Madhura Ingalhalikar

Sex differences in the structural connectome of the human brain

Significance Sex differences are of high scientific and societal interest because of their prominence in behavior of humans and nonhuman species. This work is highly significant because it studies a very large population of 949 youths (8–22 y, 428 males and 521 females) using the diffusion-based structural connectome of the brain, identifying novel sex differences. The results establish that male brains are optimized for intrahemispheric and female brains for interhemispheric communication. The developmental trajectories of males and females separate at a young age, demonstrating wide differences during adolescence and adulthood. The observations suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes. Sex differences in human behavior show adaptive complementarity: Males have better motor and spatial abilities, whereas females have superior memory and social cognition skills. Studies also show sex differences in human brains but do not explain this complementarity. In this work, we modeled the structural connectome using diffusion tensor imaging in a sample of 949 youths (aged 8–22 y, 428 males and 521 females) and discovered unique sex differences in brain connectivity during the course of development. Connection-wise statistical analysis, as well as analysis of regional and global network measures, presented a comprehensive description of network characteristics. In all supratentorial regions, males had greater within-hemispheric connectivity, as well as enhanced modularity and transitivity, whereas between-hemispheric connectivity and cross-module participation predominated in females. However, this effect was reversed in the cerebellar connections. Analysis of these changes developmentally demonstrated differences in trajectory between males and females mainly in adolescence and in adulthood. Overall, the results suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes.

Diffusion based abnormality markers of pathology: toward learned diagnostic prediction of ASD.

This paper presents a paradigm for generating a quantifiable marker of pathology that supports diagnosis and provides a potential biomarker of neuropsychiatric disorders, such as autism spectrum disorder (ASD). This is achieved by creating high-dimensional nonlinear pattern classifiers using support vector machines (SVM), that learn the underlying pattern of pathology using numerous atlas-based regional features extracted from diffusion tensor imaging (DTI) data. These classifiers, in addition to providing insight into the group separation between patients and controls, are applicable on a single subject basis and have the potential to aid in diagnosis by assigning a probabilistic abnormality score to each subject that quantifies the degree of pathology and can be used in combination with other clinical scores to aid in diagnostic decision. They also produce a ranking of regions that contribute most to the group classification and separation, thereby providing a neurobiological insight into the pathology. As an illustrative application of the general framework for creating diffusion based abnormality classifiers we create classifiers for a dataset consisting of 45 children with ASD (mean age 10.5 ± 2.5 yr) as compared to 30 typically developing (TD) controls (mean age 10.3 ± 2.5 yr). Based on the abnormality scores, a distinction between the ASD population and TD controls was achieved with 80% leave one out (LOO) cross-validation accuracy with high significance of p<0.001, ~84% specificity and ~74% sensitivity. Regions that contributed to this abnormality score involved fractional anisotropy (FA) differences mainly in right occipital regions as well as in left superior longitudinal fasciculus, external and internal capsule while mean diffusivity (MD) discriminates were observed primarily in right occipital gyrus and right temporal white matter.

DTI based diagnostic prediction of a disease via pattern classification

The paper presents a method of creating abnormality classifiers learned from Diffusion Tensor Imaging (DTI) data of a population of patients and controls. The score produced by the classifier can be used to aid in diagnosis as it quantifies the degree of pathology. Using anatomically meaningful features computed from the DTI data we train a non-linear support vector machine (SVM) pattern classifier. The method begins with high dimensional elastic registration of DT images followed by a feature extraction step that involves creating a feature by concatenating average anisotropy and diffusivity values in anatomically meaningful regions. Feature selection is performed via a mutual information based technique followed by sequential elimination of the features. A non-linear SVM classifier is then constructed by training on the selected features. The classifier assigns each test subject with a probabilistic abnormality score that indicates the extent of pathology. In this study, abnormality classifiers were created for two populations; one consisting of schizophrenia patients (SCZ) and the other with individuals with autism spectrum disorder (ASD). A clear distinction between the SCZ patients and controls was achieved with 90.62% accuracy while for individuals with ASD, 89.58% classification accuracy was obtained. The abnormality scores clearly separate the groups and the high classification accuracy indicates the prospect of using the scores as a diagnostic and prognostic marker.

Disrupted Structural Connectome Is Associated with Both Psychometric and Real-World Neuropsychological Impairment in Diffuse Traumatic Brain Injury

Traumatic brain injury (TBI) is likely to disrupt structural network properties due to diffuse white matter pathology. The present study aimed to detect alterations in structural network topology in TBI and relate them to cognitive and real-world behavioral impairment. Twenty-two people with moderate to severe TBI with mostly diffuse pathology and 18 demographically matched healthy controls were included in the final analysis. Graph theoretical network analysis was applied to diffusion tensor imaging (DTI) data to characterize structural connectivity in both groups. Neuropsychological functions were assessed by a battery of psychometric tests and the Frontal Systems Behavior Scale (FrSBe). Local connection-wise analysis demonstrated reduced structural connectivity in TBI arising from subcortical areas including thalamus, caudate, and hippocampus. Global network metrics revealed that shortest path length in participants with TBI was longer compared to controls, and that this reduced network efficiency was associated with worse performance in executive function and verbal learning. The shortest path length measure was also correlated with family-reported FrSBe scores. These findings support the notion that the diffuse form of neuropathology caused by TBI results in alterations in structural connectivity that contribute to cognitive and real-world behavioral impairment.

Automated tract extraction via atlas based Adaptive Clustering

Advancements in imaging protocols such as the high angular resolution diffusion-weighted imaging (HARDI) and in tractography techniques are expected to cause an increase in the tract-based analyses. Statistical analyses over white matter tracts can contribute greatly towards understanding structural mechanisms of the brain since tracts are representative of connectivity pathways. The main challenge with tract-based studies is the extraction of the tracts of interest in a consistent and comparable manner over a large group of individuals without drawing the inclusion and exclusion regions of interest. In this work, we design a framework for automated extraction of white matter tracts. The framework introduces three main components, namely a connectivity based fiber representation, a fiber bundle atlas, and a clustering approach called Adaptive Clustering. The fiber representation relies on the connectivity signatures of fibers to establish an easy correspondence between different subjects. A group-wise clustering of these fibers that are represented by the connectivity signatures is then used to generate a fiber bundle atlas. Finally, Adaptive Clustering incorporates the previously generated clustering atlas as a prior, to cluster the fibers of a new subject automatically. Experiments on the HARDI scans of healthy individuals acquired repeatedly, demonstrate the applicability, reliability and the repeatability of our approach in extracting white matter tracts. By alleviating the seed region selection and the inclusion/exclusion ROI drawing requirements that are usually handled by trained radiologists, the proposed framework expands the range of possible clinical applications and establishes the ability to perform tract-based analyses with large samples.

Using Multiparametric Data with Missing Features for Learning Patterns of Pathology

The paper presents a method for learning multimodal classifiers from datasets in which not all subjects have data from all modalities. Usually, subjects with a severe form of pathology are the ones failing to satisfactorily complete the study, especially when it consists of multiple imaging modalities. A classifier capable of handling subjects with unequal numbers of modalities prevents discarding any subjects, as is traditionally done, thereby broadening the scope of the classifier to more severe pathology. It also allows design of the classifier to include as much of the available information as possible and facilitates testing of subjects with missing modalities over the constructed classifier. The presented method employs an ensemble based approach where several subsets of complete data are formed and trained using individual classifiers., The output from these classifiers is fused using a weighted aggregation step giving an optimal probabilistic score for each subject. The method is applied to a spatio-temporal dataset for autism spectrum disorders (ASD) (96 patients with ASD and 42 typically developing controls) that consists of functional features from magnetoencephalography (MEG) and structural connectivity features from diffusion tensor imaging (DTI). A clear distinction between ASD and controls is obtained with an average 5-fold accuracy of 83.3% and testing accuracy of 88.4%. The fusion classifier performance is superior to the classification achieved using single modalities as well as multimodal classifier using only complete data (78.3%). The presented multimodal classifier framework is applicable to all modality combinations.

Creating multimodal predictors using missing data: Classifying and subtyping autism spectrum disorder

BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by wide range of symptoms and severity including domains such as language impairment (LI). This study aims to create a quantifiable marker of ASD and a stratification marker for LI using multimodality imaging data that can handle missing data by including subjects that fail to complete all the aspects of a multimodality imaging study, obviating the need to remove subjects with incomplete data, as is done by conventional methods. METHODS An ensemble of classifiers with several subsets of complete data is employed. The outputs from such subset classifiers are fused using a weighted aggregation giving an aggregate probabilistic score for each subject. Such fusion classifiers are created to obtain a marker for ASD and to stratify LI using three categories of features, two extracted from separate auditory tasks using magnetoencephalography (MEG) and the third extracted from diffusion tensor imaging (DTI). RESULTS A clear distinction between ASD and neurotypical controls (5-fold accuracy of 83.3% and testing accuracy of 87%) and between ASD/+LI and ASD/-LI (5-fold accuracy of 70.1% and testing accuracy of 61.1%) was obtained. One of the MEG features, mismatch field (MMF) latency contributed the most to group discrimination, followed by DTI features from superior temporal white matter and superior longitudinal fasciculus as determined by feature ranking. COMPARISON WITH EXISTING METHODS Higher classification accuracy was achieved in comparison with single modality classifiers. CONCLUSION This methodology can be readily applied in large studies where high percentage of missing data is expected.

White matter atlas generation using HARDI based automated parcellation.

Most diffusion imaging studies have used subject registration to an atlas space for enhanced quantification of anatomy. However, standard diffusion tensor atlases lack information in regions of fiber crossing and are based on adult anatomy. The degree of error associated with applying these atlases to studies of children for example has not yet been estimated but may lead to suboptimal results. This paper describes a novel technique for generating population-specific high angular resolution diffusion imaging (HARDI)-based atlases consisting of labeled regions of homogenous white matter. Our approach uses a fiber orientation distribution (FOD) diffusion model and a data driven clustering algorithm. White matter regional labeling is achieved by our automated data driven clustering algorithm that has the potential to delineate white matter regions based on fiber complexity and orientation. The advantage of such an atlas is that it is study specific and more comprehensive in describing regions of white matter homogeneity as compared to standard anatomical atlases. We have applied this state of the art technique to a dataset consisting of adolescent and preadolescent children, creating one of the first examples of a HARDI-based atlas, thereby establishing the feasibility of the atlas creation framework. The white matter regions generated by our automated clustering algorithm have lower FOD variance than when compared to the regions created from a standard anatomical atlas.

Individualized Map of White Matter Pathways: Connectivity-Based Paradigm for Neurosurgical Planning.

BACKGROUND Advances in white matter tractography enhance neurosurgical planning and glioma resection, but white matter tractography is limited by biological variables such as edema, mass effect, and tract infiltration or selection biases related to regions of interest or fractional anisotropy values. OBJECTIVE To provide an automated tract identification paradigm that corrects for artifacts created by tumor edema and infiltration and provides a consistent, accurate method of fiber bundle identification. METHODS An automated tract identification paradigm was developed and evaluated for glioma surgery. A fiber bundle atlas was generated from 6 healthy participants. Fibers of a test set (including 3 healthy participants and 10 patients with brain tumors) were clustered adaptively with this atlas. Reliability of the identified tracts in both groups was assessed by comparison with 2 experts with the Cohen κ used to quantify concurrence. We evaluated 6 major fiber bundles: cingulum bundle, fornix, uncinate fasciculus, arcuate fasciculus, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus, the last 3 tracts mediating language function. RESULTS The automated paradigm demonstrated a reliable and practical method to identify white mater tracts, despite mass effect, edema, and tract infiltration. When the tumor demonstrated significant mass effect or shift, the automated approach was useful for providing an initialization to guide the expert with identification of the specific tract of interest. CONCLUSION We report a reliable paradigm for the automated identification of white matter pathways in patients with gliomas. This approach should enhance the neurosurgical objective of maximal safe resections. ABBREVIATIONS AF, arcuate fasciculusDTI, diffusion tensor imagingIFOF, inferior fronto-occipital fasciculusILF, inferior longitudinal fasciculusROI, region of interestWM, white matter.

An Integrated Framework for High Angular Resolution Diffusion Imaging–Based Investigation of Structural Connectivity

Structural connectivity models hold great promise for expanding what is known about the ways information travels throughout the brain. The physiologic interpretability of structural connectivity models depends heavily on how the connections between regions are quantified. This article presents an integrated structural connectivity framework designed around such an interpretation. The framework provides three measures to characterize the structural connectivity of a subject: (1) the structural connectivity matrix describing the proportion of connections between pairs of nodes, (2) the nodal connection distribution (nCD) characterizing the proportion of connections that terminate in each node, and (3) the connection density image, which presents the density of connections as they traverse through white matter (WM). Individually, each possesses different information concerning the structural connectivity of the individual and could potentially be useful for a variety of tasks, ranging from characterizing and localizing group differences to identifying novel parcellations of the cortex. The efficiency of the proposed framework allows the determination of large structural connectivity networks, consisting of many small nodal regions, providing a more detailed description of a subjects connectivity. The nCD provides a gray matter contrast that can potentially aid in investigating local cytoarchitecture and connectivity. Similarly, the connection density images offer insight into the WM pathways, potentially identifying focal differences that affect a number of pathways. The reliability of these measures was established through a test/retest paradigm performed on nine subjects, while the utility of the method was evaluated through its applications to 20 diffusion datasets acquired from typically developing adolescents.