We present the unified computational framework for modeling the sulcal patterns of human brain obtained from the magnetic resonance images. The Wasserstein distance is used to align the sulcal patterns nonlinearly. These patterns are topologically different across subjects making the pattern matching a challenge. We work out the mathematical details and develop the gradient descent algorithms for estimating the deformation field. We further quantify the image registration performance. This method is applied in identifying the differences between male and female sulcal patterns.

Abstract The three-dimensional folding of DNA is essential for genome function, but its organization remains difficult to summarize quantitatively across genomic scales. Here, we study DNA folding from Hi-C contact data using a network-based notion of fractal dimension. In this representation, genomic loci are treated as nodes, and observed Hi-C contacts define weighted edges, so that frequently interacting loci are closer in the resulting network. We then estimate fractal dimension using two complementary graph-based methods: the correlation dimension and the sandbox dimension. Validation on synthetic networks shows that the proposed estimators detect clear scaling behavior in hierarchical fractal-like networks, while distinguishing them from networks with local clustering but no stable multiscale self-similarity. Applied to intrachromosomal Hi-C data from the IMR90 human cell line, the method reveals approximate linear scaling regimes on log–log plots, suggesting fractal-like organization in chromatin contact networks. At the chromosome level, estimated fractal dimension tends to increase with chromosome size: larger chromosomes often have dimensions closer to 3, consistent with more compact and space-filling organization, whereas shorter chromosomes tend to have lower dimensions, closer to 1, consistent with simpler and more open folding patterns. A sliding-window analysis at 5 kb resolution further shows that fractal organization varies substantially along chromosomes rather than remaining uniform across genomic position. These results suggest that graph-based fractal dimension provides an interpretable summary of DNA folding complexity at both global and local scales. More broadly, the proposed framework offers a quantitative way to study multiscale genome organization from Hi-C data using tools from network geometry.

Graph neural networks (GNNs) have proven effective in capturing relationships among nodes in a graph. This study introduces a novel perspective by considering a graph as a simplicial complex, encompassing nodes, edges, triangles, and $k$k-simplices, enabling the definition of graph-structured data on any $k$k-simplex. We design a novel Hodge-Laplacian heterogeneous graph attention network (HL-HGAT) to learn heterogeneous signal representations across $k$k-simplices. The HL-HGAT incorporates three key components: HL convolutional filters (HL-filters), simplicial projection (SP), and simplicial attention pooling (SAP) operators, applied to $k$k-simplices. HL-filters leverage the unique topology of $k$k-simplices encoded by the Hodge-Laplacian (HL) operator, operating within the spectral domain of the $k$k-th HL operator. To address computation challenges, we introduce a polynomial approximation for HL-filters, exhibiting spatial localization properties. Additionally, we propose a pooling operator to coarsen $k$k-simplices, combining features through simplicial attention mechanisms of self-attention and cross-attention via transformers and SP operators, capturing topological interconnections across multiple dimensions of simplices. The HL-HGAT is comprehensively evaluated across diverse graph applications, including NP-hard problems, graph multi-label and classification challenges, and graph regression tasks in logistics, computer vision, biology, chemistry, and neuroscience. The results demonstrate the model's efficacy and versatility in handling a wide range of graph-based scenarios.

We analyze brain networks by decomposing them into three orthogonal components: gradient, curl, and harmonic flows, through the Hodge decomposition, a technique advantageous for capturing complex topological features. A Wasserstein distance based topological inference is developed to determine the statistical significance of each component. The Hodge decomposition is applied to human brain networks obtained from a resting-state fMRI study. Our results indicate statistically significant differences in the topological features between male and female brain networks.

In brain network analysis using resting-state fMRI, there is growing interest in modeling higher-order interactions beyond simple pairwise connectivity via persistent homology. Despite the promise of these advanced topological tools, robust and consistently observed higher-order interactions over time remain elusive. In this study, we investigate why conventional analyses often fail to reveal complex higher-order structures - such as interactions involving four or more nodes - and explore whether such interactions truly exist in functional brain networks. We utilize a simplicial complex framework often used in persistent homology to address this question.

We present a novel topological framework for analyzing functional brain signals using time-frequency analysis. By integrating persistent homology with time-frequency representations, we capture multi-scale topological features that characterize the dynamic behavior of brain activity. This approach identifies 0D (connected components) and 1D (loops) topological structures in the signal's time-frequency domain, enabling robust extraction of features invariant to noise and temporal misalignments. The proposed method is demonstrated on resting-state functional magnetic resonance imaging (fMRI) data, showcasing its ability to discern critical topological patterns and provide insights into functional connectivity. This topological approach opens new avenues for analyzing complex brain signals, offering potential applications in neuroscience and clinical diagnostics.

This paper presents a streamlined image analysis framework for correlating behavioral measures to anatomical measures on the cortex and detecting the regions of abnormal brain-behavior correlates. We correlated a facial emotion discrimination task score and its response time to cortical thickness measurements in a group of high functioning autistic subjects. Many previous correlation studies in brain imaging neglect to account for unwanted age effect and other variables and the subsequent statistical parametric maps may report spurious results. We demonstrate that the partial correlation mapping strategy proposed here can remove the effect of age and global cortical area difference effectively while localizing the regions of high correlation difference. The advantage of the proposed correlation mapping strategy over the general linear model framework is that we can directly visualize more intuitive correlation measures across the cortex in each group.

Amnestic mild cognitive impairment and Alzheimer’s disease (aAD) exhibit degeneration of white matter (WM) tracts preceding overt cognitive decline. However, WM changes in non-amnestic AD (naAD) are understudied. We hypothesized patterns of WM degeneration would differ between aAD and naAD. We compared WM degeneration, assessed by 30-direction diffusion-weighted imaging (DWI), in 41 individuals with aAD; 67 with naAD diagnoses including logopenic-variant primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), behavioral variant AD (bvAD), and corticobasal syndrome (CBS); and 45 with normal cognition (Table 1). We performed deterministic tractography between 148 cortical/subcortical regions; connectivity was quantified by generalized fractional anisotropy (GFA). Tractwise GFA and regional grey matter (GM) volumes were converted to W-scores adjusting for age and sex. We contrasted GFA between groups using regression models covarying for MMSE score. A mixed effects model was used to assess associations between tractwise GFA and volume of GM endpoints. Additionally, we computed the number of connected components in each person’s brain graph (i.e., number of subgraphs created by progressively stricter thresholds) across 100 GFA values. We contrasted this topological metric between groups and assessed its associations with MMSE and disease duration. GM volume was lower in naAD and aAD than controls (both p<0.0001) but did not differ between patient groups (p=0.81). aAD and naAD patients had shared WM degeneration in corpus callosum, cingulum, and inferior/superior longitudinal fasciculi; however, WM degeneration was more severe in naAD (Figure 1). In lvPPA, WM degeneration was left-lateralized; in PCA, GFA was reduced in bilateral parietal, occipital, and temporal areas (Figure 2). Across groups, GM and WM degeneration were significantly associated [F(1,20442)=326.0, p<0.0001]. Topological analysis indicated naAD but not aAD patients had lower global connectivity than controls. A higher component number (indicating reduced connectivity) was associated with longer disease duration and lower MMSE. Associations between GM volume and GFA suggest WM degeneration in naAD is related to AD pathologic change and not an independent process. Greater WM disease in naAD than aAD was not attributable to GM atrophy or symptom severity. Finally, topological metrics may serve as objective markers of global disease progression.

Childhood maltreatment may adversely affect brain development and consequently influence behavioral, emotional, and psychological patterns during adulthood. In this study, we propose an analytical pipeline for modeling the altered topological structure of brain white matter in maltreated and typically developing children. We perform topological data analysis (TDA) to assess the alteration in the global topology of the brain white-matter structural covariance network among children. We use persistent homology, an algebraic technique in TDA, to analyze topological features in the brain covariance networks constructed from structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). We develop a novel framework for statistical inference based on the Wasserstein distance to assess the significance of the observed topological differences. Using these methods in comparing maltreated children to a typically developing control group, we find that maltreatment may increase homogeneity in white matter structures and thus induce higher correlations in the structural covariance; this is reflected in the topological profile. Our findings strongly suggest that TDA can be a valuable framework to model altered topological structures of the brain. The MATLAB codes and processed data used in this study can be found at https://github.com/laplcebeltrami/maltreated.

Topological data analysis (TDA) is increasingly recognized as a promising tool in the field of neuroscience, unveiling the underlying topological patterns within brain signals. However, most TDA related methods treat brain signals as if they were static, i.e., they ignore potential non-stationarities and irregularities in the statistical properties of the signals. In this study, we develop a novel fractal dimension-based testing approach that takes into account the dynamic topological properties of brain signals. By representing EEG brain signals as a sequence of Vietoris-Rips filtrations, our approach accommodates the inherent non-stationarities and irregularities of the signals. The application of our novel fractal dimension-based testing approach in analyzing dynamic topological patterns in EEG signals during an epileptic seizure episode exposes noteworthy alterations in total persistence across 0, 1, and 2-dimensional homology. These findings imply a more intricate influence of seizures on brain signals, extending beyond mere amplitude changes.

We introduce an innovative, data-driven topological data analysis (TDA) technique for estimating the state spaces of dynamically changing functional human brain networks at rest. Our method utilizes the Wasserstein distance to measure topological differences, enabling the clustering of brain networks into distinct topological states. This technique outperforms the commonly used k-means clustering in identifying brain network state spaces by effectively incorporating the temporal dynamics of the data without the need for explicit model specification. We further investigate the genetic underpinnings of these topological features using a twin study design, examining the heritability of such state changes. Our findings suggest that the topology of brain networks, particularly in their dynamic state changes, may hold significant hidden genetic information.

IntroductionMultimodal evidence indicates Alzheimer’s disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes.Materials and methodsParticipants included 45 cognitively normal (CN) individuals; 41 amnestic AD patients; and 67 patients with non-amnestic AD syndromes including logopenic-variant primary progressive aphasia (lvPPA, n = 32), posterior cortical atrophy (PCA, n = 17), behavioral variant AD (bvAD, n = 10), and corticobasal syndrome (CBS, n = 8). All had T1-weighted MRI and 30-direction diffusion-weighted imaging (DWI). We performed whole-brain deterministic tractography between 148 cortical and subcortical regions; connection strength was quantified by tractwise mean generalized fractional anisotropy. Regression models assessed effects of group and phenotype as well as associations with grey matter volume. Topological analyses assessed differences in persistent homology (numbers of graph components and cycles). Additionally, we tested associations of topological metrics with global cognition, disease duration, and DWI microstructural metrics.ResultsBoth amnestic and non-amnestic patients exhibited lower WM connection strength than CN participants in corpus callosum, cingulum, and inferior and superior longitudinal fasciculi. Overall, non-amnestic patients had more WM disease than amnestic patients. LvPPA patients had left-lateralized WM degeneration; PCA patients had reductions in connections to bilateral posterior parietal, occipital, and temporal areas. Topological analysis showed the non-amnestic but not the amnestic group had more connected components than controls, indicating persistently lower connectivity. Longer disease duration and cognitive impairment were associated with more connected components and fewer cycles in individuals’ brain graphs.DiscussionWe have previously reported syndromic differences in GM degeneration and tau accumulation between AD syndromes; here we find corresponding differences in WM tracts connecting syndrome-specific epicenters. Determining the reasons for selective WM degeneration in non-amnestic AD is a research priority that will require integration of knowledge from neuroimaging, biomarker, autopsy, and functional genetic studies. Furthermore, longitudinal studies to determine the chronology of WM vs. GM degeneration will be key to assessing evidence for WM-mediated tau spread.

Graph neural networks (GNNs) have proven effective in capturing relationships among nodes in a graph. This study introduces a novel perspective by considering a graph as a simplicial complex, encompassing nodes, edges, triangles, and $k$-simplices, enabling the definition of graph-structured data on any $k$-simplices. Our contribution is the Hodge-Laplacian heterogeneous graph attention network (HL-HGAT), designed to learn heterogeneous signal representations across $k$-simplices. The HL-HGAT incorporates three key components: HL convolutional filters (HL-filters), simplicial projection (SP), and simplicial attention pooling (SAP) operators, applied to $k$-simplices. HL-filters leverage the unique topology of $k$-simplices encoded by the Hodge-Laplacian (HL) operator, operating within the spectral domain of the $k$-th HL operator. To address computation challenges, we introduce a polynomial approximation for HL-filters, exhibiting spatial localization properties. Additionally, we propose a pooling operator to coarsen $k$-simplices, combining features through simplicial attention mechanisms of self-attention and cross-attention via transformers and SP operators, capturing topological interconnections across multiple dimensions of simplices. The HL-HGAT is comprehensively evaluated across diverse graph applications, including NP-hard problems, graph multi-label and classification challenges, and graph regression tasks in logistics, computer vision, biology, chemistry, and neuroscience. The results demonstrate the model's efficacy and versatility in handling a wide range of graph-based scenarios.

We introduce a novel, data-driven topological data analysis (TDA) approach for embedding brain networks into a lower-dimensional space in quantifying the dynamics of temporal lobe epilepsy (TLE) obtained from resting-state functional magnetic resonance imaging (rs-fMRI). This embedding facilitates the orthogonal projection of 0D and 1D topological features, allowing for the visualization and modeling of the dynamics of functional human brain networks in a resting state. We then quantify the topological disparities between networks to determine the coordinates for embedding. This framework enables us to conduct a coherent statistical inference within the embedded space. Our results indicate that brain network topology in TLE patients exhibits increased rigidity in 0D topology but more rapid flections compared to that of normal controls in 1D topology.

Developing reliable methods to discriminate different transient brain states that change over time is a key neuroscientific challenge in brain imaging studies. Topological data analysis (TDA), a novel framework based on algebraic topology, can handle such a challenge. However, existing TDA has been somewhat limited to capturing the static summary of dynamically changing brain networks. We propose a novel dynamic-TDA framework that builds persistent homology over a time series of brain networks. We construct a Wasserstein distance based inference procedure to discriminate between time series of networks. The method is applied to the resting-state functional magnetic resonance images of human brain. We demonstrate that our proposed dynamic-TDA approach can distinctly discriminate between the topological patterns of male and female brain networks. MATLAB code for implementing this method is available at https://github.com/laplcebeltrami/PH-STAT.

Topological data analysis (TDA) has become a powerful approach over the last twenty years, mainly due to its ability to capture the shape and the geometry inherent in the data. Persistence homology, which is a particular tool in TDA, has been demonstrated to be successful in analyzing functional brain connectivity. One limitation of standard approaches is that they use arbitrarily chosen threshold values for analyzing connectivity matrices. To overcome this weakness, TDA provides a filtration of the weighted brain network across a range of threshold values. However, current analyses of the topological structure of functional brain connectivity primarily rely on overly simplistic connectivity measures, such as the Pearson orrelation. These measures do not provide information about the specific oscillators that drive dependence within the brain network. Here, we develop a frequency-specific approach that utilizes coherence, a measure of dependence in the spectral domain, to evaluate the functional connectivity of the brain. Our approach, the spectral TDA (STDA), has the ability to capture more nuanced and detailed information about the underlying brain networks. The proposed STDA method leads to a novel topological summary, the spectral landscape, which is a 2D-generalization of the persistence landscape. Using the novel spectral landscape, we analyze the EEG brain connectivity of patients with attention deficit hyperactivity disorder (ADHD) and shed light on the frequency-specific differences in the topology of brain connectivity between the controls and ADHD patients.

Traditional Topological Data Analysis (TDA) methods, such as Persistent Homology (PH), rely on distance measures (e.g., cross-correlation, partial correlation, coherence, and partial coherence) that are symmetric by definition. While useful for studying topological patterns in functional brain connectivity, the main limitation of these methods is their inability to capture the directional dynamics - which are crucial for understanding effective brain connectivity. We propose the Causality-Based Topological Ranking (CBTR) method, which integrates Causal Inference (CI) to assess effective brain connectivity with Hodge Decomposition (HD) to rank brain regions based on their mutual influence. Our simulations confirm that the CBTR method accurately and consistently identifies hierarchical structures in multivariate time series data. Moreover, this method effectively identifies brain regions showing the most significant interaction changes with other regions during seizures using electroencephalogram (EEG) data. These results provide novel insights into the brain’s hierarchical organization and illuminate the impact of seizures on its dynamics.

Understanding the common topological characteristics of the human brain network across a population is central to understanding brain functions. The abstraction of human connectome as a graph has been pivotal in gaining insights on the topological properties of the brain network. The development of group-level statistical inference procedures in brain graphs while accounting for the heterogeneity and randomness still remains a difficult task. In this study, we develop a robust statistical framework based on persistent homology using the order statistics for analyzing brain networks. The use of order statistics greatly simplifies the computation of the persistent barcodes. We validate the proposed methods using comprehensive simulation studies and subsequently apply to the resting-state functional magnetic resonance images. We found a statistically significant topological difference between the male and female brain networks.

Persistent homology offers a powerful tool for extracting hidden topological signals from brain networks. It captures the evolution of topological structures across multiple scales, known as filtrations, thereby revealing topological features that persist over these scales. These features are summarized in persistence diagrams, and their dissimilarity is quantified using the Wasserstein distance. However, the Wasserstein distance does not follow a known distribution, posing challenges for the application of existing parametric statistical models. To tackle this issue, we introduce a unified topological inference framework centered on the Wasserstein distance. Our approach has no explicit model and distributional assumptions. The inference is performed in a completely data driven fashion. We apply this method to resting-state functional magnetic resonance images (rs-fMRI) of temporal lobe epilepsy patients collected from two different sites: the University of Wisconsin-Madison and the Medical College of Wisconsin. Importantly, our topological method is robust to variations due to sex and image acquisition, obviating the need to account for these variables as nuisance covariates. We successfully localize the brain regions that contribute the most to topological differences. A MATLAB package used for all analyses in this study is available at https://github.com/laplcebeltrami/PH-STAT.

We introduce PH-STAT, a comprehensive Matlab toolbox designed for performing a wide range of statistical inferences on persistent homology. Persistent homology is a prominent tool in topological data analysis (TDA) that captures the underlying topological features of complex data sets. The toolbox aims to provide users with an accessible and user-friendly interface for analyzing and interpreting topological data. The package is distributed in https://github.com/laplcebeltrami/PH-STAT.