Connectome-wide structure-function coupling models implicate polysynaptic alterations in autism.

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diagnoses. Although incompletely understood, structural and functional network alterations are increasingly recognized to be at the core of the condition. We utilized multimodal imaging and connectivity modeling to study structure-function coupling in ASD and probed mono- and polysynaptic mechanisms on structurally-governed network function. We examined multimodal magnetic resonance imaging data in 80 ASD and 61 neurotypical controls from the Autism Brain Imaging Data Exchange (ABIDE) II initiative. We predicted intrinsic functional connectivity from structural connectivity data in each participant using a Riemannian optimization procedure that varies the times that simulated signals can unfold along tractography-derived personalized connectomes. In both ASD and neurotypical controls, we observed improved structure-function prediction at longer diffusion time scales, indicating better modeling of brain function when polysynaptic mechanisms are accounted for. Prediction accuracy differences (∆prediction accuracy) were marked in transmodal association systems, such as the default mode network, in both neurotypical controls and ASD. Differences were, however, lower in ASD in a polysynaptic regime at higher simulated diffusion times. We compared regional differences in ∆prediction accuracy between both groups to assess the impact of polysynaptic communication on structure-function coupling. This analysis revealed that between-group differences in ∆prediction accuracy followed a sensory-to-transmodal cortical hierarchy, with an increased gap between controls and ASD in transmodal compared to sensory/motor systems. Multivariate associative techniques revealed that structure-function differences reflected inter-individual differences in autistic symptoms and verbal as well as non-verbal intelligence. Our network modeling approach sheds light on atypical structure-function coupling in autism, and suggests that polysynaptic network mechanisms are implicated in the condition and that these can help explain its wide range of associated symptoms.

An automatic pipeline for atlas-based fetal and neonatal brain segmentation and analysis.

BACKGROUND AND OBJECTIVE: The automatic segmentation of perinatal brain structures in magnetic resonance imaging (MRI) is of utmost importance for the study of brain growth and related complications. While different methods exist for adult and pediatric MRI data, there is a lack for automatic tools for the analysis of perinatal imaging. METHODS: In this work, a new pipeline for fetal and neonatal segmentation has been developed. We also report the creation of two new fetal atlases, and their use within the pipeline for atlas-based segmentation, based on novel registration methods. The pipeline is also able to extract cortical and pial surfaces and compute features, such as curvature, local gyrification index, sulcal depth, and thickness. RESULTS: Results show that the introduction of the new templates together with our segmentation strategy leads to accurate results when compared to expert annotations, as well as better performances when compared to a reference pipeline (developing Human Connectome Project (dHCP)), for both early and late-onset fetal brains. CONCLUSIONS: These findings show the potential of the presented atlases and the whole pipeline for application in both fetal, neonatal, and longitudinal studies, which could lead to dramatic improvements in the understanding of perinatal brain development.

BrainStat: A toolbox for brain-wide statistics and multimodal feature associations.

Analysis and interpretation of neuroimaging datasets has become a multidisciplinary endeavor, relying not only on statistical methods, but increasingly on associations with respect to other brain-derived features such as gene expression, histological data, and functional as well as cognitive architectures. Here, we introduce BrainStat - a toolbox for (i) univariate and multivariate linear models in volumetric and surface-based brain imaging datasets, and (ii) multidomain feature association of results with respect to spatial maps of post-mortem gene expression and histology, task-based fMRI meta-analysis, as well as resting-state fMRI motifs across several common surface templates. The combination of statistics and feature associations into a turnkey toolbox streamlines analytical processes and accelerates cross-modal research. The toolbox is implemented in both Python and MATLAB, two widely used programming languages in the neuroimaging and neuroinformatics communities. BrainStat is openly available and complemented by an expandable documentation.

A convergent structure-function substrate of cognitive imbalances in autism.

BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental diagnosis showing substantial phenotypic heterogeneity. A leading example can be found in verbal and nonverbal cognitive skills, which vary from elevated to impaired compared with neurotypical individuals. Moreover, deficits in verbal profiles often coexist with normal or superior performance in the nonverbal domain. METHODS: To study brain substrates underlying cognitive imbalance in ASD, we capitalized categorical and dimensional IQ profiling as well as multimodal neuroimaging. RESULTS: IQ analyses revealed a marked verbal to nonverbal IQ imbalance in ASD across 2 datasets (Dataset-1: 155 ASD, 151 controls; Dataset-2: 270 ASD, 490 controls). Neuroimaging analysis in Dataset-1 revealed a structure-function substrate of cognitive imbalance, characterized by atypical cortical thickening and altered functional integration of language networks alongside sensory and higher cognitive areas. CONCLUSION: Although verbal and nonverbal intelligence have been considered as specifiers unrelated to autism diagnosis, our results indicate that intelligence disparities are accentuated in ASD and reflected by a consistent structure-function substrate affecting multiple brain networks. Our findings motivate the incorporation of cognitive imbalances in future autism research, which may help to parse the phenotypic heterogeneity and inform intervention-oriented subtyping in ASD.

Micapipe: A pipeline for multimodal neuroimaging and connectome analysis.

Multimodal magnetic resonance imaging (MRI) has accelerated human neuroscience by fostering the analysis of brain microstructure, geometry, function, and connectivity across multiple scales and in living brains. The richness and complexity of multimodal neuroimaging, however, demands processing methods to integrate information across modalities and to consolidate findings across different spatial scales. Here, we present micapipe, an open processing pipeline for multimodal MRI datasets. Based on BIDS-conform input data, micapipe can generate i) structural connectomes derived from diffusion tractography, ii) functional connectomes derived from resting-state signal correlations, iii) geodesic distance matrices that quantify cortico-cortical proximity, and iv) microstructural profile covariance matrices that assess inter-regional similarity in cortical myelin proxies. The above matrices can be automatically generated across established 18 cortical parcellations (100-1000 parcels), in addition to subcortical and cerebellar parcellations, allowing researchers to replicate findings easily across different spatial scales. Results are represented on three different surface spaces (native, conte69, fsaverage5), and outputs are BIDS-conform. Processed outputs can be quality controlled at the individual and group level. micapipe was tested on several datasets and is available at https://github.com/MICA-MNI/micapipe, documented at https://micapipe.readthedocs.io/, and containerized as a BIDS App http://bids-apps.neuroimaging.io/apps/. We hope that micapipe will foster robust and integrative studies of human brain microstructure, morphology, function, cand connectivity.

An Open MRI Dataset For Multiscale Neuroscience.

Multimodal neuroimaging grants a powerful window into the structure and function of the human brain at multiple scales. Recent methodological and conceptual advances have enabled investigations of the interplay between large-scale spatial trends (also referred to as gradients) in brain microstructure and connectivity, offering an integrative framework to study multiscale brain organization. Here, we share a multimodal MRI dataset for Microstructure-Informed Connectomics (MICA-MICs) acquired in 50 healthy adults (23 women; 29.54 ± 5.62 years) who underwent high-resolution T1-weighted MRI, myelin-sensitive quantitative T1 relaxometry, diffusion-weighted MRI, and resting-state functional MRI at 3 Tesla. In addition to raw anonymized MRI data, this release includes brain-wide connectomes derived from (i) resting-state functional imaging, (ii) diffusion tractography, (iii) microstructure covariance analysis, and (iv) geodesic cortical distance, gathered across multiple parcellation scales. Alongside, we share large-scale gradients estimated from each modality and parcellation scale. Our dataset will facilitate future research examining the coupling between brain microstructure, connectivity, and function. MICA-MICs is available on the Canadian Open Neuroscience Platform data portal ( https://portal.conp.ca ) and the Open Science Framework ( https://osf.io/j532r/ ).

Adolescent development of multiscale structural wiring and functional interactions in the human connectome.

Adolescence is a time of profound changes in the physical wiring and function of the brain. Here, we analyzed structural and functional brain network development in an accelerated longitudinal cohort spanning 14 to 25 y (n = 199). Core to our work was an advanced in vivo model of cortical wiring incorporating MRI features of corticocortical proximity, microstructural similarity, and white matter tractography. Longitudinal analyses assessing age-related changes in cortical wiring identified a continued differentiation of multiple corticocortical structural networks in youth. We then assessed structure-function coupling using resting-state functional MRI measures in the same participants both via cross-sectional analysis at baseline and by studying longitudinal change between baseline and follow-up scans. At baseline, regions with more similar structural wiring were more likely to be functionally coupled. Moreover, correlating longitudinal structural wiring changes with longitudinal functional connectivity reconfigurations, we found that increased structural differentiation, particularly between sensory/unimodal and default mode networks, was reflected by reduced functional interactions. These findings provide insights into adolescent development of human brain structure and function, illustrating how structural wiring interacts with the maturation of macroscale functional hierarchies.

A Riemannian approach to predicting brain function from the structural connectome.

Ongoing brain function is largely determined by the underlying wiring of the brain, but the specific rules governing this relationship remain unknown. Emerging literature has suggested that functional interactions between brain regions emerge from the structural connections through mono- as well as polysynaptic mechanisms. Here, we propose a novel approach based on diffusion maps and Riemannian optimization to emulate this dynamic mechanism in the form of random walks on the structural connectome and predict functional interactions as a weighted combination of these random walks. Our proposed approach was evaluated in two different cohorts of healthy adults (Human Connectome Project, HCP; Microstructure-Informed Connectomics, MICs). Our approach outperformed existing approaches and showed that performance plateaus approximately around the third random walk. At macroscale, we found that the largest number of walks was required in nodes of the default mode and frontoparietal networks, underscoring an increasing relevance of polysynaptic communication mechanisms in transmodal cortical networks compared to primary and unimodal systems.

Population heterogeneity in clinical cohorts affects the predictive accuracy of brain imaging.

Brain imaging research enjoys increasing adoption of supervised machine learning for single-participant disease classification. Yet, the success of these algorithms likely depends on population diversity, including demographic differences and other factors that may be outside of primary scientific interest. Here, we capitalize on propensity scores as a composite confound index to quantify diversity due to major sources of population variation. We delineate the impact of population heterogeneity on the predictive accuracy and pattern stability in 2 separate clinical cohorts: the Autism Brain Imaging Data Exchange (ABIDE, n = 297) and the Healthy Brain Network (HBN, n = 551). Across various analysis scenarios, our results uncover the extent to which cross-validated prediction performances are interlocked with diversity. The instability of extracted brain patterns attributable to diversity is located preferentially in regions part of the default mode network. Collectively, our findings highlight the limitations of prevailing deconfounding practices in mitigating the full consequences of population diversity.

Shared and distinct patterns of atypical cortical morphometry in children with autism and anxiety.

Autism spectrum disorder (ASD) and anxiety disorders (ANX) are common neurodevelopmental conditions with several overlapping symptoms. Notably, many children and adolescents with ASD also have an ANX diagnosis, suggesting shared pathological mechanisms. Here, we leveraged structural imaging and phenotypic data from 112 youth (33 ASD, 37 ANX, 42 typically developing controls) to assess shared and distinct cortical thickness patterns of the disorders. ANX was associated with widespread increases in cortical thickness, while ASD related to a mixed pattern of subtle increases and decreases across the cortical mantle. Despite the qualitative difference in the case-control contrasts, the statistical maps from the ANX-vs-controls and ASD-vs-controls analyses were significantly correlated when correcting for spatial autocorrelation. Dimensional analysis, regressing trait anxiety and social responsiveness against cortical thickness measures, partially recapitulated diagnosis-based findings. Collectively, our findings provide evidence for a common axis of neurodevelopmental disturbances as well as distinct effects of ASD and ANX on cortical thickness.

Connectivity alterations in autism reflect functional idiosyncrasy.

Autism spectrum disorder (ASD) is commonly understood as an alteration of brain networks, yet case-control analyses against typically-developing controls (TD) have yielded inconsistent results. Here, we devised a novel approach to profile the inter-individual variability in functional network organization and tested whether such idiosyncrasy contributes to connectivity alterations in ASD. Studying a multi-centric dataset with 157 ASD and 172 TD, we obtained robust evidence for increased idiosyncrasy in ASD relative to TD in default mode, somatomotor and attention networks, but also reduced idiosyncrasy in lateral temporal cortices. Idiosyncrasy increased with age and significantly correlated with symptom severity in ASD. Furthermore, while patterns of functional idiosyncrasy were not correlated with ASD-related cortical thickness alterations, they co-localized with the expression patterns of ASD risk genes. Notably, we could demonstrate that patterns of atypical idiosyncrasy in ASD closely overlapped with connectivity alterations that are measurable with conventional case-control designs and may, thus, be a principal driver of inconsistency in the autism connectomics literature. These findings support important interactions between inter-individual heterogeneity in autism and functional signatures. Our findings provide novel biomarkers to study atypical brain development and may consolidate prior research findings on the variable nature of connectome level anomalies in autism.

Structural Connectivity Gradients of the Temporal Lobe Serve as Multiscale Axes of Brain Organization and Cortical Evolution.

The temporal lobe is implicated in higher cognitive processes and is one of the regions that underwent substantial reorganization during primate evolution. Its functions are instantiated, in part, by the complex layout of its structural connections. Here, we identified low-dimensional representations of structural connectivity variations in human temporal cortex and explored their microstructural underpinnings and associations to macroscale function. We identified three eigenmodes which described gradients in structural connectivity. These gradients reflected inter-regional variations in cortical microstructure derived from quantitative magnetic resonance imaging and postmortem histology. Gradient-informed models accurately predicted macroscale measures of temporal lobe function. Furthermore, the identified gradients aligned closely with established measures of functional reconfiguration and areal expansion between macaques and humans, highlighting their potential role in shaping temporal lobe function throughout primate evolution. Findings were replicated in several datasets. Our results provide robust evidence for three axes of structural connectivity in human temporal cortex with consistent microstructural underpinnings and contributions to large-scale brain network function.

Differences in subcortico-cortical interactions identified from connectome and microcircuit models in autism.

The pathophysiology of autism has been suggested to involve a combination of both macroscale connectome miswiring and microcircuit anomalies. Here, we combine connectome-wide manifold learning with biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. We studied neuroimaging and phenotypic data in 47 individuals with autism and 37 typically developing controls obtained from the Autism Brain Imaging Data Exchange initiative. Our analysis establishes significant differences in structural connectome organization in individuals with autism relative to controls, with strong between-group effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models reveal that the degree of macroscale anomalies is related to atypical increases of recurrent excitation/inhibition, as well as subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic association analysis based on postmortem datasets identifies genes expressed in cortical and thalamic areas from childhood to young adulthood. Finally, supervised machine learning finds that the macroscale perturbations are associated with symptom severity scores on the Autism Diagnostic Observation Schedule. Together, our analyses suggest that atypical subcortico-cortical interactions are associated with both microcircuit and macroscale connectome differences in autism.

Signal diffusion along connectome gradients and inter-hub routing differentially contribute to dynamic human brain function.

Human cognition is dynamic, alternating over time between externally-focused states and more abstract, often self-generated, patterns of thought. Although cognitive neuroscience has documented how networks anchor particular modes of brain function, mechanisms that describe transitions between distinct functional states remain poorly understood. Here, we examined how time-varying changes in brain function emerge within the constraints imposed by macroscale structural network organization. Studying a large cohort of healthy adults (n = 326), we capitalized on manifold learning techniques that identify low dimensional representations of structural connectome organization and we decomposed neurophysiological activity into distinct functional states and their transition patterns using Hidden Markov Models. Structural connectome organization predicted dynamic transitions anchored in sensorimotor systems and those between sensorimotor and transmodal states. Connectome topology analyses revealed that transitions involving sensorimotor states traversed short and intermediary distances and adhered strongly to communication mechanisms of network diffusion. Conversely, transitions between transmodal states involved spatially distributed hubs and increasingly engaged long-range routing. These findings establish that the structure of the cortex is optimized to allow neural states the freedom to vary between distinct modes of processing, and so provides a key insight into the neural mechanisms that give rise to the flexibility of human cognition.

Convergence of cortical types and functional motifs in the human mesiotemporal lobe.

The mesiotemporal lobe (MTL) is implicated in many cognitive processes, is compromised in numerous brain disorders, and exhibits a gradual cytoarchitectural transition from six-layered parahippocampal isocortex to three-layered hippocampal allocortex. Leveraging an ultra-high-resolution histological reconstruction of a human brain, our study showed that the dominant axis of MTL cytoarchitectural differentiation follows the iso-to-allocortical transition and depth-specific variations in neuronal density. Projecting the histology-derived MTL model to in-vivo functional MRI, we furthermore determined how its cytoarchitecture underpins its intrinsic effective connectivity and association to large-scale networks. Here, the cytoarchitectural gradient was found to underpin intrinsic effective connectivity of the MTL, but patterns differed along the anterior-posterior axis. Moreover, while the iso-to-allocortical gradient parametrically represented the multiple-demand relative to task-negative networks, anterior-posterior gradients represented transmodal versus unimodal networks. Our findings establish that the combination of micro- and macrostructural features allow the MTL to represent dominant motifs of whole-brain functional organisation.

A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.

Handling confounding variables in statistical shape analysis - application to cardiac remodelling.

Statistical shape analysis is a powerful tool to assess organ morphologies and find shape changes associated to a particular disease. However, imbalance in confounding factors, such as demographics might invalidate the analysis if not taken into consideration. Despite the methodological advances in the field, providing new methods that are able to capture complex and regional shape differences, the relationship between non-imaging information and shape variability has been overlooked. We present a linear statistical shape analysis framework that finds shape differences unassociated to a controlled set of confounding variables. It includes two confounding correction methods: confounding deflation and adjustment. We applied our framework to a cardiac magnetic resonance imaging dataset, consisting of the cardiac ventricles of 89 triathletes and 77 controls, to identify cardiac remodelling due to the practice of endurance exercise. To test robustness to confounders, subsets of this dataset were generated by randomly removing controls with low body mass index, thus introducing imbalance. The analysis of the whole dataset indicates an increase of ventricular volumes and myocardial mass in athletes, which is consistent with the clinical literature. However, when confounders are not taken into consideration no increase of myocardial mass is found. Using the downsampled datasets, we find that confounder adjustment methods are needed to find the real remodelling patterns in imbalanced datasets.

The relationship between individual variation in macroscale functional gradients and distinct aspects of ongoing thought.

Contemporary accounts of ongoing thought recognise it as a heterogeneous and multidimensional construct, varying in both form and content. An emerging body of evidence demonstrates that distinct types of experience are associated with unique neurocognitive profiles, that can be described at the whole-brain level as interactions between multiple large-scale networks. The current study sought to explore the possibility that whole-brain functional connectivity patterns at rest may be meaningfully related to patterns of ongoing thought that occurred over this period. Participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) followed by a questionnaire retrospectively assessing the content and form of their ongoing thoughts during the scan. A non-linear dimension reduction algorithm was applied to the rs-fMRI data to identify components explaining the greatest variance in whole-brain connectivity patterns. Using these data, we examined whether specific types of thought measured at the end of the scan were predictive of individual variation along the first three low-dimensional components of functional connectivity at rest. Multivariate analyses revealed that individuals for whom the connectivity of the sensorimotor system was maximally distinct from the visual system were most likely to report thoughts related to finding solutions to problems or goals and least likely to report thoughts related to the past. These results add to an emerging literature that suggests that unique patterns of experience are associated with distinct distributed neurocognitive profiles and highlight that unimodal systems may play an important role in this process.

A novel approach to multiple anatomical shape analysis: Application to fetal ventriculomegaly.

Fetal ventriculomegaly (VM) is a condition in which one or both lateral ventricles are enlarged, and is diagnosed as an atrial diameter larger than 10 mm. Evidence of altered cortical folding associated with VM has been shown in the literature. However, existing works use a single scalar value such as diagnosis or lateral ventricular volume to characterize VM and study its relationship with alterations in cortical folding, thus failing to reveal the spatially-heterogeneous associations. In this work, we propose a novel approach to identify fine-grained associations between cortical folding and ventricular enlargement by leveraging the vertex-wise correlations between their growth patterns in terms of area expansion and curvature. Our approach comprises three steps. In the first step, we define a joint graph Laplacian matrix using cortex-to-ventricle correlations. The joint Laplacian is built based on multiple cortical features. Next, we propose a spectral embedding of the cortex-to-ventricle graph into a common underlying space where its nodes are projected according to the joint ventricle-cortex growth patterns. In this low-dimensional joint ventricle-cortex space, associated growth patterns lie close to each other. In the final step, we perform hierarchical clustering in the joint embedded space to identify associated sub-regions between cortex and ventricle. Using a dataset of 25 healthy fetuses and 23 fetuses with isolated non-severe VM within the age range of 26-29 gestational weeks, our approach reveals clinically relevant and heterogeneous regional associations. Cortical regions forming these associations are further validated using statistical analysis, revealing regions with altered folding that are significantly associated with ventricular dilation.