Tau follows principal axes of functional and structural brain organization in Alzheimer's disease.

Alzheimer's disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns ("gradient contraction") are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.

The human brain connectome weighted by the myelin content and total intra-axonal cross-sectional area of white matter tracts.

A central goal in neuroscience is the development of a comprehensive mapping between structural and functional brain features, which facilitates mechanistic interpretation of brain function. However, the interpretability of structure-function brain models remains limited by a lack of biological detail. Here, we characterize human structural brain networks weighted by multiple white matter microstructural features including total intra-axonal cross-sectional area and myelin content. We report edge-weight-dependent spatial distributions, variance, small-worldness, rich club, hubs, as well as relationships with function, edge length, and myelin. Contrasting networks weighted by the total intra-axonal cross-sectional area and myelin content of white matter tracts, we find opposite relationships with functional connectivity, an edge-length-independent inverse relationship with each other, and the lack of a canonical rich club in myelin-weighted networks. When controlling for edge length, networks weighted by either fractional anisotropy, radial diffusivity, or neurite density show no relationship with whole-brain functional connectivity. We conclude that the co-utilization of structural networks weighted by total intra-axonal cross-sectional area and myelin content could improve our understanding of the mechanisms mediating the structure-function brain relationship.

Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex.

Recent theories of cortical organisation suggest features of function emerge from the spatial arrangement of brain regions. For example, association cortex is located furthest from systems involved in action and perception. Association cortex is also 'interdigitated' with adjacent regions having different patterns of functional connectivity. It is assumed that topographic properties, such as distance between regions, constrains their functions, however, we lack a formal description of how this occurs. Here we use variograms, a quantification of spatial autocorrelation, to profile how function changes with the distance between cortical regions. We find function changes with distance more gradually within sensory-motor cortex than association cortex. Importantly, systems within the same type of cortex (e.g., fronto-parietal and default mode networks) have similar profiles. Primary and association cortex, therefore, are differentiated by how function changes over space, emphasising the value of topographical features of a region when estimating its contribution to cognition and behaviour.

Assortative mixing in micro-architecturally annotated brain connectomes.

The wiring of the brain connects micro-architecturally diverse neuronal populations, but the conventional graph model, which encodes macroscale brain connectivity as a network of nodes and edges, abstracts away the rich biological detail of each regional node. Here, we annotate connectomes with multiple biological attributes and formally study assortative mixing in annotated connectomes. Namely, we quantify the tendency for regions to be connected based on the similarity of their micro-architectural attributes. We perform all experiments using four cortico-cortical connectome datasets from three different species, and consider a range of molecular, cellular, and laminar annotations. We show that mixing between micro-architecturally diverse neuronal populations is supported by long-distance connections and find that the arrangement of connections with respect to biological annotations is associated to patterns of regional functional specialization. By bridging scales of cortical organization, from microscale attributes to macroscale connectivity, this work lays the foundation for next-generation annotated connectomics.

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.

Long-range functional connections mirror and link microarchitectural and cognitive hierarchies in the human brain.

BACKGROUND: Higher-order cognition is hypothesized to be implemented via distributed cortical networks that are linked via long-range connections. However, it is unknown how computational advantages of long-range connections reflect cortical microstructure and microcircuitry. METHODS: We investigated this question by (i) profiling long-range cortical connectivity using resting-state functional magnetic resonance imaging (MRI) and cortico-cortical geodesic distance mapping, (ii) assessing how long-range connections reflect local brain microarchitecture, and (iii) examining the microarchitectural similarity of regions connected through long-range connections. RESULTS: Analysis of 2 independent datasets indicated that sensory/motor areas had more clustered short-range connections, while transmodal association systems hosted distributed, long-range connections. Meta-analytical decoding suggested that this topographical difference mirrored shifts in cognitive function, from perception/action towards emotional/social processing. Analysis of myelin-sensitive in vivo MRI as well as postmortem histology and transcriptomics datasets established that gradients in functional connectivity distance are paralleled by those present in cortical microarchitecture. Notably, long-range connections were found to link spatially remote regions of association cortex with an unexpectedly similar microarchitecture. CONCLUSIONS: By mapping covarying topographies of long-range functional connections and cortical microcircuits, the current work provides insights into structure-function relations in human neocortex.

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.

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/ ).

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.

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.

Genetic and phylogenetic uncoupling of structure and function in human transmodal cortex.

Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral flexibility. However, it remains unclear how a static, genetically controlled architecture supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and cognitive analyses to understand how the macroscale organization of structure-function coupling across the cortex can inform its role in cognition. In humans, structure-function coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-function uncoupling in macaques had a similar spatial distribution, but we observed an increased coupling between structure and function in association cortices relative to humans. Meta-analysis suggested regions with the least genetic control (low heritable correspondence and different across primates) are linked to social-cognition and autobiographical memory. Our findings suggest that genetic and evolutionary uncoupling of structure and function in different transmodal systems may support the emergence of complex forms of cognition.

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.

Perceptual coupling and decoupling of the default mode network during mind-wandering and reading.

While reading, our mind can wander to unrelated autobiographical information, creating a perceptually decoupled state detrimental to narrative comprehension. To understand how this mind-wandering state emerges, we asked whether retrieving autobiographical content necessitates functional disengagement from visual input. In Experiment 1, brain activity was recorded using functional magnetic resonance imaging (fMRI) in an experimental situation mimicking naturally occurring mind-wandering, allowing us to precisely delineate neural regions involved in memory and reading. Individuals read expository texts and ignored personally relevant autobiographical memories, as well as the opposite situation. Medial regions of the default mode network (DMN) were recruited during memory retrieval. In contrast, left temporal and lateral prefrontal regions of the DMN, as well as ventral visual cortex, were recruited when reading for comprehension. Experiment two used functional connectivity both at rest and during tasks to establish that (i) DMN regions linked to memory are more functionally decoupled from regions of ventral visual cortex than regions in the same network engaged when reading; and (ii) individuals with more self-generated mental contents and poorer comprehension, while reading in the lab, showed more decoupling between visually connected DMN sites important for reading and primary visual cortex. A similar pattern of connectivity was found in Experiment 1, with greater coupling between this DMN site and visual cortex when participants reported greater focus on reading in the face of conflict from autobiographical memory cues; moreover, the retrieval of personally relevant memories increased the decoupling of these sites. These converging data suggest we lose track of the narrative when our minds wander because generating autobiographical mental content relies on cortical regions within the DMN which are functionally decoupled from ventral visual regions engaged during reading.

As your eyes scan these words, you may be thinking about what to make for dinner, how to address an unexpected hurdle at work, or how many emails are sitting, unread, in your inbox. This type of mind-wandering disrupts our focus and limits how much information we comprehend, whilst also being conducive to creative thinking and problem-solving. Despite being an everyday occurrence, exactly how our mind wanders remains elusive. One possible explanation is that the brain disengages from visual information from the external world and turns its attention inwards. A greater understanding of which neural circuits are involved in this process could reveal insights about focus, attention, and reading comprehension. Here, Zhang et al. investigated whether the brain becomes disengaged from visual input when our mind wanders while reading. Recalling personal events was used as a proxy for mind-wandering. Brain activity was recorded as participants were shown written statements; sometimes these were preceded by cues to personal memories. People were asked to focus on reading the statements or they were instructed to concentrate on their memories while ignoring the text. The analyses showed that recalling memories and reading stimulated distinct parts of the brain, which were in direct competition during mind-wandering. Further work examined how these regions were functionally connected. In individuals who remained focused on reading despite memory cues, the areas activated by reading showed strong links to the visual cortex. Conversely, these reading-related areas became 'decoupled' from visual processing centres in people who were focusing more on their internal thoughts. These results shed light on why we lose track of what we are reading when our mind wanders: recalling personal memories activates certain brain areas which are functionally decoupled from the regions involved in processing external information ­ such as the words on a page. In summary, the work by Zhang et al. builds a mechanistic understanding of mind-wandering, a natural feature of our daily brain activity. These insights may help to inform future interventions in education to improve reading, comprehension and focus.

Individual differences in gradients of intrinsic connectivity within the semantic network relate to distinct aspects of semantic cognition.

Semantic cognition allows us to make sense of our varied experiences, including the words we hear and the objects we see. Contemporary accounts identify multiple interacting components that underpin semantic cognition, including diverse unimodal "spoke" systems that are integrated by a heteromodal "hub", and control processes that allow us to access weakly-encoded as well as dominant aspects of knowledge to suit the circumstances. The current study examined how these dimensions of semantic cognition might be related to whole-brain-derived components (or gradients) of connectivity. A nonlinear dimensionality reduction technique was applied to resting-state functional magnetic resonance imaging from 176 participants to characterise the strength of two key connectivity gradients in each individual: the principal gradient captured the separation between unimodal and heteromodal cortex, while the second gradient corresponded to the distinction between motor and visual cortex. We then examined whether the magnitude of these gradients within the semantic network was related to specific aspects of semantic cognition by examining individual differences in semantic and non-semantic tasks. Participants whose intrinsic connectivity showed a better fit with Gradient 1 had faster identification of weak semantic associations. Furthermore, a better fit with Gradient 2 was linked to faster performance on picture semantic judgements. These findings show that individual differences in aspects of semantic cognition can be related to components of connectivity within the semantic network.

A tale of two gradients: differences between the left and right hemispheres predict semantic cognition.

Decomposition of whole-brain functional connectivity patterns reveals a principal gradient that captures the separation of sensorimotor cortex from heteromodal regions in the default mode network (DMN). Functional homotopy is strongest in sensorimotor areas, and weakest in heteromodal cortices, suggesting there may be differences between the left and right hemispheres (LH/RH) in the principal gradient, especially towards its apex. This study characterised hemispheric differences in the position of large-scale cortical networks along the principal gradient, and their functional significance. We collected resting-state fMRI and semantic, working memory and non-verbal reasoning performance in 175 + healthy volunteers. We then extracted the principal gradient of connectivity for each participant, tested which networks showed significant hemispheric differences on the gradient, and regressed participants' behavioural efficiency in tasks outside the scanner against interhemispheric gradient differences for each network. LH showed a higher overall principal gradient value, consistent with its role in heteromodal semantic cognition. One frontotemporal control subnetwork was linked to individual differences in semantic cognition: when it was nearer heteromodal DMN on the principal gradient in LH, participants showed more efficient semantic retrieval-and this network also showed a strong hemispheric difference in response to semantic demands but not working memory load in a separate study. In contrast, when a dorsal attention subnetwork was closer to the heteromodal end of the principal gradient in RH, participants showed better visual reasoning. Lateralization of function may reflect differences in connectivity between control and heteromodal regions in LH, and attention and visual regions in RH.

Multiscale communication in cortico-cortical networks.

Signaling in brain networks unfolds over multiple topological scales. Areas may exchange information over local circuits, encompassing direct neighbours and areas with similar functions, or over global circuits, encompassing distant neighbours with dissimilar functions. Here we study how the organization of cortico-cortical networks mediate localized and global communication by parametrically tuning the range at which signals are transmitted on the white matter connectome. We show that brain regions vary in their preferred communication scale. By investigating the propensity for brain areas to communicate with their neighbors across multiple scales, we naturally reveal their functional diversity: unimodal regions show preference for local communication and multimodal regions show preferences for global communication. We show that these preferences manifest as region- and scale-specific structure-function coupling. Namely, the functional connectivity of unimodal regions emerges from monosynaptic communication in small-scale circuits, while the functional connectivity of transmodal regions emerges from polysynaptic communication in large-scale circuits. Altogether, the present findings reveal that communication preferences are highly heterogeneous across the cortex, shaping regional differences in structure-function coupling.

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.

Atypical neural topographies underpin dysfunctional pattern separation in temporal lobe epilepsy.

Episodic memory is the ability to remember events from our past accurately. The process of pattern separation is hypothesized to underpin this ability and is defined as the capacity to orthogonalize memory traces, to maximize the features that make them unique. Contemporary cognitive neuroscience suggests that pattern separation entails complex interactions between the hippocampus and neocortex, where specific hippocampal subregions shape neural reinstatement in the neocortex. To test this hypothesis, the current work studied both healthy controls and patients with temporal lobe epilepsy who presented with hippocampal structural anomalies. We measured neural activity in all participants using functional MRI while they retrieved memorized items or lure items, which shared features with the target. Behaviourally, patients with temporal lobe epilepsy were less able to exclude lures than controls and showed a reduction in pattern separation. To assess the hypothesized relationship between neural patterns in the hippocampus and neocortex, we identified the topographic gradients of intrinsic connectivity along neocortical and hippocampal subfield surfaces and determined the topographic profile of the neural activity accompanying pattern separation. In healthy controls, pattern separation followed a graded topography of neural activity, both along the hippocampal long axis (and peaked in anterior segments that are more heavily engaged in transmodal processing) and along the neocortical hierarchy running from unimodal to transmodal regions (peaking in transmodal default mode regions). In patients with temporal lobe epilepsy, however, this concordance between task-based functional activations and topographic gradients was markedly reduced. Furthermore, person-specific measures of concordance between task-related activity and connectivity gradients in patients and controls were related to inter-individual differences in behavioural measures of pattern separation and episodic memory, highlighting the functional relevance of the observed topographic motifs. Our work is consistent with an emerging understanding that successful discrimination between memories with similar features entails a shift in the locus of neural activity away from sensory systems, a pattern that is mirrored along the hippocampal long axis and with respect to neocortical hierarchies. More broadly, our study establishes topographic profiling using intrinsic connectivity gradients, capturing the functional underpinnings of episodic memory processes in a manner that is sensitive to their reorganization in pathology.