NeuroImage

Population-graph models aggregate a query subject with an unlabeled cohort, so their reported performance can depend on the evaluation regime rather than on predictive information alone. Evaluation context has two separable axes: the visibility of the cohort during training, and the context available at inference. We study the training-time axis under a protocol fixed before analysis, on an ABIDE-I cohort of 871 subjects (20 acquisition sites). Two population-graph implementations are compared: a learned/adaptive graph (EV-GCN) and a static weighted graph (Parisot-GCN). Within each implementation the cohort, connectivity features, outer splits and training and selection rules are held fixed, and only the information available to the graph varies. The primary estimand is the implementation-by-training-context interaction: the difference between the P0-to-P1 AUC changes of the two implementations ({Delta}{Delta}AUC). Across three preselected outer splits (666, 1024, 2024) the direction is consistent and positive, with observed interaction range 0.06285-0.13090; uncertainty is assessed separately within each split by paired subject and site-cluster bootstrap resampling and is reported per split. Splits are replication units: they are not pooled and no cross-split average is reported, so the result is not a claim of invariance to arbitrary splits. These findings tie reported population-graph performance to the evaluation information regime and motivate explicit reporting of cohort visibility. The contribution is methodological: a two-axis taxonomy of information regimes, preselected cross-split evidence that the sensitivity of reported performance to cohort context depends on the implementation, and a reusable reporting checklist.

The superficial white matter (SWM), a thin layer of white matter beneath the cortex, contains a complex arrangement of short- and long-range fiber systems that support communication between cortical regions. These fiber populations include subcortical U-shaped fibers (U-fibers) that predominantly follow a tangential trajectory along the gray matter-white matter interface and long-range fibers that extend more radially through the deeper white matter to connect distant cortical regions. Here, we developed a surface-based framework to dissociate radial and tangential fiber components within the human SWM and investigated their microstructural properties and functional relevance using in-vivo high-field MRI. These components were quantified using apparent fiber density (AFD), fractional anisotropy (FA), and mean diffusivity (MD). We further contextualized SWM fiber architecture by examining depth-dependent microstructural profiles and their relationship with normative patterns of cortical organization and hierarchical specialization. The anatomical assessment of the proposed fiber orientation separation was supported by tractography-based bundle analyses, while the anatomical accuracy of tractography reconstructions was confirmed through comparison with post-mortem white matter dissection data. To assess their functional relevance, the fiber predominance map derived from radial and tangential AFD was related to spatial patterns of functional variability across the cortex. Regions with greater radially oriented fiber contribution exhibited more gradual changes in functional similarity across geodesic distance, whereas tangentially oriented fiber-enriched regions showed more rapid local functional differentiation. These findings reveal distinct structural and functional signatures of radial and tangential SWM fiber components and provide a framework for investigating their contributions to cortical organization and functional specialization. SIGNIFICANCE STATEMENTThe human cerebral cortex is organized into specialized regions that support diverse functions, but the structural principles underlying this organization remain incompletely understood. The superficial white matter (SWM), a thin layer of white matter beneath the cortex, contains intermingled short- and long-range fiber systems that support communication between cortical regions. However, these fiber populations have remained difficult to characterize because they are closely intertwined within the SWM. By developing a reproducible framework for mapping and quantifying distinct SWM fiber systems, this work provides a foundation for systematic investigation of this complex compartment. Integration of multimodal datasets, together with open sharing of analytical tools and standardized features, promotes transparency, reproducibility, enabling future studies of how superficial connectivity supports brain organization.

The posterior parietal cortex integrates somatosensory information with signals supporting action, spatial cognition, and multisensory processing, yet the fine-scale topographic relationship between the intraparietal sulcus (IPS) and primary somatosensory cortex (S1) remains poorly understood. Here, we used resting-state fMRI in 10 awake rhesus macaques to characterize functional connectivity between four S1 subregions (areas 3a, 3b, 1, and 2) and 223 single-voxel seeds densely sampling an IPS-centered parietal territory. Across S1 subregions and hemispheres, IPS-S1 connectivity exhibited a highly structured spatial organization characterized by systematic anteroposterior and mediolateral gradients and a prominent semi-oval topology following the geometry of the intraparietal sulcus. Connectivity was generally stronger toward the cortical banks and convexities and weaker near the sulcal fundus, a pattern that could not be explained by reduced local temporal signal-to-noise ratio. Unsupervised hierarchical clustering independently recovered this spatial organization and identified connectivity-defined subdivisions that only partially corresponded to classical cytoarchitectonic boundaries. Along the S1 mediolateral axis, prominent troughs in cluster-averaged connectivity profiles corresponded to several previously described somatotopic transitions, allowing to consistently map putative boundaries between tongue and face representations and between hand and trunk-leg representations. Based on these boundaries, individual IPS clusters exhibited connectivity with multiple S1 body-part sectors, with the pattern of connectivity across these sectors varying across IPS clusters and S1 subregions. Together, our findings reveal that IPS-S1 functional connectivity is organized by a large-scale sulcal topology while preserving fine-grained features of S1 somatotopic organization. These findings suggest that the functional organization of the IPS is shaped by multiple spatial dimensions, including large-scale sulcal topology and the organization of S1 subregions and body-part representations, which may together contribute to the functional specialization of individual IPS regions.

Submillimeter functional magnetic resonance imaging (fMRI) based on blood-oxygenation-level-dependent (BOLD) signal enables the study of brain function at the submillimeter level, uncovering insights into fine-scale organisations like cortical layers and columns. However, its inherently low contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) often limit its reliability and applicability. Noise Reduction with Distribution Corrected Principal Components Analysis (NORDIC PCA) is a locally low-rank denoising algorithm that reduces thermal noise levels in BOLD fMRI in a local patch manner. However, local patches often contain a mixture of signals from multiple tissues that negatively affects the low-rank structure of the patches, which limits the denoising capabilities of the algorithm. We propose an alternative approach for patch formation by gathering similar non-local voxels, dubbed voxel-matching (VM) NORDIC. The results on submillimeter-resolution BOLD fMRI data indicate that VM-NORDIC effectively promotes the low rank of the patches by boosting signal redundancy, allowing for more efficient noise attenuation. Moreover, the method barely affects spatial smoothness due to the non-local voxel selection based on time-series similarity. In particular, VM-NORDIC outperforms standard NORDIC with default local patching (Standard-NORDIC) in terms of temporal SNR (tSNR) (~9-90% larger than Standard-NORDIC; ~23-250% larger than the original) and spatial smoothness estimates (~20% of the smoothness induced by Standard-NORDIC). These improvements are fundamental to improving the validity and precision of fMRI studies at submillimeter resolutions.

Subcortical structures are central to cognition, emotion, and social processing, and their dysfunction underlies a wide range of neurological and psychiatric conditions. Yet subcortical fine-scale functional organization has remained largely inaccessible to group-level fMRI analysis: nuclei are small and low-SNR, and their functional topography varies idiosyncratically across individuals in ways that anatomical alignment cannot resolve. This idiosyncrasy carries real stakes. For example, deep brain stimulation targets with more variable functional connectivity across individuals show correspondingly less consistent clinical outcomes. Here we show that this seemingly idiosyncratic subcortical organization in fact reflects shared, fine-grained structure that can be recovered by modeling each individual's connectivity in a common functional space (connectivity hyperalignment, CHA), rather than relying on anatomical correspondence. Applying CHA to fMRI data collected during naturalistic movie viewing, we found that aligning subcortical voxels by their cortical connectivity, rather than their anatomical location, sharply increased cross-subject correspondence in both stimulus-evoked response and connectivity profiles. Critically, this alignment sharpened rather than blurred local structure: neighboring voxels became more functionally distinct from one another, and cortical connectivity targets became substantially more decodable across subjects. These results indicate that human subcortical nuclei possess a common fine-scale functional architecture that is masked by anatomical variability but recoverable at the individual level. This reframes a central methodological constraint in subcortical neuroimaging: rather than trading spatial resolution for signal quality via smoothing, group-level analyses can achieve voxel-level precision by aligning function rather than anatomy, opening a path to studying cortical-subcortical circuit organization in greater detail.

Background: High-density electroencephalography (EEG) improves spatial sampling but entails greater acquisition cost, preparation time, participant burden, and computational demand. However, the extent to which electrode reduction affects successive levels of EEG analysis from global signal properties to cortical network inference remains insufficiently understood. Methods: We systematically subsampled two independent resting-state EEG datasets comprising 120 children recorded with 128 channels and 98 adults recorded with 256 channels. Density-dependent effects were assessed across 128-, 256-, 64-, 32-, and 19-channel configurations using a multilevel framework encompassing signal representation and quality, global and regional spectral power, EEG microstates, scalp-level effective connectivity, traveling waves, and source-level cortical hub topology. Results: Sensitivity to electrode reduction increased with the spatial specificity of the outcome. Global relative spectral power and explained variance were comparatively stable across configurations. In contrast, signal-to-noise ratio, entropy, reconstruction error, regional spectral distributions, traveling-wave estimates, effective connectivity, and microstate dynamics became progressively more density-sensitive. Although canonical microstate classes remained broadly identifiable at lower densities, their global explained variance, temporal parameters, and transition structure were altered. Source-level hub identity and centrality ranking showed the greatest vulnerability, with markedly reduced cross-density agreement at 32 and 19 channels. Across both datasets, several spatially dependent measures showed a transition around 64 channels, whereas estimates obtained with 128 and 256 channels were generally more similar. Conclusions: Electrode density affects EEG outcomes according to the spatial scale of the intended inference. Sparse montages may preserve broad global summaries but are less reliable for regional, spatiotemporal, and source-network analyses. Under the resting-state conditions examined here, approximately 64 channels represented a pragmatic transition for several spatially dependent measures. This value should be interpreted as context-specific guidance rather than a universal threshold.

Estimating population-level dependence between brain regions is challenging when the number of regions greatly exceeds the number of individuals. We introduce an information-borrowing generalized Bayesian method for high-dimensional covariance estimation from region-level brain measurements. A divide-and-conquer parameterization separates marginal variances from correlation calibrations: an empirical \emph{pilot} correlation matrix--by default, obtained by standardizing a sample covariance matrix (SCM)--provides a reference structure that is adaptively calibrated through region-specific parameters shared across pairwise correlations, reducing the number of free parameters from $\mathcal{O}(d^2)$ to $\mathcal{O}(d)$ ($d$ is the number of regions) while guaranteeing a positive-definite covariance through the inclusion of a ridge term. Horseshoe priors on the calibration parameters enable selective borrowing and shrinkage of pilot information. Under suitable conditions on pilot accuracy, we establish theoretical guarantees for covariance estimation while retaining scalability in ultra-high-dimensional settings via a low-rank likelihood representation and a Woodbury-accelerated Hamiltonian Monte Carlo algorithm. Simulations showed lower estimation error than the SCM, bagging and iteratively refined principal orthogonal complement thresholding (POETRY). Applications to a semi-synthetic cortical-thickness and ADHD resting-state fMRI data revealed significant group differences in the default-mode--visual network and somatomotor network--limbic network blocks after Benjamini--Hochberg correction.

Lesion Network Mapping (LNM) is a method used to map symptom-related circuits in the human brain. Recent work has raised concerns about the method and the specificity of LNM-derived networks, which often show high spatial overlap across unrelated conditions. Null models have been proposed to address the raised limitations1. Useful statistical tools in network neuroscience, they are reference procedures; in LNM, the normative connectome matrix C remains the source of the derived networks also under null modelling. Their broader role as a general solution for LNM therefore warrants careful evaluation. Here, we examine the proposed null models step-by-step and test them empirically across multiple datasets. We show that the proposed null-model correction effectively only replaces C with a transformed matrix C' (e.g., C' ~ C - mean(C)), one that is directly derived from C and retains much of its low-dimensional structure. Consequently, null-model-corrected LNM maps remain shaped by the same standard set of connectome-derived patterns and continue to show repetition and non-specificity across unrelated conditions. We discuss the scope and limitations of null models for LNM, showing that they can statistically benchmark LNMs, but that their application does not resolve the core limitation of non-specificity of LNM networks.

When human beings navigate through an environment, a conceptual space, memories or even imagined spaces, fMRI signals in select brain regions vary with movement direction, alternating in strength with a periodicity of 60 degrees. At the cellular level, certain neurons called grid-cells form a hexagonal lattice representation of physical space. Given that the axes of the lattices align across neurons, the concerted directional and spatial firing of populations of these neurons may form the basis of the hexadirectional modulation of the fMRI signal. However, the exact link between the two remains unclear. Multiple mechanisms have been proposed that could couple neuronal activity to the fMRI signal. These include (1) preferential neuronal discharge when the direction of motion coincides with the lattice axes, (2) repetition suppression when multiple fields are traversed in succession, or alternatively, (3) a nonlinear transduction step. Here, we propose targeted experiments that can distinguish these mechanisms, for which we assess the expected effect sizes via simulations. In particular, by introducing calibrated pauses between linear path segments, it is possible to differentiate the repetition-suppression hypothesis from the nonlinear transduction model. By additionally varying the subjects movement speed and path lengths, the proposed protocol can distinguish conjunctive neuronal tuning (in which neurons respond to both speed and location or direction and location) from the other hypotheses. Crucially, if either the repetition-suppression or the nonlinear-transduction hypothesis holds, then the scale of the lattices will play a role. According to our analysis, hexadirectional signals should emerge only when a linear path segment is longer than half of the spatial lattice period. As grid cells with different scales are grouped into distinct modules along the dorso-ventral axis of the entorhinal cortex, this may make it possible to non-invasively measure the hierarchy of grid scales in the human brain.

Introduction: Before asking which microstate an EEG sample belongs to, there is a simpler question: can it look like a microstate at all? Yet a winning correlation mixes three different properties: how microstate-like the scalp field is, where it lies within that geometry, and how well the available templates represent that direction. We asked whether a fixed geometry, independent of any microstate solution, could explain common structure of microstate maps, constrain how strongly EEG patterns can match them, and describe that structure in interpretable terms. Methods: We introduce First-Order spherical haRMonic (FORM), projecting normalized scalp topographies onto a fixed three-dimensional subspace defined only by sensor geometry. Direction describes field geometry; projection norm, {rho}, measures FORM conformity and the maximum correlation attainable by any FORM topography. We tested simulations, literature templates, and 374 recordings from 187 LEMON participants. Results: FORM captured canonical microstate geometry despite being defined a priori of a microstate solution: FORM explained energy, {rho} squared, was 0.990-0.998 for five meta-microstates and 0.966-0.986 for pooled LEMON maps. Across 313 literature templates, FORM angular distances preserved their independently derived organization (Spearman {rho}=0.987). In continuous EEG, FORM conformity explained a median 74.4% of within-subject variance in winning-template correlation, versus 21.7% for GFP. As independently estimated dictionaries increased from k=1 to k=12, the median fitted fraction of the FORM ceiling rose from 0.613 to 0.970. Discussion: FORM places an a priori continuous geometry beneath discrete microstate labels. It separates properties intrinsic to the scalp field - whether it is microstate-like and where it lies within that geometry - from how well the chosen template dictionary represents it. FORM therefore provides an interpretable, clustering-independent reference for assignment strength, template comparison and continuous microstate dynamics.

Efficient neuronal communication relying on rapid saltatory conduction depends not only on the amount of myelin wrapping axons but also on myelin compact organisation. Yet, current quantitative MRI myelin imaging methods, such as Myelin Water Imaging (MWI) and quantitative Magnetization Transfer (qMT), are designed to estimate myelin content and are often treated as interchangeable, overlooking myelin organisation. We introduce Structural Myelin Integrity (SMI), a quantitative MRI metric designed to distinguish myelin compact organisation from content. SMI combines the distinct biophysical sensitivities of MWI and qMT to separate the water confined between myelin layers from the total myelin membrane mass. We evaluated SMI in two rodent models of myelin decompaction and one remyelination model, validating our findings with synchrotron small-angle X-ray scattering and electron microscopy. SMI detected myelin layers decompaction despite largely preserved myelin membranes, revealing structural abnormalities that were not explained by myelin content alone. During remyelination, SMI returned closer to healthy values at early timepoints than myelin-content metrics, consistent with the formation of thin-but-compact sheaths. These findings indicate that myelin content and organisation can dissociate and establish SMI as a non-invasive marker of myelin organisation, compatible with existing clinical MRI approaches for studying white matter changes not detected today.

Blind source separation (BSS) recovers latent sources from observed mixtures. In brain imaging, sources occur in two domains, spatial and temporal, so a criterion applied in one leaves the other unconstrained. Independent component analysis, the most used BSS tool, exploits diversity such as non-Gaussianity and sample dependence, but in one domain at a time. Methods that use both domains apply the same criterion to each and weight them against each other. We propose spatio-dynamical decomposition (SDD), scoring maps by non-Gaussianity and timecourses by dynamical independence: how much each source's dynamics depend on the others. We normalize each score by how much it can improve on the data, eliminating the need for a weight. Across simulations and 130 naturalistic fMRI runs, SDD recovers sources distinguished by either maps or dynamics and reproduces both across disjoint episodes, while baselines trade off the two; map and timescale together also better predict stimulus tracking, with the largest gain for SDD. Together, these results show that separation is strongest when spatial and temporal domains each carry their own criterion.

Myelin supports rapid and efficient neural communication and is implicated in brain development, learning, aging, and neurological disease. Although numerous magnetic resonance imaging (MRI) approaches have been proposed to characterize myelin in vivo, they have rarely been evaluated together within the same participants and across repeated acquisitions. To address these gaps, we introduce the Myelin Imaging Reliability and ReprOducibility Resource (MIRROR), an openly available multimodal test--retest MRI dataset of diffusion MRI (dMRI), inhomogeneous magnetization transfer imaging (ihMT), quantitative susceptibility mapping (QSM), MP2RAGE, T1w/T2w ratio mapping, and transverse relaxometry in 22 healthy adults. We evaluated gray--white matter differentiation, intermetric correspondence, test--retest reliability, and participant specificity across 27 myelin-sensitive metrics. Gray--white matter differentiation was strong for dMRI derivatives, MP2RAGE-derived R1, T1w/T2w, and ihMT, while being substantially weaker for QSM measures. Intermetric spatial correlations were generally strongest within acquisition or modeling families. Test--retest reliability was generally high, particularly for dMRI-derived metrics, but was more variable among QSM-, ihMT-, and R2*-derived measures. Regional spatial profiles were also highly participant-specific, with discriminability approaching its upper bound for most metrics. All imaging data, derived maps, and processing code are openly released. MIRROR provides a benchmark for characterizing the measurement properties and practical tradeoffs of scalable myelin-sensitive MRI methods, supporting principled acquisition selection and accelerating methodological development and validation.

Evidence from in-silico, ex vivo and invasive animal studies suggested the function of neural tissue to be inextricably linked to its structural and microstructural organization. However, this link has never been assessed non-invasively in humans. Here, we established a simple quantitative framework linking cerebral oxygen metabolism to gray matter microstructural features in healthy humans using advanced non-invasive MRI methods. The cerebral metabolic rate of oxygen consumption (CMRO2) was quantified with calibrated fMRI, whereas microstructural properties were estimated from diffusion MRI data fitted to the Soma and Neurite Density Imaging (SANDI) model, yielding soma radius (R soma) and soma volume fraction (fsoma) metrics, from which we derived maps of soma surface area density (SAD) and soma numerical density (ND) under the assumption of a spherical soma. CMRO2 was positively associated with SAD (r = 0.29, p < 0.01), fsoma (r = 0.28, p < 0.05) and ND (r = 0.25, p < 0.05), and negatively associated with Rsoma (r = -0.23, p < 0.05) across cortical brain regions. These relationships are consistent with predictions from experimental and theoretical studies, providing the first quantitative evidence that cerebral metabolic demand is coupled to microstructure in humans. The positive association of energy consumption with SAD is consistent with the notion that both the number of synapses (energy-demanding structures), and the energy required to maintain a membrane potential, scale with soma surface area. Our findings establish a non-invasive MRI framework for investigating the microstructural determinants of brain energy metabolism in health and potentially in disease.

Multi-echo functional magnetic resonance imaging (fMRI) acquires signals with distinct contrast profiles across echo times (TEs). Empirical evidence suggests that different TEs capture distinct signal contributions with varying sensitivity to BOLD and non-BOLD processes from long to short TEs (Stroman, 2002; Krishnamurthy, 2023; Dong, 2024). Previous literature has not yet examined how brain states extracted from temporal dynamic functional connectivity (dFNC) evolve across TEs. Here we present a methodological and empirical study of TE-dependent evolution of dynamic connectivity states, with a phenomenological two-component model for interpretation. Multiple echoes were acquired with an echo planar time-resolved imaging (EPTI) sequence. TE-specific components were extracted via atlas-based group ICA (Neuromark 1.0), and brain connectivity states were generated via windowed dFNC and spatial ICA clustering of windows. Within-subject and group-level states evolved across TEs in network organization and variance. States exhibited TE-dependent variance profiles, with distinct peak echo times; and group-level points of state transition were independently mapped to TE-dependent transitions in variance. We modified a bi-exponential model to simulate and model changes in the dFNC time-course across TEs. The bi-exponential model revealed high consistency with subject states (R2 fit=0.86, res. error=0.55, 86% model convergence rate), suggesting a two-component signal system contributing to dynamic TE-dependent connectivity changes in state. A significant correlation between relative model terms was estimated on a cell-wise basis across states (r(24) = -0.43, p=0.03, 95% CI [-0.70, -0.04]). This suggests that specific bi-exponential signal parameters (i.e., short FNC1,TE=0, long FNC2,TE=0, and long FNC2,decay) were associated with the observed TE-dependent variations in connectivity states across TEs. In sum, our analyses provide downstream implications for TE-aware state analysis dependent on connectivity magnitude (FNCTE=0) and rate of connectivity decay (FNCdecay), in a two-component signal model, with future implications for TE-dependent state biomarkers.

Three recent publications have reported selective fMRI responses to images of food in the human ventral visual pathway. However, all three studies were based primarily on the Natural Scenes Dataset (NSD), in which high-level categories like food are correlated with other image properties such as the color and size of objects, and the distance of the scene. To test whether the reported food selectivity might reflect these or other correlates of food images rather than (or in addition to) food, we constructed novel stimuli that manipulated these properties on both food and non-food images, and collected data from new subjects in a data-rich design across two experiments pre-registered in OSF. We used a localizer paradigm based on a subset of NSD images to infer the "food component" in new subjects and then measured responses of this component to our new stimuli. In Experiment 1, we found that the food component response magnitude i) had a higher response to color than to greyscale images but showed no interaction between food and color, ii) showed a reduced preference for food over non-food when both were within reaching distance, and most importantly iii) was no higher for food than non-food when both were visually matched and presented as Cutouts on a white background. In Experiment 2, we found that the response of the food component could not be explained by object distance, real-world size, or mid-level visual image statistics. However, the response to non-food images with "gooey" material properties was as high as the response to food. Across both experiments, we consistently found a very low response (at or below fixation baseline) to NSD non-food images, which were predominantly outdoor scenes. Together, our results prompt a revision of prior claims including our own, indicating that the previously reported food component is better characterized as food-biased rather than strictly food-selective, and is driven in part by contextual or material features that are also present in non-food images. Our findings further highlight the importance of supplementing studies based on naturalistic images with experiments that unconfound image properties with carefully designed stimuli.

The human subcortex integrates information from distributed cortical regions through functionally organized cortico-subcortical systems. Using the publicly available MICA-MICs multimodal MRI dataset of 50 healthy adults, we characterized the microstructural organization of functionally converging cortical regions. First, using resting-state fMRI., we identified cortical regions converging on subcortical targets, including thalamic, basal ganglia, and subcortical limbic structures. Then, using depth-resolved quantitative T1 profiles, we constructed a convergence-restricted microstructural profile covariance matrix, followed by diffusion-map embedding. The first microstructural gradient predominantly differentiated primary and association cortex, whereas the second gradient showed target-related differentiation beyond differences in primary versus association cortex. Cytoarchitectural analysis further revealed target-related differences in cortical composition. Together, these findings reveal complementary dimensions of cortico-subcortical functional organization, spanning broad cortical hierarchy, target-related microstructural differentiation, and cytoarchitectural composition.

Brain metabolic connectivity is increasingly studied using positron emission tomography (PET), but multiple analytical approaches exist with unknown comparability. Here we compared metabolic connectivity approaches in 80 participants who underwent simultaneous dynamic PET with 18F-fluorodeoxyglucose and functional magnetic resonance imaging (fMRI) scans and cognitive testing. Six connectivity approaches were compared, including the traditional across-subject method (often labelled metabolic covariance) and five approaches that estimate individual-level connectivity: across-subject metabolic covariance with individual scores derived using leave one out (LOO); functional PET (fPET) within-subject correlations of regional timeseries; and three approaches that use distance-based measures to estimate individual-level connectivity based on within-region tracer distribution and kinetic compartment C1 and C2 time activity curves. fMRI connectivity was also calculated. Each method showed distinct topological, behavioural, structural and genetic signatures. fPET connectivity demonstrated the strongest cognitive associations and largest age-related declines, with unique predictive power for cognition independent of age. Tracer distribution showed strong age group discrimination although with mixed direction of age and cognitive effects. Metabolic covariance (LOO) and kinetic C2 showed no significant age group differences and their cognition associations reflected age-related variance. Gene expression associations implicated a shared core glycolytic-insulin machinery in all approaches, but the direction of the association with regional connectivity diverged across approaches and unique gene signatures further distinguished most methods. Collectively, these results indicate that the optimal connectivity approach depends on the research question. fPET connectivity with dynamic scans offers utility for cognition and ageing studies, tracer distribution for single-scan designs with careful interpretation of age and cognition relationships, kinetic approaches for novel biological insights into glucose kinetics and fMRI for multi-modal integration. Metabolic covariance (LOO) should be used with caution for brain-behaviour investigations. Researchers should weigh trade-offs between physiological specificity, analytical complexity, acquisition requirements and interpretability when selecting a metabolic connectivity approach.

Early human cortical development involves rapid changes in cytoarchitecture that remain difficult to interrogate non-invasively. Biophysical diffusion MRI models provide a potential window onto this microstructure, including water exchange across cell membranes, but their assumptions are difficult to validate directly in developing human tissue. Human cortical organoids provide a tractable biological model in which diffusion measurements can be related to tissue architecture within the same specimen. We scanned six fixed cortical organoids at 9.4~T, three grown under a directed and three under an undirected differentiation protocol, at three diffusion times and b-values up to 7000~s/mm$^2$. Center-to-periphery profiles of DKI-derived diffusion metrics were reproducible across the directed organoids but more variable across the undirected organoids, while nuclear staining revealed greater variability in the internal architecture of the undirected organoids. Unexpectedly, mean diffusivity increased with diffusion time in more than 80% of tissue voxels in both batches, opposite to previous organoid measurements. Across 12,348 simulated two-compartment substrates, this increase was reproduced only with permeable membranes and an extracellular diffusivity substantially exceeding the apparent intracellular diffusivity, a regime that challenges assumptions commonly used in current gray-matter exchange models. These results support cortical organoids as biologically realistic platforms for probing early cortical microstructure and testing diffusion models under controlled conditions, while remaining amenable to post-MRI histological validation.

A central goal of neuroscience is to establish how similar (or different) brain networks are across individuals, development, psychiatric conditions, and even between biological and artificial brains. Whenever one such comparison is made, it relies on the assumption that we have a measure that produces an accurate and plausible similarity score. Yet, the field lacks one such measure, and the wide variety of existing measures often produces conflicting results. To address this problem, we perform a systematic comparison of 16 established similarity measures. First, we show that different measures consistently disagree on which brain networks are most similar. Second, we rank all measures according to multiple criteria such as biological plausibility, computational efficiency, and sensitivity. We show that DeltaCon is the most accurate measure in terms of parameter recovery, and that it ranks among the fastest and most noise-tolerant. For this reason, we conclude that DeltaCon is the best general-purpose similarity measure. However, no measure ranks best on more than two of the five criteria we assessed, and different measures should be preferred depending on the exact research question. Measure selection can now be made on evidence and should be a crucial decision in any study that compares brain networks.