Diffusion-informed spatial smoothing of fMRI data in white matter using spectral graph filters.

Brain activation mapping using functional magnetic resonance imaging (fMRI) has been extensively studied in brain gray matter (GM), whereas in large disregarded for probing white matter (WM). This unbalanced treatment has been in part due to controversies in relation to the nature of the blood oxygenation level-dependent (BOLD) contrast in WM and its detectability. However, an accumulating body of studies has provided solid evidence of the functional significance of the BOLD signal in WM and has revealed that it exhibits anisotropic spatio-temporal correlations and structure-specific fluctuations concomitant with those of the cortical BOLD signal. In this work, we present an anisotropic spatial filtering scheme for smoothing fMRI data in WM that accounts for known spatial constraints on the BOLD signal in WM. In particular, the spatial correlation structure of the BOLD signal in WM is highly anisotropic and closely linked to local axonal structure in terms of shape and orientation, suggesting that isotropic Gaussian filters conventionally used for smoothing fMRI data are inadequate for denoising the BOLD signal in WM. The fundamental element in the proposed method is a graph-based description of WM that encodes the underlying anisotropy observed across WM, derived from diffusion-weighted MRI data. Based on this representation, and leveraging graph signal processing principles, we design subject-specific spatial filters that adapt to a subject's unique WM structure at each position in the WM that they are applied at. We use the proposed filters to spatially smooth fMRI data in WM, as an alternative to the conventional practice of using isotropic Gaussian filters. We test the proposed filtering approach on two sets of simulated phantoms, showcasing its greater sensitivity and specificity for the detection of slender anisotropic activations, compared to that achieved with isotropic Gaussian filters. We also present WM activation mapping results on the Human Connectome Project's 100-unrelated subject dataset, across seven functional tasks, showing that the proposed method enables the detection of streamline-like activations within axonal bundles.

Quantification of volumetric morphometry and optical property in the cortex of human cerebellum at micrometer resolution.

The surface of the human cerebellar cortex is much more tightly folded than the cerebral cortex. Volumetric analysis of cerebellar morphometry in magnetic resonance imaging studies suffers from insufficient resolution, and therefore has had limited impact on disease assessment. Automatic serial polarization-sensitive optical coherence tomography (as-PSOCT) is an emerging technique that offers the advantages of microscopic resolution and volumetric reconstruction of large-scale samples. In this study, we reconstructed multiple cubic centimeters of ex vivo human cerebellum tissue using as-PSOCT. The morphometric and optical properties of the cerebellar cortex across five subjects were quantified. While the molecular and granular layers exhibited similar mean thickness in the five subjects, the thickness varied greatly in the granular layer within subjects. Layer-specific optical property remained homogenous within individual subjects but showed higher cross-subject variability than layer thickness. High-resolution volumetric morphometry and optical property maps of human cerebellar cortex revealed by as-PSOCT have great potential to advance our understanding of cerebellar function and diseases.

Quantification of structural brain connectivity via a conductance model.

Connectomics has proved promising in quantifying and understanding the effects of development, aging and an array of diseases on the brain. In this work, we propose a new structural connectivity measure from diffusion MRI that allows us to incorporate direct brain connections, as well as indirect ones that would not be otherwise accounted for by standard techniques and that may be key for the better understanding of function from structure. From our experiments on the Human Connectome Project dataset, we find that our measure of structural connectivity better correlates with functional connectivity than streamline tractography does, meaning that it provides new structural information related to function. Through additional experiments on the ADNI-2 dataset, we demonstrate the ability of this new measure to better discriminate different stages of Alzheimer's disease. Our findings suggest that this measure is useful in the study of the normal brain structure, and for quantifying the effects of disease on the brain structure.

as-PSOCT: Volumetric microscopic imaging of human brain architecture and connectivity.

Polarization sensitive optical coherence tomography (PSOCT) with serial sectioning has enabled the investigation of 3D structures in mouse and human brain tissue samples. By using intrinsic optical properties of back-scattering and birefringence, PSOCT reliably images cytoarchitecture, myeloarchitecture and fiber orientations. In this study, we developed a fully automatic serial sectioning polarization sensitive optical coherence tomography (as-PSOCT) system to enable volumetric reconstruction of human brain samples with unprecedented sample size and resolution. The 3.5 µm in-plane resolution and 50 µm through-plane voxel size allow inspection of cortical layers that are a single-cell in width, as well as small crossing fibers. We show the abilities of as-PSOCT in quantifying layer thicknesses of the cerebellar cortex and creating microscopic tractography of intricate fiber networks in the subcortical nuclei and internal capsule regions, all based on volumetric reconstructions. as-PSOCT provides a viable tool for studying quantitative cytoarchitecture and myeloarchitecture and mapping connectivity with microscopic resolution in the human brain.

Noninvasive mapping of pancreatic inflammation in recent-onset type-1 diabetes patients.

The inability to visualize the initiation and progression of type-1 diabetes (T1D) noninvasively in humans is a major research and clinical stumbling block. We describe an advanced, exportable method for imaging the pancreatic inflammation underlying T1D, based on MRI of the clinically approved magnetic nanoparticle (MNP) ferumoxytol. The MNP-MRI approach, which reflects nanoparticle uptake by macrophages in the inflamed pancreatic lesion, has been validated extensively in mouse models of T1D and in a pilot human study. The methodological advances reported here were enabled by extensive optimization of image acquisition at 3T, as well as by the development of improved MRI registration and visualization technologies. A proof-of-principle study on patients recently diagnosed with T1D versus healthy controls yielded two major findings: First, there was a clear difference in whole-pancreas nanoparticle accumulation in patients and controls; second, the patients with T1D exhibited pronounced inter- and intrapancreatic heterogeneity in signal intensity. The ability to generate noninvasive, 3D, high-resolution maps of pancreatic inflammation in autoimmune diabetes should prove invaluable in assessing disease initiation and progression and as an indicator of response to emerging therapies.

Functional density and edge maps: Characterizing functional architecture in individuals and improving cross-subject registration.

Population-level inferences and individual-level analyses are two important aspects in functional magnetic resonance imaging (fMRI) studies. Extracting reliable and informative features from fMRI data that capture biologically meaningful inter-subject variation is critical for aligning and comparing functional networks across subjects, and connecting the properties of functional brain organization with variations in behavior, cognition and genetics. In this study, we derive two new measures, which we term functional density map and edge map, and demonstrate their usefulness in characterizing the function of individual brains. Specifically, using data from the Human Connectome Project (HCP), we show that (1) both functional maps capture intrinsic properties of the functional connectivity pattern in individuals while exhibiting large variation across subjects; (2) functional maps derived from either resting-state or task-evoked fMRI can be used to accurately identify subjects from a population; and (3) cross-subject alignment using these functional maps considerably reduces functional variation and improves functional correspondence across subjects over state-of-the-art multimodal registration algorithms. Our results suggest that the proposed functional density and edge maps are promising features in characterizing the functional architecture in individuals and provide an alternative way to explore the functional variation across subjects.

Mid-space-independent deformable image registration.

Aligning images in a mid-space is a common approach to ensuring that deformable image registration is symmetric - that it does not depend on the arbitrary ordering of the input images. The results are, however, generally dependent on the mathematical definition of the mid-space. In particular, the set of possible solutions is typically restricted by the constraints that are enforced on the transformations to prevent the mid-space from drifting too far from the native image spaces. The use of an implicit atlas has been proposed as an approach to mid-space image registration. In this work, we show that when the atlas is aligned to each image in the native image space, the data term of implicit-atlas-based deformable registration is inherently independent of the mid-space. In addition, we show that the regularization term can be reformulated independently of the mid-space as well. We derive a new symmetric cost function that only depends on the transformation morphing the images to each other, rather than to the atlas. This eliminates the need for anti-drift constraints, thereby expanding the space of allowable deformations. We provide an implementation scheme for the proposed framework, and validate it through diffeomorphic registration experiments on brain magnetic resonance images.

Multimodal Image Registration through Simultaneous Segmentation.

Multimodal image registration facilitates the combination of complementary information from images acquired with different modalities. Most existing methods require computation of the joint histogram of the images, while some perform joint segmentation and registration in alternate iterations. In this work, we introduce a new non-information-theoretical method for pairwise multimodal image registration, in which the error of segmentation - using both images - is considered as the registration cost function. We empirically evaluate our method via rigid registration of multi-contrast brain magnetic resonance images, and demonstrate an often higher registration accuracy in the results produced by the proposed technique, compared to those by several existing methods.

Avoiding symmetry-breaking spatial non-uniformity in deformable image registration via a quasi-volume-preserving constraint.

The choice of a reference image typically influences the results of deformable image registration, thereby making it asymmetric. This is a consequence of a spatially non-uniform weighting in the cost function integral that leads to general registration inaccuracy. The inhomogeneous integral measure--which is the local volume change in the transformation, thus varying through the course of the registration--causes image regions to contribute differently to the objective function. More importantly, the optimization algorithm is allowed to minimize the cost function by manipulating the volume change, instead of aligning the images. The approaches that restore symmetry to deformable registration successfully achieve inverse-consistency, but do not eliminate the regional bias that is the source of the error. In this work, we address the root of the problem: the non-uniformity of the cost function integral. We introduce a new quasi-volume-preserving constraint that allows for volume change only in areas with well-matching image intensities, and show that such a constraint puts a bound on the error arising from spatial non-uniformity. We demonstrate the advantages of adding the proposed constraint to standard (asymmetric and symmetrized) demons and diffeomorphic demons algorithms through experiments on synthetic images, and real X-ray and 2D/3D brain MRI data. Specifically, the results show that our approach leads to image alignment with more accurate matching of manually defined neuroanatomical structures, better tradeoff between image intensity matching and registration-induced distortion, improved native symmetry, and lower susceptibility to local optima. In summary, the inclusion of this space- and time-varying constraint leads to better image registration along every dimension that we have measured it.

An algorithm for optimal fusion of atlases with different labeling protocols.

In this paper we present a novel label fusion algorithm suited for scenarios in which different manual delineation protocols with potentially disparate structures have been used to annotate the training scans (hereafter referred to as "atlases"). Such scenarios arise when atlases have missing structures, when they have been labeled with different levels of detail, or when they have been taken from different heterogeneous databases. The proposed algorithm can be used to automatically label a novel scan with any of the protocols from the training data. Further, it enables us to generate new labels that are not present in any delineation protocol by defining intersections on the underling labels. We first use probabilistic models of label fusion to generalize three popular label fusion techniques to the multi-protocol setting: majority voting, semi-locally weighted voting and STAPLE. Then, we identify some shortcomings of the generalized methods, namely the inability to produce meaningful posterior probabilities for the different labels (majority voting, semi-locally weighted voting) and to exploit the similarities between the atlases (all three methods). Finally, we propose a novel generative label fusion model that can overcome these drawbacks. We use the proposed method to combine four brain MRI datasets labeled with different protocols (with a total of 102 unique labeled structures) to produce segmentations of 148 brain regions. Using cross-validation, we show that the proposed algorithm outperforms the generalizations of majority voting, semi-locally weighted voting and STAPLE (mean Dice score 83%, vs. 77%, 80% and 79%, respectively). We also evaluated the proposed algorithm in an aging study, successfully reproducing some well-known results in cortical and subcortical structures.

Automatic clustering and population analysis of white matter tracts using maximum density paths.

We introduce a framework for population analysis of white matter tracts based on diffusion-weighted images of the brain. The framework enables extraction of fibers from high angular resolution diffusion images (HARDI); clustering of the fibers based partly on prior knowledge from an atlas; representation of the fiber bundles compactly using a path following points of highest density (maximum density path; MDP); and registration of these paths together using geodesic curve matching to find local correspondences across a population. We demonstrate our method on 4-Tesla HARDI scans from 565 young adults to compute localized statistics across 50 white matter tracts based on fractional anisotropy (FA). Experimental results show increased sensitivity in the determination of genetic influences on principal fiber tracts compared to the tract-based spatial statistics (TBSS) method. Our results show that the MDP representation reveals important parts of the white matter structure and considerably reduces the dimensionality over comparable fiber matching approaches.

Selective Functional Connectivity between Ocular Dominance Columns in the Primary Visual Cortex.

The primary visual cortex (V1) in humans and many animals is comprised of fine-scale neuronal ensembles that respond preferentially to the stimulation of one eye over the other, also known as the ocular dominance columns (ODCs). Despite its importance in shaping our perception, to date, the nature of the functional interactions between ODCs has remained poorly understood. In this work, we aimed to improve our understanding of the interaction mechanisms between fine-scale neuronal structures distributed within V1. To that end, we applied high-resolution functional MRI to study mechanisms of functional connectivity between ODCs. Using this technique, we quantified the level of functional connectivity between ODCs as a function of the ocular preference of ODCs, showing that alike ODCs are functionally more connected compared to unalike ones. Through these experiments, we aspired to contribute to filling the gap in our knowledge of the functional connectivity of ODCs in humans as compared to animals.

Harmonization of Structural Brain Connectivity through Distribution Matching.

The increasing prevalence of multi-site diffusion-weighted magnetic resonance imaging (dMRI) studies potentially offers enhanced statistical power for investigating brain structure. However, these studies face challenges due to variations in scanner hardware and acquisition protocols. While several methods exist for dMRI data harmonization, few specifically address structural brain connectivity. We introduce a new distribution-matching approach to harmonizing structural brain connectivity across different sites and scanners. We evaluate our method using structural brain connectivity data from two distinct datasets of OASIS-3 and ADNI-2, comparing its performance to the widely used ComBat method. Our approach is meant to align the statistical properties of connectivity data from these two datasets. We examine the impact of harmonization on the correlation of brain connectivity with the Mini-Mental State Examination score and age. Our results demonstrate that our distribution-matching technique more effectively harmonizes structural brain connectivity, often producing stronger and more significant correlations compared to ComBat. Qualitative assessments illustrate the desired distributional alignment of ADNI-2 with OASIS-3, while quantitative evaluations confirm robust performance. This work contributes to the growing field of dMRI harmonization, potentially improving the reliability and comparability of structural connectivity studies that combine data from different sources in neuroscientific and clinical research.

Automatic Geometry-based Estimation of the Locus Coeruleus Region on T1-Weighted Magnetic Resonance Images.

The locus coeruleus (LC) is a key brain structure implicated in cognitive function and neurodegenerative disease. Automatic segmentation of the LC is a crucial step in quantitative non-invasive analysis of the LC in large MRI cohorts. Most publicly available imaging databases for training automatic LC segmentation models take advantage of specialized contrast-enhancing (e.g., neuromelanin-sensitive) MRI. Segmentation models developed with such image contrasts, however, are not readily applicable to existing datasets with conventional MRI sequences. In this work, we evaluate the feasibility of using non-contrast neuroanatomical information to geometrically approximate the LC region from standard 3-Tesla T1-weighted images of 20 subjects from the Human Connectome Project (HCP). We employ this dataset to train and internally/externally evaluate two automatic localization methods, the Expected Label Value and the U-Net. We also test the hypothesis that using the phase image as input can improve the robustness of out-of-sample segmentation. We then apply our trained models to a larger subset of HCP, while exploratorily correlating LC imaging variables and structural connectivity with demographic and clinical data. This report contributes and provides an evaluation of two computational methods estimating neural structure.

Automatic geometry-based estimation of the locus coeruleus region on T1-weighted magnetic resonance images.

The locus coeruleus (LC) is a key brain structure implicated in cognitive function and neurodegenerative disease. Automatic segmentation of the LC is a crucial step in quantitative non-invasive analysis of the LC in large MRI cohorts. Most publicly available imaging databases for training automatic LC segmentation models take advantage of specialized contrast-enhancing (e.g., neuromelanin-sensitive) MRI. Segmentation models developed with such image contrasts, however, are not readily applicable to existing datasets with conventional MRI sequences. In this work, we evaluate the feasibility of using non-contrast neuroanatomical information to geometrically approximate the LC region from standard 3-Tesla T1-weighted images of 20 subjects from the Human Connectome Project (HCP). We employ this dataset to train and internally/externally evaluate two automatic localization methods, the Expected Label Value and the U-Net. For out-of-sample segmentation, we compare the results with atlas-based segmentation, as well as test the hypothesis that using the phase image as input can improve the robustness. We then apply our trained models to a larger subset of HCP, while exploratorily correlating LC imaging variables and structural connectivity with demographic and clinical data. This report provides an evaluation of computational methods estimating neural structure.

Multi-Head Graph Convolutional Network for Structural Connectome Classification.

We tackle classification based on brain connectivity derived from diffusion magnetic resonance images. We propose a machine-learning model inspired by graph convolutional networks (GCNs), which takes a brain-connectivity input graph and processes the data separately through a parallel GCN mechanism with multiple heads. The proposed network is a simple design that employs different heads involving graph convolutions focused on edges and nodes, thoroughly capturing representations from the input data. To test the ability of our model to extract complementary and representative features from brain connectivity data, we chose the task of sex classification. This quantifies the degree to which the connectome varies depending on the sex, which is important for improving our understanding of health and disease in both sexes. We show experiments on two publicly available datasets: PREVENT-AD (347 subjects) and OASIS3 (771 subjects). The proposed model demonstrates the highest performance compared to the existing machine-learning algorithms we tested, including classical methods and (graph and non-graph) deep learning. We provide a detailed analysis of each component of our model.

Intermediate Deformable Image Registration via Windowed Cross-Correlation.

In population and longitudinal imaging studies that employ deformable image registration, more accurate results can be achieved by initializing deformable registration with the results of affine registration where global misalignments have been considerably reduced. Such affine registration, however, is limited to linear transformations and it cannot account for large nonlinear anatomical variations, such as those between pre- and post-operative images or across different subject anatomies. In this work, we introduce a new intermediate deformable image registration (IDIR) technique that recovers large deformations via windowed cross-correlation, and provide an efficient implementation based on the fast Fourier transform. We evaluate our method on 2D X-ray and 3D magnetic resonance images, demonstrating its ability to align substantial nonlinear anatomical variations within a few iterations.

Exploratory Correlation of The Human Structural Connectome with Non-MRI Variables in Alzheimer's Disease.

INTRODUCTION: Discovery of the associations between brain structural connectivity and clinical and demographic variables can help to better understand the vulnerability and resilience of the brain architecture to neurodegenerative diseases and to discover biomarkers. METHODS: We used four diffusion-MRI databases, three related to Alzheimer's disease, to exploratorily correlate structural connections between 85 brain regions with non-MRI variables, while stringently correcting the significance values for multiple testing and ruling out spurious correlations via careful visual inspection. We repeated the analysis with brain connectivity augmented with multi-synaptic neural pathways. RESULTS: We found 85 and 101 significant relationships with direct and augmented connectivity, respectively, which were generally stronger for the latter. Age was consistently linked to decreased connectivity, and healthier clinical scores were generally linked to increased connectivity. DISCUSSION: Our findings help to elucidate which structural brain networks are affected in Alzheimer's disease and aging and highlight the importance of including indirect connections.

IA-GCN: Interpretable Attention based Graph Convolutional Network for Disease Prediction.

Interpretability in Graph Convolutional Networks (GCNs) has been explored to some extent in general in computer vision; yet, in the medical domain, it requires further examination. Most of the interpretability approaches for GCNs, especially in the medical domain, focus on interpreting the output of the model in a post-hoc fashion. In this paper, we propose an interpretable attention module (IAM) that explains the relevance of the input features to the classification task on a GNN Model. The model uses these interpretations to improve its performance. In a clinical scenario, such a model can assist the clinical experts in better decision-making for diagnosis and treatment planning. The main novelty lies in the IAM, which directly operates on input features. IAM learns the attention for each feature based on the unique interpretability-specific losses. We show the application of our model on two publicly available datasets, Tadpole and the UK Biobank (UKBB). For Tadpole we choose the task of disease classification, and for UKBB, age, and sex prediction. The proposed model achieves an increase in an average accuracy of 3.2% for Tadpole and 1.6% for UKBB sex and 2% for the UKBB age prediction task compared to the state-of-the-art. Further, we show exhaustive validation and clinical interpretation of our results.

Exploratory correlation of the human structural connectome with non-MRI variables in Alzheimer's disease.

Introduction: Discovery of the associations between brain structural connectivity and clinical and demographic variables can help to better understand the vulnerability and resilience of the brain architecture to neurodegenerative diseases and to discover biomarkers. Methods: We used four diffusion-MRI databases, three related to Alzheimer's disease (AD), to exploratorily correlate structural connections between 85 brain regions with non-MRI variables, while stringently correcting the significance values for multiple testing and ruling out spurious correlations via careful visual inspection. We repeated the analysis with brain connectivity augmented with multi-synaptic neural pathways. Results: We found 85 and 101 significant relationships with direct and augmented connectivity, respectively, which were generally stronger for the latter. Age was consistently linked to decreased connectivity, and healthier clinical scores were generally linked to increased connectivity. Discussion: Our findings help to elucidate which structural brain networks are affected in AD and aging and highlight the importance of including indirect connections.