration to support flexible cognitive function. However, the developmental principles shaping brain network dynamics remain poorly understood. Here, we report the longitudinal development of large-scale brain network dynamics during childhood and adolescence, and its connection with gene expression profiles. Using a multilayer network model, we show the temporally varying modular architecture of child brain networks, with higher network switching primarily in the association cortex and lower switching in the primary regions. This topographical profile exhibits progressive maturation, which manifests as reduced modular dynamics, particularly in the transmodal (e.g., default-mode and frontoparietal) and sensorimotor regions. These developmental refinements mediate age-related enhancements of global network segregation and are linked with the expression profiles of genes associated with the enrichment of ion transport and nucleobase-containing compound transport. These results highlight a progressive stabilization of brain dynamics, which expand our understanding of the neural mechanisms that underlie cognitive development.

Individual Uniqueness in the Neonatal Functional Connectome.

The functional connectome is highly distinctive in adults and adolescents, underlying individual differences in cognition and behavior. However, it remains unknown whether the individual uniqueness of the functional connectome is present in neonates, who are far from mature. Here, we utilized the multiband resting-state functional magnetic resonance imaging data of 40 healthy neonates from the Developing Human Connectome Project and a split-half analysis approach to characterize the uniqueness of the functional connectome in the neonatal brain. Through functional connectome-based individual identification analysis, we found that all the neonates were correctly identified, with the most discriminative regions predominantly confined to the higher-order cortices (e.g., prefrontal and parietal regions). The connectivities with the highest contributions to individual uniqueness were primarily located between different functional systems, and the short- (0-30 mm) and middle-range (30-60 mm) connectivities were more distinctive than the long-range (>60 mm) connectivities. Interestingly, we found that functional data with a scanning length longer than 3.5 min were able to capture the individual uniqueness in the functional connectome. Our results highlight that individual uniqueness is present in the functional connectome of neonates and provide insights into the brain mechanisms underlying individual differences in cognition and behavior later in life.

Association of aerobic glycolysis with the structural connectome reveals a benefit-risk balancing mechanism in the human brain.

Aerobic glycolysis (AG), that is, the nonoxidative metabolism of glucose, contributes significantly to anabolic pathways, rapid energy generation, task-induced activity, and neuroprotection; yet high AG is also associated with pathological hallmarks such as amyloid-ß deposition. An important yet unresolved question is whether and how the metabolic benefits and risks of brain AG is structurally shaped by connectome wiring. Using positron emission tomography and magnetic resonance imaging techniques as well as computational models, we investigate the relationship between brain AG and the macroscopic connectome. Specifically, we propose a weighted regional distance-dependent model to estimate the total axonal projection length of a brain node. This model has been validated in a macaque connectome derived from tract-tracing data and shows a high correspondence between experimental and estimated axonal lengths. When applying this model to the human connectome, we find significant associations between the estimated total axonal projection length and AG across brain nodes, with higher levels primarily located in the default-mode and prefrontal regions. Moreover, brain AG significantly mediates the relationship between the structural and functional connectomes. Using a wiring optimization model, we find that the estimated total axonal projection length in these high-AG regions exhibits a high extent of wiring optimization. If these high-AG regions are randomly rewired, their total axonal length and vulnerability risk would substantially increase. Together, our results suggest that high-AG regions have expensive but still optimized wiring cost to fulfill metabolic requirements and simultaneously reduce vulnerability risk, thus revealing a benefit-risk balancing mechanism in the human brain.

Development of the default-mode network during childhood and adolescence: A longitudinal resting-state fMRI study.

The default-mode network (DMN) is a set of functionally connected regions that play crucial roles in internal cognitive processing. Previous resting-state fMRI studies have demonstrated that the intrinsic functional organization of the DMN undergoes remarkable reconfigurations during childhood and adolescence. However, these studies have mainly focused on cross-sectional designs with small sample sizes, limiting the consistency and interpretations of the findings. Here, we used a large sample of longitudinal resting-state fMRI data comprising 305 typically developing children (6-12 years of age at baseline, 491 scans in total) and graph theoretical approaches to delineate the developmental trajectories of the functional architecture of the DMN. For each child, the DMN was constructed according to a prior parcellation with 32 brain nodes. We showed that the overall connectivity increased in strength from childhood to adolescence and became spatially similar to that in the young adult group (N = 61, 18-28 years of age). These increases were primarily located in the midline structures. Global and local network efficiency in the DMN also increased with age, indicating an enhanced capability in parallel information communication within the brain system. Based on the divergent developmental rates of nodal centrality, we identified three subclusters within the DMN, with the fastest rates in the cluster mainly comprising the anterior medial prefrontal cortex and posterior cingulate cortex. Together, our findings highlight the developmental patterns of the functional architecture in the DMN from childhood to adolescence, which has implications for the understanding of network mechanisms underlying the cognitive development of individuals.

The spatial organization of the chronnectome associates with cortical hierarchy and transcriptional profiles in the human brain.

The chronnectome of the human brain represents dynamic connectivity patterns of brain networks among interacting regions, but its organization principle and related transcriptional signatures remain unclear. Using task-free fMRI data from the Human Connectome Project (681 participants) and microarray-based gene expression data from the Allen Institute for Brain Science (1791 brain tissue samples from six donors), we conduct a transcriptome-chronnectome association study to investigate the spatial configurations of dynamic brain networks and their linkages with transcriptional profiles. We first classify the dynamic brain networks into four categories of nodes according to their time-varying characteristics in global connectivity and modular switching: the primary sensorimotor regions with large global variations, the paralimbic/limbic regions with frequent modular switching, the frontoparietal cortex with both high global and modular dynamics, and the sensorimotor association cortex with limited dynamics. Such a spatial layout reflects the cortical functional hierarchy, microarchitecture, and primary connectivity gradient spanning from primary to transmodal areas, and the cognitive spectrum from perception to abstract processing. Importantly, the partial least squares regression analysis reveals that the transcriptional profiles could explain 28% of the variation in this spatial layout of network dynamics. The top-related genes in the transcriptional profiles are enriched for potassium ion channel complex and activity and mitochondrial part of the cellular component. These findings highlight the hierarchically spatial arrangement of dynamic brain networks and their coupling with the variation in transcriptional signatures, which provides indispensable implications for the organizational principle and cellular and molecular functions of spontaneous network dynamics.