Cerebellar Structure Segmentation and Shape Analysis with Application to Cerebellar Ataxia

The cerebellum plays an important role in motor control and cognitive functions. Cerebellar dysfunction can lead to a wide range of movement disorders. Despite the significant impact on the lives of patients, the current standard of diagnosis, prognosis, and treatment for cerebellar disease is limited. Magnetic resonance (MR) imaging based morphometric analysis of the cerebellum, which studies the brain structural pattern associated with disease and functional decline, is of great interest and importance. It sets the stage for developing disease-modifying therapies, monitoring individual patient progress, and designing efficient therapeutic trials. Compared to the cerebrum, morphometric analysis in the cerebellum has been limited. Automated and accurate volumetric analysis techniques are lacking. Methods using MR based morphometric biomarkers to predict disease type and functional decline have been lacking or inconclusive. The work presented in this thesis is motivated by the need for better cerebellar structure segmentation and effective structure-function correlation and prediction methods in cerebellar disease. The thesis makes four major contributions. First, we proposed an automated method for segmenting cerebellar lobules from MR images. The proposed method achieved better performance than two state-of-the-art segmentation methods when validated on a cohort of 15 subjects including both healthy controls and patients with various degrees of cerebellar atrophy. Second, we presented two highly-informative shape representations to characterize cerebellar structures: a landmark shape representation of the collection of cerebellar lobules and a level set based whole cerebellar shape representation. Third, we developed an analysis pipeline to classify healthy controls and different ataxia types and to visualize disease specific cerebellar atrophy patterns based on the proposed shape representations and high-dimensional pattern classification methods. The classification performance is evaluated on a cohort consisting of healthy controls and different cerebellar ataxia types. The visualized cerebellar atrophy patterns are consistent with the regional volume decreases observed in previous studies in cerebellar ataxia. Compared to existing analysis methods, the proposed method provides intuitive and detailed visualization of the differences of overall size and shape of the cerebellum, as well as that of individual lobules. Fourth and the last, we developed and tested a similar analysis pipeline for functional score prediction and function specific cerebellar atrophy pattern visualization

Molecular genetic characterization of ataxic movement disorders in mouse and human

Deletion at ITPR1 underlies a young onset autosomal recessive ataxia in mice and a late onset autosomal dominant ataxia (SCA15) in humans. Data presented show the utility of investigating spontaneous mouse mutations in understanding human disease. Through linkage and sequence analysis a novel mutation in the gene encoding inositol 1,4,5-triphosphate receptor type 1 was identified to underlie a severe movement disorder in mice. The 18bp in frame deletion in Itpr1 exon 36 was shown to be allelic to that of another model, opisthotonos (Lane 1972). The Itpr1Δ18 mutation leads to a decreased to almost total lack in the normally high level of ITPR1 expression in cerebellar Purkinje cells. In addition, high density genome wide SNP genotype data in humans showed a SUMF1-ITPR1 deletion to segregate with spinocerebellar ataxia 15 (SCA15), a late-onset autosomal dominant disorder, which was previously mapped to the genomic region containing ITPR1; however, no causal mutations had been identified (Knight et al. 2003). With this deletion not observed in a control population, decreased ITPR1 protein levels in individuals carrying the deletion, and subsequent identification of similar deletions in additional spinocerebellar ataxia families, the data provide compelling evidence that heterozygous deletion in ITPR1 underlies SCA15. As demonstrated, high density genome wide SNP analysis can facilitate rapid detection of structural genomic mutations that may underlie disease when standard sequencing approaches are insufficient. The data suggest genetic alterations at ITPR1 underlie approximately over 1% of autosomal dominant SCA type III (ADCA III) cases for which currently no genetic cause has been identified. Data described herein add weight to a role for aberrant intracellular Ca2+ signaling in Purkinje cells in the pathogenesis of spinocerebellar ataxia

Comparing fully automated state-of-the-art cerebellum parcellation from magnetic resonance images

[EN] The human cerebellum plays an essential role in motor control, is involved in cognitive function (i.e., attention, working memory, and language), and helps to regulate emotional responses. Quantitative in-vivo assessment of the cerebellum is important in the study of several neurological diseases including cerebellar ataxia, autism, and schizophrenia. Different structural subdivisions of the cerebellum have been shown to correlate with differing pathologies. To further understand these pathologies, it is helpful to automatically parcellate the cerebellum at the highest fidelity possible. In this paper, we coordinated with colleagues around the world to evaluate automated cerebellum parcellation algorithms on two clinical cohorts showing that the cerebellum can be parcellated to a high accuracy by newer methods. We characterize these various methods at four hierarchical levels: coarse (i.e., whole cerebellum and gross structures), lobe, subdivisions of the vermis, and the lobules. Due to the number of labels, the hierarchy of labels, the number of algorithms, and the two cohorts, we have restricted our analyses to the Dice measure of overlap. Under these conditions, machine learning based methods provide a collection of strategies that are efficient and deliver parcellations of a high standard across both cohorts, surpassing previous work in the area. In conjunction with the rank-sum computation, we identified an overall winning method.The data collection and labeling of the cerebellum was supported in part by the NIH/NINDS grant R01 NS056307 (PI: J.L. Prince) and NIH/NIMH grants R01 MH078160 & R01 MH085328 (PI: S.H. Mostofsky). PMT is supported in part by the NIH/NIBIB grant U54 EB020403. CERES2 development was supported by grant UPV2016-0099 from the Universitat Politecnica de Valencia (PI: J.V. Manjon); the French National Research Agency through the Investments for the future Program IdEx Bordeaux (ANR-10-IDEX-03-02, HL-MRI Project; PI: P. Coupe) and Cluster of excellence CPU and TRAIL (HR-DTI ANR-10-LABX-57; PI: P. Coupe). Support for the development of LiviaNET was provided by the National Science and Engineering Research Council of Canada (NSERC), discovery grant program, and by the ETS Research Chair on Artificial Intelligence in Medical Imaging. The authors wish to acknowledge the invaluable contributions offered by Dr. George Fein (Dept. of Medicine and Psychology, University of Hawaii) in preparing this manuscript.Carass, A.; Cuzzocreo, JL.; Han, S.; Hernandez-Castillo, CR.; Rasser, PE.; Ganz, M.; Beliveau, V.... (2018). Comparing fully automated state-of-the-art cerebellum parcellation from magnetic resonance images. NeuroImage. 183:150-172. https://doi.org/10.1016/j.neuroimage.2018.08.003S15017218

Human mutations in integrator complex subunits link transcriptome integrity to brain development

Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3’-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development

Motor patterns evaluation of people with neuromuscular disorders for biomechanical risk management and job integration/reintegration

Neurological diseases are now the most common pathological condition and the leading cause of disability, progressively worsening the quality of life of those affected. Because of their high prevalence, they are also a social issue, burdening both the national health service and the working environment. It is therefore crucial to be able to characterize altered motor patterns in order to develop appropriate rehabilitation treatments with the primary goal of restoring patients' daily lives and optimizing their working abilities. In this thesis, I present a collection of published scientific articles I co-authored as well as two in progress in which we looked for appropriate indices for characterizing motor patterns of people with neuromuscular disorders that could be used to plan rehabilitation and job accommodation programs. We used instrumentation for motion analysis and wearable inertial sensors to compute kinematic, kinetic and electromyographic indices. These indices proved to be a useful tool for not only developing and validating a clinical and ergonomic rehabilitation pathway, but also for designing more ergonomic prosthetic and orthotic devices and controlling collaborative robots

Insight in the physiopathology of the developing brain: prenatal imaging and experimental models

This phD research line has been developed into 3 branches as follows: - the main part (A) focused on a specific aspect of the ventral induction and its failure: the developing cerebellum, with a special insight in the midline structures of the posterior fossa. This main part explores the diagnostic potentialities of prenatal imaging such as ultrasound and magnetic resonance imaging (MRI), which, thanks to the ongoing technical and scientific progress, have evolved from almost exclusively experimental examinations to clinically important tools, which impact decision making in the field of pre- and perinatal medicine; - the second part (B) has been dedicated to the prenatal ultrasonographic imaging of neuronal migration, with special attention to the growing fetal cortex, whose fissures and sulci mark progressively its development throughout gestation; - an ancillary part (C) has dealt with experimental translational stem cell research in acquired fetal brain injuries. This is a currently ongoing project, including in-vitro experiments as well as in- vivo-transplantation of stem cells and stem cell derivates for peripartum neuro-regeneration in an experimental model. Only the little contribution of this thesis to this ongoing project has here briefly reported

Diseases of the Brain, Head and Neck, Spine 2020–2023

This open access book offers an essential overview of brain, head and neck, and spine imaging. Over the last few years, there have been considerable advances in this area, driven by both clinical and technological developments. Written by leading international experts and teachers, the chapters are disease-oriented and cover all relevant imaging modalities, with a focus on magnetic resonance imaging and computed tomography. The book also includes a synopsis of pediatric imaging. IDKD books are rewritten (not merely updated) every four years, which means they offer a comprehensive review of the state-of-the-art in imaging. The book is clearly structured and features learning objectives, abstracts, subheadings, tables and take-home points, supported by design elements to help readers navigate the text. It will particularly appeal to general radiologists, radiology residents, and interventional radiologists who want to update their diagnostic expertise, as well as clinicians from other specialties who are interested in imaging for their patient care