Assumption-Free Assessment of Corpus Callosum Shape: Benchmarking and Application

Shape analysis provides a unique insight into biological processes. This paper evaluates the properties, performance, and utility of elliptical Fourier (eFourier) analysis to operationalise global shape, focussing on the human corpus callosum. 8000 simulated corpus callosum contours were generated, systematically varying in terms of global shape (midbody arch, splenium size), local complexity (surface smoothness), and nonshape characteristics (e.g., rotation). 2088 real corpus callosum contours were manually traced from the PATH study. Performance of eFourier was benchmarked in terms of its capacity to capture and then reconstruct shape and systematically operationalise that shape via principal components analysis. We also compared the predictive performance of corpus callosum volume, position in Procrustes-aligned Landmark tangent space, and position in eFourier n-dimensional shape space in relation to the Symbol Digit Modalities Test. Jaccard index for original vs. reconstructed from eFourier shapes was excellent (M=0.98). The combination of eFourier and PCA performed particularly well in reconstructing known n-dimensional shape space but was disrupted by the inclusion of local shape manipulations. For the case study, volume, eFourier, and landmark measures were all correlated. Mixed effect model results indicated all methods detected similar features, but eFourier estimates were most predictive, and of the two shape operationalization techniques had the least error and better model fit. Elliptical Fourier analysis, particularly in combination with principal component analysis, is a powerful, assumption-free and intuitive method of quantifying global shape of the corpus callosum and shows great promise for shape analysis in neuroimaging more broadly.Te study was supported by NHMRC of Australia Grant No. 1002160, 1063907 and ARC Grant 130101705. Tis research was partly undertaken on the National Computational Infrastructure (NCI) facility in Canberra, Australia, which is supported by the Australian Commonwealth Government

Estimating brain volume loss after radiation therapy in children treated for posterior fossa tumors (Corpus callosum and whole brain volume changes following radiotherapy in children).

Background More than half of pediatric tumors of central nervous system (CNS) primarily originate in the posterior fossa and are conventionally treated with radiation therapy (RT).Objectives The objective of this study was to establish whether corpus callosum volumes (CCV) and whole brain volumes (WBV) are correlated and to determine the impact of whole-brain lowvs high-dose RT on brain parenchymal volume loss as assessed using each technique.Material and methods Of the 30 identified children (6-12 years) with newly diagnosed posterior fossa tumors treated with cranial RT, including focal and whole-brain RT, suitable imaging was obtained for 23. Radiotherapy regimens were the following: no whole-brain RT (Group 1, n = 7), low-dose whole-brain RT (30 Gy, Group 3, n = 7) in addition to focal boost. Magnetic resonance images (MRIs) were analyzed at baseline and follow-up (median 14 months). The CCVs were manually segmented on midline sagittal slice (n = 23), while WBVs were segmented semi-automatically using Freesurfer (n = 15). This was done twice (6-month interval) for all baseline CCV measurements and 5 randomly selected WBV measurements to establish measurement reproducibility. Correlations between CCV and WBV were investigated and percentage of children demonstrating reduction in CCV or WBV noted.Results Correlation between baseline CCV and WBV was not significant (p = 0.37). Measurement reproducibility was from 6% to -9% for CCV and from 4.8% to -1.2% for WBV. Among the children studied, 30.4% (7/23) had >9% reduction in CCV at follow-up, while 33.3% (5/15) had >1.2% reduction in WBV. Five of 7 patients with CCV loss were not picked up by WBV measurements. Similarly, 3 of 5 patients with WBV loss were not picked up by CCV measurements.Conclusions The CCV and the WBV are unrelated and may indicate different brain parenchymal losses following RT. Up to a third of posterior fossa tumors treated with RT have measurable CCV or WBV loss; incidence was equivalent in lowvs high-dose whole-brain RT

Idiopathic scoliosis : aspects on surgical and non-surgical treatment

The term scoliosis has been used to describe conditions that lead to deformation of the spine. It derives from the ancient Greek ‘σκολίωσις’ and the root word ‘σκολιός’ which means ‘bent or crooked’. In its most common form, scoliosis is of unknown - idiopathic - cause and origin. It affects roughly 3% of children and adolescents during growth and in mild cases no treatment is required. In moderate cases, bracing has been proposed, with the aim to halt progression of idiopathic scoliosis. It is most common with full-time bracing using rigid, custom made thoracolumbosacral orthoses. It is worn for 16-20 hours per day until skeletal maturity and has been shown to prevent scoliosis progression to a surgical threshold in about 70% of the cases. However, compliance to the treatment has been one of the major drawbacks seen with the full-time brace. Therefore, night-time braces, worn only during the night, have started to gain popularity over the years. Nevertheless, evidence on the effectiveness of night-time bracing has only been based on retrospective studies. More recently, specific scoliosis exercise regimes consisting of self-mediated correction maneuvers in 3 dimensions have also emerged. So far, there has been only one high quality study showing effectiveness of this modality, in patients with mild idiopathic scoliosis. A trial was performed consisting of 135 patients randomized to self-mediated physical activity in combination with either night-time brace, or scoliosis-specific exercise, or self-mediated physical activity alone. Night-time brace was shown to be more effective than self-mediated physical activity in preventing scoliosis progression. On the other hand, scoliosis-specific exercise did not show any clinical benefit when compared to the self-mediated physical activity. Additionally, comparison between the nigh-time brace group and a group of patients who declined participation in the trial and received a full-time brace showed similar effectiveness on the prevention of curve progression. In case the deformity progresses to more severe curves, surgery may be suggested. Over the last decades, a posterior exposure to the spine with a high number of implants and predominantly pedicle screw based fixation techniques has been favored over traditional techniques with low number of implants for the correction of scoliosis. These techniques have been suggested to increase correction and fusion rates and eliminate the risks associated with exposure of the chest wall and/or abdomen in anterior approaches to the spine. Disadvantages of the posterior approach to the spine include extended muscle dissection, need for a higher number of vertebrae to be fused and risk for neurological injuries to the spinal cord. To date, whether posterior based fusion may result in better clinical and radiographic outcomes compared to anterior fusion is still unclear. Moreover, whether higher number of implants per vertebra (implant density) results in better clinical and radiographic outcomes is still debatable. In a nationwide registry-based cohort, we identified patients who underwent anterior (n=27) and posterior (n=32) fusion surgery for a thoracolumbar/lumbar type of scoliosis. We found that despite a longer operative time in the anterior group and higher blood loss and longer fusion constructs in the posterior group, both procedures resulted in significant correction of the scoliosis with similar patient-reported outcome and satisfaction; suggesting that the type of approach is not related to health-reported quality of life. By using the same nationwide database, we also identified 328 surgically treated idiopathic scoliosis patients who were then divided into tertiles based on the number of implants used per operated vertebra. We found no differences in the correction rate of the curve and health-reported quality of life in the different tertiles, suggesting that a high number of implants is not necessarily beneficial in the surgical treatment of idiopathic scoliosis. Studies have shown that, what is perceived as successful radiographic outcome, may not necessarily correlate with patient´s own perception of successful outcome after surgery for idiopathic scoliosis. Patients may still experience persistent back pain and worse quality of life, despite an excellent radiographic outcome. By using the same nationwide database, we identified 280 patients treated with posterior fusion surgery for idiopathic scoliosis and divided them into a high (n=67) and a low (=213) postoperative pain group, based on their self-reported postoperative back pain scores. We found that patients in the high pain group also reported higher back pain and worse quality of life before surgery, compared to the low postoperative pain group. High preoperative back pain and low preoperative mental health were identified as predictors of persistent pain after surgery

Statistical Shape Analysis for the Human Back

A thesis submitted to the department of Engineering and Technology in partial fulfilment of the requirements for the degree of Master of Philosophy in Production and Manufacturing Engineering at the University of WolverhamptonIn this research, Procrustes and Euclidean distance matrix analysis (EDMA) have been investigated for analysing the three-dimensional shape and form of the human back. Procrustes analysis is used to distinguish deformed backs from normal backs. EDMA is used to locate the changes occurring on the back surface due to spinal deformity (scoliosis, kyphosis and lordosis) for back deformity patients. A surface topography system, ISIS2 (Integrated Shape Imaging System 2), is available to measure the three-dimensional back surface. The system presents clinical parameters, which are based on distances and angles relative to certain anatomical landmarks on the back surface. Location, rotation and scale definitely influence these parameters. Although the anatomical landmarks are used in the present system to take some account of patient stance, it is still felt that variability in the clinical parameters is increased by the use of length and angle data. Patients also grow and so their back size, shape and form change between appointments with the doctor. Instead of distances and angles, geometric shape that is independent of location, rotation and scale effects could be measured. This research is mainly focusing on the geometric shape and form change in the back surface, thus removing the unwanted effects. Landmarks are used for describing back information and an analysis of the variability in positioning the landmarks has been carried out for repeated measurements. Generalized Procrustes analysis has been applied to all normal backs to calculate a mean Procrustes shape, which is named the standard normal shape (SNS). Each back (normal and deformed) is then translated, rotated and scaled to give a best fit with the SNS using ordinary Procrustes analysis. Riemannian distances are then estimated between the SNS and all individual backs. The highest Riemannian distance value between the normal backs and the SNS is lower than the lowest Riemannian distance value between the deformed backs and the SNS. The results shows that deformed backs can be differentiated from normal backs. EDMA has been used to estimate a mean form, variance-covariance matrix and mean form difference from all the normal backs. This mean form is named the standard normal form (SNF). The influence of individual landmarks for form difference between each deformed back and the SNF is estimated. A high value indicates high deformity on the location of that landmark and a low value close to 1 indicates less deformity. The result is displayed in a graph that provides information regarding the degree and location of the deformity. The novel aspects of this research lie in the development of an effective method for assessing the three-dimensional back shape; extracting automatic landmarks; visualizing back shape and back form differences

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

Études protéomiques et fonctionnelles des variants rares responsables de la scoliose idiopathique de l’adolescent (SIA)

La scoliose est une déformation de la colonne vertébrale dans les trois plans de l’espace (frontal, sagittal et transverse), et la forme la plus fréquente est la scoliose idiopathique (SI) dont la cause est encore très mal comprise. La scoliose idiopathique de l’adolescent (SIA) est une forme de SI qui se développe au cours de la puberté, plus souvent chez les filles, et présente une importante hétérogénéité phénotypique. Les très nombreuses recherches afin de comprendre les mécanismes qui entrent en jeu dans le développement de cette maladie et afin de déterminer l’étiologie ont permis de mettre en évidence un très grand nombre de théories regroupant des facteurs endocriniens et métaboliques, des facteurs biomécaniques et musculosquelettiques, des facteurs neurologiques et vestibulaires ainsi que des facteurs génétiques et épigénétiques. L’identification du gène candidat POC5 dans la SI par notre laboratoire, un gène crucial dans la formation du cil primaire, a été un tournant majeur apportant la première pièce d’un puzzle plaçant le cil primaire au centre des hypothèses concernant la mise en place de la maladie. Le cil primaire est une organelle non-motile retrouvée à la surface de la totalité des cellules du corps humain à l’exception des cellules sanguines. Grâce à son axonème formé de tubuline capable de subir des modifications post-traductionnelles appelées « code tubuline » et sa membrane ciliaire ultra spécialisée, le cil primaire joue un rôle mécanosenseur important tout au long de la vie, dès le développement embryonnaire. Il prend part à de nombreux mécanismes dont la formation et l’homéostasie osseuse et a déjà été mis en cause dans les maladies osseuses. En effet, lorsque le cil primaire est défectueux, il est responsable de syndromes complexes regroupés sous le nom de ciliopathie dont un des symptômes est la scoliose. L’hypothèse générale de la présente thèse est que des variants rares dans des gènes ciliaires, particulièrement le gène POC5 et le gène TTLL11, agissent sur les mécanismes cellulaires responsables de la mise en place de la SIA faisant d’elle une maladie appartenant à la grande famille des ciliopathies. L’objectif de cette thèse a été de documenter l’implication et la pathogénicité des gènes POC5 et TTLL11 dans la SIA. Nous avons d’abord déterminé la prévalence des variants du gène POC5 dans une cohorte de patients d’origine franco-canadienne ou britannique atteints de SIA (Manuscrit 1). Ensuite, nous avons créé trois modèles de souris Knock-in pour l’équivalent des variants du gène POC5 humain afin d’analyser la pathogénicité et le phénotype éventuel de ciliopathie (Manuscrit 2). Finalement, la pathogénicité du gène TTLL11 muté a été analysée dans des cellules issues de patients atteints de SIA et dans un modèle animal, le poisson zèbre (Manuscrit 3). Les travaux réalisés au cours de cette thèse ont montré que les deux gènes ciliaire POC5 et TTLL11 sont des gènes candidats probablement impliqués dans les mécanismes cellulaires fondamentaux induisant la mise en place de la SIA et ont permis d’identifier un mécanisme, la polyglutamylation du cil primaire, comme étant relié à la SIA.Scoliosis is a 3D spinal curvature, in the frontal, sagittal and transverse plans, and the most common form is the idiopathic scoliosis (IS) with a cause that remains very poorly understood. Adolescent Idiopathic Scoliosis (AIS) is a subtype of IS that develops during the puberty, most commonly in girls, and has a significant phenotypic heterogeneity. To date, a large amount of research on scoliosis etiology highlighted various hypotheses based on endocrine and metabolic factors, biomechanical and musculoskeletal factors, neurological and vestibular factors, as well as genetic and epigenetic factors. The identification of the IS candidate gene POC5 by our laboratory, a crucial gene in the formation of the primary cilium, was a major turning point bringing the first piece of a puzzle where the primary cilium is a central hypothesis concerning the onset of the disease. The primary cilium is a non-motile organelle found at the cell surface of all the human body cells, except for blood cells. The primary cilium plays an important mechano-sensor role throughout life, from embryonic development through its axoneme composed by tubulin that hosted post-translational modifications called “tubulin code”, and its ultra-specialized ciliary membrane. It is involved in many mechanisms including bone formation and homeostasis and has already been implicated in bone diseases. Indeed, the defective primary cilium is responsible for human ciliopathy syndromes that are associated with scoliosis. The main hypothesis of this thesis is that rare variants in ciliary genes, especially the POC5 gene and the TTLL11 gene, participate on cellular mechanisms responsible for the onset of AIS supporting the idea that scoliosis is a form of ciliopathy. The specific objective of this thesis was to document the involvement and pathogenicity of the POC5 and TTLL11 genes in AIS. We first determined the prevalence of POC5 gene variants in a cohort of French-Canadian and British AIS patients (Manuscript 1). Then, we created three knock-in mouse models carrying the equivalent of the human POC5 gene variants to analyze the pathogenicity and the possible phenotype of ciliopathy (Manuscript 2). Finally, the pathogenicity of the mutated TTLL11 gene was analyzed in cells extracted from AIS patients and in an animal model, the zebrafish (Manuscript 3). The work presented in this thesis showed that the two ciliary genes POC5 and TTLL11 are candidate genes probably involved in the fundamental cellular mechanisms inducing the onset of AIS and allowed us to identify the primary cilium polyglutamylation, as a mechanism being related to AIS