Altered topological structure of the brain white matter in maltreated children through topological data analysis

Child maltreatment can have severe lifelong mental, emotional, physical, and sexual health outcomes (World Health Organization, 2022). These serious long-term consequences are notable given that the US Department of Health and Human Services estimates over 680,000 children suffer different forms of maltreatment, such as child abuse or neglect, every year. Many of the adverse impacts likely emerge through changes in neurobiology, such as reduced brain volumes and altered brain connectivity (Herringa et al., 2013). Indeed, a growing body of scientific research has found altered brain functioning in those who have suffered early childhood abuse and neglect (Hanson et al., 2010; McCrory, De Brito, & Viding, 2010; Shonkoff et al., 2012; Wilson, Hansen, & Li, 2011). Multiple studies have shown that maltreatment in childhood can lead to a decrease in the volume of the corpus callosum, the largest white matter structure in the brain, which is critical for interhemispheric communication (McCrory et al., 2010; Wilson et al., 2011). Similarly, neglected children tend to have smaller prefrontal cortex volumes, which play a role in regulating behavior, emotion, and cognition (National Scientific Council on the Developing Child, 2010; US Department of Health and Human Services, 2010). These neurological changes, especially those in brain connectivity, may profoundly influence children’s emotional, social, and behavioral functioning (Hostinar, Stellern, Schaefer, Carlson, & Gunnar, 2012; US Department of Health and Human Services, 2010).

Both structural magnetic resonance imaging (MRI) and diffusion MRI facilitate studies on the impact of abuse and neglect on brain development during childhood (Hanson et al., 2012; Jackowski, De Araújo, De Lacerda, de Jesus Mari, & Kaufman, 2009; Loman et al., 2013; Pollak, 2008). Tensor-based morphometry (TBM) serves as a powerful tool to quantify the variations in neuroanatomical structures by analyzing the spatial derivatives of deformation fields. These fields are obtained via nonlinear image registration techniques that warp individual structural MRI scans to a common template (M. K. Chung et al., 2001; Thompson et al., 1998). The Jacobian determinant, derived from this warping process, measures the volumetric changes in brain tissue at the voxel level (Davatzikos et al., 1996; Dubb, Gur, Avants, & Gee, 2003; Machado & Gee, 1998). For each voxel, a linear model is set up to use tensor maps, such as the Jacobian determinant, as a response variable for obtaining voxel-level statistics. Although univariate TBM has been widely utilized (M. K. Chung et al., 2001; Thompson & Toga, 1998), its limitations emerge when hypothesis testing extends to multiple anatomical brain regions; it may not adequately capture the interrelationships between volume changes in different voxels. This gap underscores the need for a network analysis approach to model the Jacobian determinant, linking variations in one region to another through structural covariance (Cao & Worsley, 1999; He, Chen, & Evans, 2007, 2008; J. P. Lerch et al., 2006; Rao, Aljabar, & Rueckert, 2008; K. J. Worsley, Charil, Lerch, & Evans, 2005; K. J. Worsley, Chen, Lerch, & Evans, 2005).

Keith J. Worsley laid the foundation for modeling structural covariance using cortical thickness obtained from T1-MRI in 2005 (J. P. Lerch et al., 2006; K. J. Worsley, Charil, et al., 2005; K. J. Worsley, Chen, et al., 2005). Worsley’s contributions were instrumental in framing the concept of structural covariance as the statistical association between morphological characteristics of different brain regions. His work inspired a wealth of research that employed statistical models to quantify these associations. After Worsley’s initial contributions, the field saw significant developments with greater sophistication (He et al., 2007, 2008; J. P. Lerch et al., 2006). In the early 2010s, studies began to explore the application of structural covariance in various neurological and psychiatric conditions, such as Alzheimer’s disease (AD), schizophrenia, and developmental disorders including fragile X syndrome (Cao & Worsley, 1999; Rao et al., 2008; Saggar et al., 2015). DuPre and Spreng (2017) used the gray matter probability map obtained from the SPM package in modeling the life span of structural covariance networks in the normal population. These studies often employed machine learning and network theory to create more complex models that could capture the intricate relationships between different brain regions. Most recently, the notion of structural covariance has been integrated into multimodal imaging studies, which combine different types of neuroimaging data to provide a more comprehensive view of brain structure and function (M. K. Chung, Hanson, Ye, Davidson, & Pollak, 2015; Davatzikos et al., 1996; Machado & Gee, 1998).

Graph theory–based methods have been frequently used to uncover the topological properties of brain networks including the investigation of topological alterations in white matter for neuromyelitis optica (Y. Liu et al., 2012), exploring abnormal topological organization in the structure of cortical networks in AD (Lo et al., 2010), alterations in the topological properties of the anatomical network in early blindness (Shu et al., 2009), and abnormal topological changes during AD progression (Daianu et al., 2015; Kuang et al., 2020; T. Qiu et al., 2016). Graph theory also has been used to measure and evaluate the integration and segregation of the brain network (Kuang et al., 2020; Rubinov & Sporns, 2010). In the standard graph theory–based brain network analysis, graph features such as node degrees and clustering coefficients are obtained after thresholding connectivity matrices (M. K. Chung, 2019; M. K. Chung et al., 2017; Van Wijk, Stam, & Daffertshofer, 2010). Depending on the choice of these thresholds, the final statistical results can be drastically different (M. K. Chung et al., 2013; M. K. Chung, Hanson, Ye, Davidson, & Pollak, 2015; H. Lee, Kang, Chung, Kim, & Lee, 2012). Thus, there is a practical need to develop a multiscale network analysis framework that provides a consistent result and interpretation regardless of the choice of thresholding. Persistent homology offers one possible solution to the multiscale problem (Carlsson & Mémoli, 2008; M. K. Chung et al., 2013; M. K. Chung, Singh, Kim, Dalton, & Davidson, 2009; Edelsbrunner, Letscher, & Zomorodian, 2000; Ghrist, 2008; H. Lee, Chung, Kang, Kim, & Lee, 2011; H. Lee et al., 2012; Singh et al., 2008).

Persistent homology has gained popularity for its capability to analyze high-dimensional feature spaces without model assumptions (M. K. Chung et al., 2009; Edelsbrunner et al., 2000; Ghrist, 2008; H. Lee et al., 2011). Instead of studying networks at a fixed scale, persistent homology summarizes the changes of topological features over different scales and finds the most persistent topological features that are robust to perturbations (M. K. Chung, Lee, DiChristofano, Ombao, & Solo, 2019). This robust performance under different scales is needed for network models that are parameter and scale dependent. In persistent homology, instead of building networks at one fixed parameter that may not be optimal (Edelsbrunner & Harer, 2008; Ghrist, 2008), we analyze the collection of networks over every possible threshold (H. Lee et al., 2011, 2012). It has been shown that the persistent homology approach can be effectively used to overcome the problem related to the arbitrariness of thresholding (D. S. Lee, 2019). Persistent homology can detect subtle topological differences between networks while existing statistical models might fail to differentiate the differences (A. Qiu, Lee, Tan, & Chung, 2015; Solo et al., 2018; Zhu, Suk, & Shen, 2014). In C. Liu et al. (2021), persistent homology has been applied to characterize the neuropsychological properties of the brain. In Xing, Jia, Wu, and Kuang (2022), persistent homology has been used to study the evolution of a spatiotemporal brain network of AD. They have also proposed that persistent homology can be considered as a framework to assess the neurophysiological properties of image quality. Topological data analysis (TDA) has been applied to brain networks to classify altered brain states (Caputi, Pidnebesna, & Hlinka, 2021). TDA also has been used to extract the topology of brain connectomes in attention deficit hyperactivity disorder (ADHD) (Gracia-Tabuenca, Díaz-Patiño, Arelio, & Alcauter, 2020). TDA also found applications in EEG signal analysis (Khalid, Kim, Chung, Ye, & Jeon, 2014; Piangerelli, Rucco, Tesei, & Merelli, 2018; Wang, Ombao, & Chung, 2019).

Various topological features and embedding have been developed. The persistence diagram serves as an indicator, displaying the birth and death times of holes or cycles as the scale changes. Important topological invariants, known as Betti numbers, count the number of holes in networks and can be used to visualize and quantify underlying topology. Betti curves, which plot these Betti numbers over changing scales, have been employed to detect abnormal functional brain networks in the study of AD progression (Kuang et al., 2020). Furthermore, a variety of quantitative persistent homology features exist, such as persistence landscapes (Bubenik & Dłotko, 2017), persistent entropy (Rucco, Castiglione, Merelli, & Pettini, 2016), and persistence images (Adams et al., 2017). These features have been utilized to analyze and compare brain networks across different patients (Caputi et al., 2021). Mapper is another commonly used TDA technique, particularly useful for simplifying high-dimensional data into network representations by providing insights into the clustering and connectedness of data points in a feature space (Patania et al., 2019; Saggar et al., 2018). Mapper can be effective in capturing the network modularity and revealing the hierarchical organization of functional brain connectivity (Patania et al., 2019). Saggar et al. (2018) used Mapper to construct the low-dimensional representations of temporally changing task fMRI brain networks. Petri et al. (2014) introduces the clique filtration in building homological scaffolds that serve as the backbone for understanding the topological organization of fMRI brain networks. These tools are particularly useful in capturing the intricate higher order topological features, such as loops and voids, that are often not readily accessible in existing methods.

In this study, we use TDA to investigate alterations in the white matter structures of children who have experienced maltreatment. Utilizing both T1-MRI and diffusion tensor imaging (DTI) scans, we focus on the structural covariance of the brain’s white matter. Techniques from persistent homology are employed to characterize these changes, specifically using the Jacobian determinant from tensor-based morphometry (TBM) and fractional anisotropy (FA) values from DTI. Unlike univariate-TBM, persistent homology enables us to examine more intricate network hypotheses, capturing subtle variations across voxels. We quantify these topological properties using Betti curves and apply the Wasserstein distance to differentiate between maltreated and control groups. This methodology allows us to robustly characterize topological structures at multiple scales. Our results reveal that maltreated children exhibit significant alterations in white matter topology compared with controls, including a lower number of connected components, suggesting less heterogeneous white matter structures.

Figure 1 displays the overall pipeline for group-level network analysis. Even though the method is applied to structural covariance networks, it works for any type of network as long as the networks are represented as weighted graphs.

The topological distance between persistence diagrams is often measured using the 2-Wasserstein distance. For graph filtrations, the persistence diagrams consist of 1D sorted birth or death values. Thus, the Wasserstein distance can be computed through order statistics on edge weights (Das, Anand, & Chung, 2023; Songdechakraiwut & Chung, 2023).

To see the effect of the Wasserstein distance, we generated four circular patterns of identical topology (Figure 3). Along the circles, we uniformly sampled 60 nodes and added Gaussian noise N(0, 0.3²) on the coordinates. We generated five random networks per group. The Euclidean distance (L₂-norm) between randomly generated points are used to build connectivity matrices. Figure 3 displays the superposition of nodes from five networks in each group. Since they are topologically equivalent, the distance between networks should show no clustering pattern. In fact the Wasserstein distance d = d₀ + d₁ shows no discernible clustering pattern, while L₂-norm shows the clustering pattern. The L₂-norm distance is particularly large between horizontal (Groups 1 and 2) and vertical (Groups 3 and 4) patterns.

In numerical implementation, to mitigate potential bias and hasten convergence, we intersperse a full permutation among every 1,000 transpositions. Figure 4 shows distributions of within- and between-group distance and the convergence plot of the transposition test. Our approach does not assume any specific distribution for the test statistic, making it robust against varying variances between groups. Like the standard permutation test, the transposition test approximates the null distribution of the test statistic, allowing us to quantify deviations in the observed data from the null distribution (Bullmore et al., 1999; M. K. Chung, Wang, Huang, & Lyu, 2018; Hayasaka, Phan, Liberzon, Worsley, & Nichols, 2004; Nichols & Holmes, 2002).

The between-group distance is expected to be larger than the within-group distance. Under the null hypothesis, Z should asymptotically follow the standard normal distribution N(0, 1). Figure 4 displays the distributions of within- and between-group distances for each topological distance used in our study.

The study included 23 children who suffered maltreatment in early life, and 31 age-matched typically developing comparison children (M. K. Chung et al., 2013, 2015; Hanson et al., 2013). All subjects were scanned at the University of Wisconsin–Madison. The maltreated sample suffered early childhood neglect, as they were initially raised in institutional settings; in such settings, there is a lack of toys or stimulation, unresponsive caregiving, and an overall dearth of individualized care and attention (Rutter, 1998). These children were, however, then adopted and then moved into normative caregiving environments. For the controls, we selected children without a history of maltreatment from families with similar ranges of socioeconomic statuses. The exclusion criteria include, among many others, congenital abnormalities (e.g., Down syndrome or cerebral palsy) and fetal alcohol syndrome. The average age for maltreated children was 11.26 ± 1.71 years while that of controls was 11.58 ± 1.61 years. This particular age range was selected since this development period is characterized by major regressive and progressive brain changes (Hanson et al., 2013; Lenroot & Giedd, 2006). There were 10 boys and 13 girls in the maltreated group and 18 boys and 13 girls in the control group. Groups did not statistically differ on age, pubertal stage, sex, or socioeconomic status (Hanson et al., 2013). The average amount of time spent in institutional care by children was 2.5 years ± 1.4 years, with a range from 3 months to 5.4 years. Children were on average 3.2 years old ± 1.9 months when they were adopted, with a range of 3 months to 7.7 years. T1-weighted MRI were collected using a 3T General Electric SIGNA scanner (Waukesha, WI) with a quadrature birdcage head coil. DTI were also collected in the same scanner using a cardiac-gated, diffusion-weighted, spin-echo, single-shot, EPI pulse sequence (Hanson et al., 2013). Diffusion tensor encoding was achieved using 12 optimum non-collinear encoding directions with a diffusion weighting of 1,114 s/mm² and a non-DW T2-weighted reference image. Other imaging parameters were TE = 78.2 ms, 3 averages (NEX: magnitude averaging), and an image acquisition matrix of 120 × 120 over a field of view of 240 × 240 mm². The acquired voxel size of 2 × 2 × 3 mm was interpolated to 0.9375 mm isotropic dimensions (256 × 256 in plane image matrix). To minimize field inhomogeneity and image artifacts, high-order shimming and field map images were collected using a pair of non-EPI gradient echo images at two echo times: TE1 = 8 ms and TE2 = 11 ms.

For T1-MRI, a study-specific template was constructed using the diffeomorphic shape and intensity averaging technique through Advanced Normalization Tools (ANTS) (Avants, Epstein, Grossman, & Gee, 2008). Image normalization of each individual image to the template was done using symmetric normalization with cross-correlation as the similarity metric. The 1-mm resolution inverse deformation fields are then smoothed out with a Gaussian kernel of 4-mm (full width at half maximum). The Jacobian determinants of the inverse deformations from the template to individual subjects were computed at each voxel. The Jacobian determinants measure the amount of voxel-wise change from the template to the individual subjects (M. K. Chung et al., 2001). For diffusion MRI, images were corrected for eddy current–related distortion and head motion via FSL software, and distortions from field inhomogeneities were corrected using custom software based on the method given in Jezzard and Clare (1999) before performing a nonlinear tensor estimation using CAMINO (Camino, 2006). Subsequently, we used an iterative tensor image registration strategy for spatial normalization using DTI-ToolKit (Joshi, Davis, Jomier, & Gerig, 2004; Zhang et al., 2007). Then fractional anisotropy (FA) values were calculated for diffusion tensor volumes diffeomorphically registered to the study-specific template.

White matter was segmented into tissue probability maps using template-based priors and then registered to a study-specific template (Bonner & Grossman, 2012; M. K. Chung et al., 2015). We thresholded the white matter density at a value of 0.7 to obtain an isosurface, which is located within the white matter rather than at the boundary between gray and white matter. Our interest lies in detecting changes along this surface close to the actual tissue boundary. This isosurface was represented as a triangle mesh with 189,536 vertices, resulting in an average internodal distance of 0.98 mm. Given the high correlation between Jacobian determinants and FA values at neighboring voxels, we uniformly sampled the mesh vertices to yield q = 548 nodes, which produced an average internodal distance of 15.7 mm. This distance is sufficiently large to avoid spuriously high correlations between adjacent nodes (see Figure 5). Subsequently, we computed 548 × 548 sample correlation matrices across subjects. Functional parcellations such as those by Gordon (Gordon et al., 2016) and Schaefer (Schaefer et al., 2018) are primarily based on fMRI studies and may not be well suited for structural covariance networks, which operate at higher spatial resolutions based on anatomical measurements. Furthermore, many existing parcellations focus mainly on gray matter, where DTI measurements such as FA can be difficult to estimate reliably. White matter tracts, reconstructed using tractography algorithms, do not consistently extend all the way to the gray matter, making it challenging to robustly estimate FA values from DTI in these regions (Maier-Hein et al., 2017).

Tractography was performed in the normalized space using the TEND algorithm and warped into the study template (Lazar et al., 2003). We utilized the Anatomical Automatic Labeling (AAL) atlas with 116 parcellations (Tzourio-Mazoyer et al., 2002). This atlas was registered to the study template via diffeomorphic image registration. The endpoints of fiber tracts were identified with respect to these 116 parcellations, and tracts passing between parcellations were counted. Tracts not passing through two given parcellations were excluded. We applied the proposed topological inference methods to the resulting structural connectivity matrices (Figure 6). The transposition test was conducted with 1 million transpositions. To accelerate convergence and mitigate potential bias, one permutation was introduced for every sequence of 1,000 consecutive transpositions. We did not observe any statistically significant topological differences between the groups. All three topological distances d₀, d₁, and d₀ + d₁ yielded p values of 0.56, 0.34, and 0.57, respectively.

Structural connectivity is characterized predominantly by a single, large connected component with few loops (M. K. Chung, Adluru, Dalton, Alexander, & Davidson, 2011). We found that 96% of all nodes formed a single gigantic connected tree. Thus, structural connectivity is primarily characterized by 0D homology, highlighting the deterministic and hierarchical nature of anatomical pathways between brain regions. Given trees with an identical number of nodes, they are all topologically equivalent. The direct application of TDA methods to structural connectivity matrices, therefore, diminishes statistical power.

We sequentially thresholded the correlation matrices to obtain graph filtrations. Figure 7 displays the thresholded structural covariance networks at correlation values 0.5, 0.6, 0.7, and 0.8. These networks reveal strongly correlated connections in maltreated children, indicating a highly homogeneous nature of white matter structures in this group. Higher correlation values would be expected if FA and Jacobian determinants are homogeneous within each group.

Since there is only one correlation matrix per group, this presents a challenge in group-level topological inference. Thus, we adapted the leave-one-out jackknife resampling to generate multiple correlation matrices per group as follows. There are m = 31 normal controls and n = 23 maltreated children in our sample. For the normal controls, we leave the ith subject out and compute the group-level correlation matrix using the remaining 30 subjects, denoting this matrix as X_i. This process is repeated for all subjects to obtain the structural covariance networks X₁, …, X_m. Similarly, for the maltreated children, we leave the ith subject out and compute the group-level correlation matrix using the remaining 22 subjects, denoting this as Y_i. This process is repeated to obtain Y₁, …, Y_n. These resampled correlation matrices are then fed into the proposed topological data analysis.

Using the resampled correlation matrices of the Jacobian determinants and FA values on 548 nodes, we calculated both the Betti-0 and the Betti-1 curves for all subjects (Figure 8). For the same filtration values, the Betti-0 curves indicated higher values, that is, more connected components, in the control group compared with the maltreated group. This observation implies that brain regions in the control group are less correlated across different regions, suggesting a more heterogeneous anatomical structure. This is in contrast to the maltreated group, which exhibited higher Betti-0 curves in the tractography-based connectivity study in the previous section. This suggests a less fractured and more interconnected network in the control group.

On the other hand, the Betti-1 curves for the maltreated group were higher than those for the control group (Figure 8). This indicates that maltreated children have more loops, which can occur only if there are denser and higher correlations in their structural covariance networks. This again points to a more homogeneous nature of the structural covariance networks in maltreated children. The pattern is reversed in the tractography-based connectivity study, where lower Betti-1 curves are observed for the maltreated group. While the loops in the structural covariance networks are statistical in nature, the loops in tractography-based connectivity represent actual physical connections. In summary, by employing Betti-0 and Betti-1 curves, we are able to visualize and characterize the topological differences between the maltreated and control groups, particularly in terms of connected components and loops. These Betti curves may serve as potential biomarkers for distinguishing between maltreated subjects and the control group.

To more rigorously quantify the topological differences, we used the Wasserstein distance–based ratio statistic. First, we performed the jackknife resampling. Then we computed the between-group and within-group Wasserstein distances using d₀, d₁, and d₀ + d₁. Figure 4 displays the distribution of between-group and within-group Wasserstein distances. We notice a significant distinction between the jackknife-resampled Betti curves of both groups, which is much larger than within-group variability using all three d₀, d₁, and d₀ + d₁ distances and reveals that the between-group difference is highly significant. Figure 4 clearly shows that the variability between groups is far larger than within-group variability. The p values are very small (p value < 0.001) for d₀, d₁, and d₀ + d₁ for both Jacobian determinants and FA values. We conclude that there are significant topological differences in the topological structure of MRI and DTI structural covariance networks. Note that our ratio test statistic is a global test procedure over the range of filtration values and space, so there is no need for multiple comparisons.

We also performed the parametric Z-test. Figure 4 displays the distributions of within- and between-group distances for the topological distances d₀, d₁, and d = d₀ + d₁ used in our study. The distribution of the Z-statistic is also displayed for each distance. We evaluated the normality of the Z-statistic under the null hypothesis using the Kolmogorov-Smirnov test, which is a nonparametric statistical test used to compare a sample distribution with a reference probability distribution (Conover, 1980; Gibbons & Chakraborti, 2011). The statistical significance for all distance metrics were below 0.001, indicating a high likelihood that the Z-statistic follows a normal distribution. Therefore, we can proceed with parametric tests based on the normal distribution. The resulting p values were all below 0.001, indicating statistically significant differences between the groups for all distance metrics.

To investigate the topological impact of maltreatment on brain networks, we applied TDA methods to structural covariance networks. We observed fewer disconnected components in maltreated children compared with controls (Figure 7). This may be attributed to the higher anatomical homogeneity observed in the white matter structure of maltreated children. Hanson et al. (2013) also noted disrupted white matter organization in neglected children, which resulted in more diffused connections between brain regions. This will likely increase anatomical homogeneity across brain regions. Our topology-based approach successfully revealed these alterations and suggests that TDA could serve as a biomarker for identifying the neurobiological impacts of maltreatment (Besthorn, Sattel, Geiger-Kabisch, Zerfass, & Förstl, 1995; Dastgheib, Lithgow, & Moussavi, 2011; Gómez, Mediavilla, Hornero, Abásolo, & Fernández, 2009; Jeong, 2004).

Maltreatment and malnutrition often co-occur, typically in the form of neglect. For instance, a caregiver might intentionally or unintentionally fail to provide adequate nutrition, leading to malnutrition and a range of developmental, psychological, and health issues (Aber & Cicchetti, 1984; Baer & Martinez, 2006). Neglect is often the predominant form of maltreatment leading to malnutrition, making malnourished children more susceptible to illness, developmental delays, and in extreme cases, death (Perez & Widom, 1994). Both maltreatment and malnutrition can have severe and often synergistic neurodevelopmental consequences, affecting regions of the brain responsible for cognitive function and emotional regulation (Teicher, Anderson, Ohashi, & Polcari, 2014; Teicher, Samson, Anderson, & Ohashi, 2016).

Teicher et al. (2014) employed structural covariance network analysis using cortical thickness and considered various nodal centrality measures like degree, betweenness, closeness, and eigenvector. The study observed a significant decrease in nodal centralities across most brain regions, except for an increase in the right anterior insular gyrus and right precuneus gyrus. An increase in correlation in structural covariance networks could lead to an increased degree centrality if new edges are formed or existing edges are strengthened. M. K. Chung et al. (2017) conducted a study using DTI to examine the probability distribution of node degrees in maltreated children. The study revealed that maltreated children tend to have a higher concentration of low-degree nodes and fewer hub nodes when compared with controls. This observation is consistent with a potential increase in the Betti-0 number in the DTI connectivity of maltreated children. This finding contrasts with the higher correlations observed in structural covariance networks. However, if there is a consistently higher level of correlation leading to homogeneous measurements across all brain regions, such a discrepancy can occur. Puetz et al. (2017) found that maltreated children show significant reductions in global connectivity strength and local connectivity, along with increased path lengths. High correlations in structural covariance networks usually translate into more numerous connections between nodes. This creates more direct routes from one node to another, reducing the need for intermediate steps and thereby shortening the average path length.

Persistent homology offers several strengths for neuroimaging research. PH provides a multiscale framework that allows for the study of brain networks at various resolutions (H. Lee et al., 2012). Unlike traditional approaches that rely on a fixed threshold for connectivity, PH accounts for a range of scales, thereby offering a more comprehensive view of brain topology. PH is sensitive to subtle topological differences between networks, making it particularly useful for identifying early markers of neurological diseases and conditions (M. K. Chung, Lee, et al., 2019). Further, PH does not make strong assumptions about the underlying statistical distribution, making it more robust to noise and artifacts commonly encountered in imaging studies. However, PH is not without its limitations. The computation of persistent homology can be computationally expensive, particularly for large and complex networks (A. Zomorodian & Carlsson, 2005). This computational burden may limit its applicability in real-time or large-scale brain imaging studies. PH can sometimes be too sensitive to small topological features that may not be of clinical relevance. The interpretation of PH features, such as Betti numbers and persistence diagrams, can be challenging without a strong mathematical background, which may limit its widespread adoption in the clinical setting. Future work on PH may focus on optimizing the computational aspects of PH and developing user-friendly software tools to promote its application in clinical research. Integrating PH with other machine learning approaches could further refine our understanding of complex brain networks.

To develop a clinically accurate diagnostic tool from TDA, we need to extend our study to a larger population size, such as the Adolescent Brain Cognitive Development (ABCD) database, the largest long-term study of brain development and child health in the US with more than 100 psychiatric and 11 cognitive measures. In the ABCD database, youth (n = 11,875) 9–11 years of age were recruited for the study. This age range is important as it is a period of development critical to an individual’s life trajectory. The incidence of psychiatric illnesses, such as attention deficit hyperactivity disorder (ADHD), anxiety, mood disorders, and psychosis, increases through adolescence (Paus, Keshavan, & Giedd, 2008). The application of our methods to larger datasets such as the ABCD database is left as a future study.

We would like to thank Sixtus Dakurah of the University of Wisconsin–Madison and Yuan Wang of the University of South Carolina for discussion on statistical methods. We would also like to thank Vijay Anand of the University of Exeter and Anass El Yaagoubi Bourakna for discussion on validation methods.

Moo Chung: Conceptualization; Data curation; Funding acquisition; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing. Tahmineh Azizi: Formal analysis; Investigation; Methodology; Visualization; Writing – original draft. Jamie Hanson: Data curation; Writing – review & editing. Andrew Alexander: Data curation; Resources. Richard J. Davidson: Funding acquisition; Resources. Seth Pollak: Funding acquisition; Resources.

Moo Chung, National Institutes of Health, Award ID: EB 022856. Moo Chung, National Institutes of Health, Award ID: MH133614. Moo Chung, National Science Foundation (https://dx.doi.org/10.13039/100000001), Award ID: MDS-2010778. Seth Pollak, National Institutes of Health, Award ID: MH61285. Seth Pollak, National Institutes of Health, Award ID: P50HD105353. Richard J. Davidson, National Institutes of Health, Award ID: MH43454.

Jacobian determinant:

Metric for analyzing local brain volume changes at the voxel level in tensor-based morphometry.

Structural covariance:

Statistical relationship in morphological brain metrics, like cortical thickness or volume, across regions.

Persistence diagram:

A plot used in topological data analysis representing the birth and death of topological features across various scales.

Betti curves:

Graphical representations showing the change in the number of topological features like holes or connected components across different scales or parameters.

Wasserstein distance:

Metric quantifying dissimilarity between two probability distributions, used in analyzing topological features.

Rips filtration:

A method in computational topology that builds a series of simplicial complexes from a point cloud, based on proximity.

Graph filtration:

Sequential process of simplifying a graph by progressively removing edges or nodes based on certain criteria.

Birth-death decomposition:

Network decomposition into birth and death sets for components and loops in graph filtration.

Transposition:

A specific permutation that swaps two elements while leaving all others in their original positions.

https://github.com/laplcebeltrami/maltreated