A large range of sophisticated brain image analysis tools have been developed by the neuroscience community, greatly advancing the field of human brain mapping. Here we introduce the Computational Anatomy Toolbox (CAT)-a powerful suite of tools for brain morphometric analyses with an intuitive graphical user interface but also usable as a shell script. CAT is suitable for beginners, casual users, experts, and developers alike, providing a comprehensive set of analysis options, workflows, and integrated pipelines. The available analysis streams-illustrated on an example dataset-allow for voxel-based, surface-based, and region-based morphometric analyses. Notably, CAT incorporates multiple quality control options and covers the entire analysis workflow, including the preprocessing of cross-sectional and longitudinal data, statistical analysis, and the visualization of results. The overarching aim of this article is to provide a complete description and evaluation of CAT while offering a citable standard for the neuroscience community.

Research on the local hippocampal atrophy for early detection of dementia has gained considerable attention. However, accurately quantifying subtle atrophy remains challenging in existing morphological methods due to the lack of consistent biological correspondence with the complex curving regions like the hippocampal head. Thereby, this article presents an innovative axis-referenced morphometric model (ARMM) that follows the anatomical lamellar organization of the hippocampus, which capture its precise and consistent longitudinal curving trajectory. Specifically, we establish an \"axis-referenced coordinate system\" based on a 7 T ex vivo hippocampal atlas following its entire curving longitudinal axis and orthogonal distributed lamellae. We then align individual hippocampi by deforming this template coordinate system to target spaces using boundary-guided diffeomorphic transformation, while ensuring that the lamellar vectors adhere to the constraint of medial-axis geometry. Finally, we measure local thickness and curvatures based on the coordinate system and boundary surface reconstructed from vector tips. The morphometric accuracy is evaluated by comparing reconstructed surfaces with those directly extracted from 7 T and 3 T MRI hippocampi. The results demonstrate that ARMM achieves the best performance, particularly in the curving head, surpassing the state-of-the-art morphological models. Additionally, morphological measurements from ARMM exhibit higher discriminatory power in distinguishing early Alzheimer\'s disease from mild cognitive impairment compared to volume-based measurements. Overall, the ARMM offers a precise morphometric assessment of hippocampal morphology on MR images, and sheds light on discovering potential image markers for neurodegeneration associated with hippocampal impairment.

Morphological variations in the left atrial appendage (LAA) are associated with different levels of ischemic stroke risk for patients with atrial fibrillation (AF). Studying LAA morphology can elucidate mechanisms behind this association and lead to the development of advanced stroke risk stratification tools. However, current categorical descriptions of LAA morphologies are qualitative and inconsistent across studies, which impedes advancements in our understanding of stroke pathogenesis in AF. To mitigate these issues, we introduce a quantitative pipeline that combines elastic shape analysis with unsupervised learning for the categorization of LAA morphology in AF patients. As part of our pipeline, we compute pairwise elastic distances between LAA meshes from a cohort of 20 AF patients, and leverage these distances to cluster our shape data. We demonstrate that our method clusters LAA morphologies based on distinctive shape features, overcoming the innate inconsistencies of current LAA categorization systems, and paving the way for improved stroke risk metrics using objective LAA shape groups.

Morphometric (i.e., shape and size) differences in the anatomy of cortical structures are associated with neurodevelopmental and neuropsychiatric disorders. Such differences can be quantized and detected by a powerful tool called Labeled Cortical Distance Map (LCDM). The LCDM method provides distances of labeled gray matter (GM) voxels from the GM/white matter (WM) surface for specific cortical structures (or tissues). Here we describe a method to analyze morphometric variability in the particular tissue using LCDM distances. To extract more of the information provided by LCDM distances, we perform pooling and censoring of LCDM distances. In particular, we employ Brown-Forsythe (BF) test of homogeneity of variance (HOV) on the LCDM distances. HOV analysis of pooled distances provides an overall analysis of morphometric variability of the LCDMs due to the disease in question, while the HOV analysis of censored distances suggests the location(s) of significant variation in these differences (i.e., at which distance from the GM/WM surface the morphometric variability starts to be significant). We also check for the influence of assumption violations on the HOV analysis of LCDM distances. In particular, we demonstrate that BF HOV test is robust to assumption violations such as the non-normality and within sample dependence of the residuals from the median for pooled and censored distances and are robust to data aggregation which occurs in analysis of censored distances. We recommend HOV analysis as a complementary tool to the analysis of distribution/location differences. We also apply the methodology on simulated normal and exponential data sets and assess the performance of the methods when more of the underlying assumptions are satisfied. We illustrate the methodology on a real data example, namely, LCDM distances of GM voxels in ventral medial prefrontal cortices (VMPFCs) to see the effects of depression or being of high risk to depression on the morphometry of VMPFCs. The methodology used here is also valid for morphometric analysis of other cortical structures.

Statistical shape modeling is an indispensable tool in the quantitative analysis of anatomies. Particle-based shape modeling (PSM) is a state-of-the-art approach that enables the learning of population-level shape representation from medical imaging data (e.g., CT, MRI) and the associated 3D models of anatomy generated from them. PSM optimizes the placement of a dense set of landmarks (i.e., correspondence points) on a given shape cohort. PSM supports multi-organ modeling as a particular case of the conventional single-organ framework via a global statistical model, where multi-structure anatomy is considered as a single structure. However, global multi-organ models are not scalable for many organs, induce anatomical inconsistencies, and result in entangled shape statistics where modes of shape variation reflect both within- and between-organ variations. Hence, there is a need for an efficient modeling approach that can capture the inter-organ relations (i.e., pose variations) of the complex anatomy while simultaneously optimizing the morphological changes of each organ and capturing the population-level statistics. This paper leverages the PSM approach and proposes a new approach for correspondence-point optimization of multiple organs that overcomes these limitations. The central idea of multilevel component analysis, is that the shape statistics consists of two mutually orthogonal subspaces: the within-organ subspace and the between-organ subspace. We formulate the correspondence optimization objective using this generative model. We evaluate the proposed method using synthetic shape data and clinical data for articulated joint structures of the spine, foot and ankle, and hip joint.

Genetic diseases affecting the skeletal system present with a wide range of symptoms that make diagnosis and treatment difficult. Genome-wide association and sequencing studies have identified genes linked to human skeletal diseases. Gene editing of zebrafish models allows researchers to further examine the link between genotype and phenotype, with the long-term goal of improving diagnosis and treatment. While current automated tools enable rapid and in-depth phenotyping of the axial skeleton, characterizing the effects of mutations on the craniofacial skeleton has been more challenging. The objective of this study was to evaluate a semi-automated screening tool can be used to quantify craniofacial variations in zebrafish models using four genes that have been associated with human skeletal diseases (meox1, plod2, sost, and wnt16) as test cases. We used traditional landmarks to ground truth our dataset and pseudolandmarks to quantify variation across the 3D cranial skeleton between the groups (somatic crispant, germline mutant, and control fish). The proposed pipeline identified variation between the crispant or mutant fish and control fish for four genes. Variation in phenotypes parallel human craniofacial symptoms for two of the four genes tested. This study demonstrates the potential as well as the limitations of our pipeline as a screening tool to examine multi-dimensional phenotypes associated with the zebrafish craniofacial skeleton.

The Kawase approach is one of the most used trajectories in skull base surgery. The exposure range of the approach and its correlation with skull base anatomy still demand more exploration. With the help of digital rebuilding, analysis, and measurement, we evaluated the exposure range of the Kawase and extended Kawase approaches and analyzed the correlation between the exposure range and the variants of the petrosal and clival anatomy. The finding of the study demonstrated that compared to the sub-temporal approach, the Kawase approach and the extended Kawase approach significantly added the exposure range in the upper, middle, and partial inferior regions of the clivus. The gains in the exposure volume and area are more when the manipulation angle is less than 135°.

Like neocortical structures, the archicortical hippocampus differs in its folding patterns across individuals. Here, we present an automated and robust BIDS-App, HippUnfold, for defining and indexing individual-specific hippocampal folding in MRI, analogous to popular tools used in neocortical reconstruction. Such tailoring is critical for inter-individual alignment, with topology serving as the basis for homology. This topological framework enables qualitatively new analyses of morphological and laminar structure in the hippocampus or its subfields. It is critical for refining current neuroimaging analyses at a meso- as well as micro-scale. HippUnfold uses state-of-the-art deep learning combined with previously developed topological constraints to generate uniquely folded surfaces to fit a given subject\'s hippocampal conformation. It is designed to work with commonly employed sub-millimetric MRI acquisitions, with possible extension to microscopic resolution. In this paper, we describe the power of HippUnfold in feature extraction, and highlight its unique value compared to several extant hippocampal subfield analysis methods.

Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic obstruction of the left ventricular (LV) outflow tract (LVOT). Although this may be mediated by interplay between the hypertrophied septal wall, systolic anterior motion of the mitral valve, and papillary muscle abnormalities, the mechanistic role of LV shape is still not fully understood. This study sought to identify the LV end-diastolic morphology underpinning oHCM.
Cardiovascular magnetic resonance images from 2398 HCM individuals were obtained as part of the NHLBI HCM Registry. Three-dimensional LV models were constructed and used, together with a principal component analysis, to build a statistical shape model capturing shape variations. A set of linear discriminant axes were built to define and quantify (Z-scores) the characteristic LV morphology associated with LVOT obstruction (LVOTO) under different physiological conditions and the relationship between LV phenotype and genotype. The LV remodelling pattern in oHCM consisted not only of basal septal hypertrophy but a combination with LV lengthening, apical dilatation, and LVOT inward remodelling. Salient differences were observed between obstructive cases at rest and stress. Genotype negative cases showed a tendency towards more obstructive phenotypes both at rest and stress.
LV anatomy underpinning oHCM consists of basal septal hypertrophy, apical dilatation, LV lengthening, and LVOT inward remodelling. Differences between oHCM cases at rest and stress, as well as the relationship between LV phenotype and genotype, suggest different mechanisms for LVOTO. Proposed Z-scores render an opportunity of redefining management strategies based on the relationship between LV anatomy and LVOTO.

Neonatal coarctation of the aorta (CoA) is a common congenital heart defect. Its antenatal diagnosis remains challenging, and its pathophysiology is poorly understood. We present a novel statistical shape modeling (SSM) pipeline to study the role and predictive value of arch shape in CoA in utero. Cardiac magnetic resonance imaging (CMR) data of 112 fetuses with suspected CoA was acquired and motion-corrected to three-dimensional volumes. Centerlines from fetal arches were extracted and used to build a statistical shape model capturing relevant anatomical variations. A linear discriminant analysis was used to find the optimal axis between CoA and false positive cases. The CoA shape risk score classified cases with an area under the curve of 0.907. We demonstrate the feasibility of applying a SSM pipeline to three-dimensional fetal CMR data while providing novel insights into the anatomical determinants of CoA and the relevance of in utero arch anatomy for antenatal diagnosis of CoA.