Diffusion and Perfusion MRI in Paediatric Posterior Fossa Tumours

Brain tumours in children frequently occur in the posterior fossa. Most undergo surgical resection, after which up to 25% develop cerebellar mutism syndrome (CMS), characterised by mutism, emotional lability and cerebellar motor signs; these typically improve over several months. This thesis examines the application of diffusion (dMRI) and arterial spin labelling (ASL) perfusion MRI in children with posterior fossa tumours. dMRI enables non-invasive in vivo investigation of brain microstructure and connectivity by a computational process known as tractography. The results of a unique survey of British neurosurgeons’ attitudes towards tractography are presented, demonstrating its widespread adoption and numerous limitations. State-of-the-art modelling of dMRI data combined with tractography is used to probe the anatomy of cerebellofrontal tracts in healthy children, revealing the first evidence of a topographic organization of projections to the frontal cortex at the superior cerebellar peduncle. Retrospective review of a large institutional series shows that CMS remains the most common complication of posterior fossa tumour resection, and that surgical approach does not influence surgical morbidity in this cohort. A prospective case-control study of children with posterior fossa tumours treated at Great Ormond Street Hospital is reported, in which children underwent longitudinal MR imaging at three timepoints. A region-of-interest based approach did not reveal any differences in dMRI metrics with respect to CMS status. However, the candidate also conducted an analysis of a separate retrospective cohort of medulloblastoma patients at Stanford University using an automated tractography pipeline. This demonstrated, in unprecedented spatiotemporal detail, a fine-grained evolution of changes in cerebellar white matter tracts in children with CMS. ASL studies in the prospective cohort showed that following tumour resection, increases in cortical cerebral blood flow were seen alongside reductions in blood arrival time, and these effects were modulated by clinical features of hydrocephalus and CMS. The results contained in this thesis are discussed in the context of the current understanding of CMS, and the novel anatomical insights presented provide a foundation for future research into the condition

Texture analysis of multimodal magnetic resonance images in support of diagnostic classification of childhood brain tumours

Primary brain tumours are recognised as the most common form of solid tumours in children, with pilocytic astrocytoma, medulloblastoma and ependymoma being found most frequently. Despite their high mortality rate, early detection can be facilitated through the use of Magnetic Resonance Imaging (MRI), which is the preferred scanning technique for paediatric patients. MRI offers a variety of imaging sequences through structural and functional imaging, as well as providing complementary tissue information. However visual examination of MR images provides limited ability to characterise distinct histological types of brain tumours. In order to improve diagnostic classification, we explore the use of a computer-aided system based on texture analysis (TA) methods. TA has been applied on conventional MRI but has been less commonly studied on diffusion MRI of brain-related pathology. Furthermore, the combination of textural features derived from both imaging approaches has not yet been widely studied. In this thesis, the aim of the research is to investigate TA based on multi-centre multimodal MRI, in order to provide more comprehensive information and develop an automated processing framework for the classification of childhood brain tumours

Relationships between Regional Radiation Doses and Cognitive Decline in Children Treated with Cranio-Spinal Irradiation for Posterior Fossa Tumors

Pediatric posterior fossa tumor (PFT) survivors who have been treated with cranial radiation therapy often suffer from cognitive impairments that might relate to IQ decline. Radiotherapy (RT) distinctly affects brain regions involved in different cognitive functions. However, the relative contribution of regional irradiation to the different cognitive impairments still remains unclear. We investigated the relationships between the changes in different cognitive scores and radiation dose distribution in 30 children treated for a PFT. Our exploratory analysis was based on a principal component analysis (PCA) and an ordinary least square regression approach. The use of a PCA was an innovative way to cluster correlated irradiated regions due to similar radiation therapy protocols across patients. Our results suggest an association between working memory decline and a high dose (equivalent uniform dose, EUD) delivered to the orbitofrontal regions, whereas the decline of processing speed seemed more related to EUD in the temporal lobes and posterior fossa. To identify regional effects of RT on cognitive functions may help to propose a rehabilitation program adapted to the risk of cognitive impairment

MRI-only radiotherapy treatment planning of the brain

Advancements in imaging methods have made it possible to create synthetic computed tomography (sCT) images from magnetic resonance imaging (MRI) data. MRI-based methods enable computed tomography (CT) to be omitted from the radiotherapy (RT) workflow and transitioning into MRI-only radiotherapy planning (RTP) of the brain. Geometric distortions in magnetic resonance (MR) images and the resulting image quality of generated sCTs are a challenge for the accuracy requirements of RT compared with CT-based methods of RTP. The current dissertation evaluated the suitability of the latest MRI scanners for MRI-only RTP, and the clinical feasibility of present quality assurance methods for measuring geometric accuracy. The clinical feasibility of MRI-only brain RTP of two different sCT generation methods was also investigated. The magnetic resonance attenuation correction (MRAC) based sCT generation method was evaluated for dosimetric accuracy. Additionally, the clinical feasibility of a commercially available deep learning based sCT generation algorithm was evaluated in terms of dosimetric and patient positioning accuracy. Based on the results of the current dissertation, the geometric accuracy of stateof-the-art MRI scanners were shown to meet the requirements of MRI-only based brain RTP. The results also showed that the sCT images generated by the MRAC method are useful for performing dose calculation in the brain. The sCTs generated using a commercial method demonstrated clinical feasibility of dose calculation and patient positioning for MRI-only brain RTP.Magneettikuvauspohjainen sädehoidon suunnittelu aivojen alueella Kuvantamismenetelmien kehitys on mahdollistanut pelkästään magneettikuvauksesta (MK) saatavaan informaatioon perustuen ns. synteettisten tietokonetomografiakuvien (sTT) muodostamisen aivojen alueella. MK-pohjaisten menetelmien avulla on mahdollista luopua kokonaan tietokonetomografiasta (TT) osana sädehoidon suunnitteluketjua ja siirtyä aivojen alueella kokonaan MKpohjaiseen sädehoidon suunnitteluun. Magneettikuvissa esiintyvät geometriset vääristymät, sekä niiden pohjalta muodostettavien sTT-kuvien laatu ovat mahdollinen haaste sädehoidon tarkkuusvaatimusten kannalta verrattuna TTkuvaukseen pohjautuviin menetelmiin. Tässä väitöstutkimuksessa arvioitiin nykyisin käytössä olevien MKlaitteiden soveltuvuutta MK-pohjaiseen sädehoidon suunnitteluun, ja nykyisin käytössä olevien geometrisen tarkkuuden laadunvarmistusmenetelmien soveltuvuutta kliiniseen laadunvalvontaan sädehoidossa. MK-pohjaisen sädehoidon suunnittelun kliinistä soveltuvuutta aivojen alueelle tutkittiin kahdella eri menetelmällä. MK-pohjaiseen vaimennuskorjausmenetelmään perustuvan sTTgenerointimallin soveltuvuutta arvioitiin annoslaskennan tarkkuuden osalta. Lisäksi tutkittiin kaupallisen, syväoppimiseen pohjautuvan algoritmin tuottamien sTTkuvien soveltuvuutta kliiniseen käyttöön annoslaskennan ja potilasasettelun verifioinnin tarkkuuden osalta. Väitöstutkimuksen tulosten perusteella voitiin osoittaa, että nykyaikaiset MK-laitteet täyttävät geometrisen tarkkuuden osalta vaatimukset MK-pohjaiseen sädehoidon suunnittelukuvantamiseen pään alueella. Lisäksi tulokset osoittivat, että MK-pohjaiseen vaimennuskorjaukseen pohjautuvalla menetelmällä luodut sTTkuvat soveltuvat sädehoidon annoslaskennan toteuttamiseen aivojen alueella. Kaupallisella menetelmällä luodut sTT-kuvat voitiin todeta soveltuviksi kliiniseen käyttöön sädehoidon suunnittelussa aivojen alueella annoslaskennan ja potilasasettelun verifioinnin tarkkuuden osalta

Diffusion imaging and tractography in the paediatric neurosurgical population

Diffusion MRI uses magnetic field gradients to sensitise a MR sequence to in vivo water diffusion. Application of these gradients in specific directions (20 in this work) enables a 3D representation of diffusion on a voxel basis. Quantitative diffusion measures are derived; using the voxel maximal diffusion direction and linking neighbouring voxels iteratively based on this creates a visual construct of the white matter: tractography. It is not possible, currently, to non-invasively determine the histological nature of an intracranial tumour. We recruited paediatric patients with radiological evidence of such lesions from April 2006 to January 2008 and retrospectively to August 2003. We used diffusion MR metrics to discriminate paediatric central nervous system tumours based on existing histological diagnoses. Using apparent diffusion coefficient histograms, common posterior fossa childhood tumours were differentiated with 93% success; Primitive neuroectodermal tumours (PNET) and supratentorial atypical teratoid rhabdoid tumours (ATRT) were separated in 100% of cases. Development of these methods with a larger population may facilitate the obviation of surgical biopsy and its attendant risks. Diffusion data was used to reconstruct the cerebellar white matter anatomy using tractography. Initially a population of normal subjects were investigated using single region of interest (ROI) analysis. DTI metrics were implemented, demonstrating the existence of white matter asymmetry where lateralisation corresponded to handedness in 17 right-handed subjects. To asses functional significance of changes in DTI metrics; clinical cerebellar dysfunction was correlated with changes in cerebellar white matter DTI metrics in a patient population with posterior fossa tumours and with the normal population. Fractional anisotropy of the tracts was reduced in patients with tumours d clinical cerebellar signs as compared to healthy individuals. This work demonstrates that diffusion MRI and tractography metrics may enable discrimination of paediatric CNS tumour type and are related to the functional integrity of cerebellar white matter tracts

Sensitivity analysis and automation for intraoperative implementation of the atlas-based method for brain shift correction

ABSTRACT The use of biomechanical models to correct the misregistration due to deformation in image guided neurosurgical systems has been a growing area of investigation. In previous work, an atlas-based inverse model was developed to account for soft-tissue deformations during image-guided surgery. Central to that methodology is a considerable amount of pre-computation and planning. The goal of this work is to evaluate techniques that could potentially reduce that burden. Distinct from previous manual techniques, an automated segmentation technique is described for the cerebrum and dural septa. The shift correction results using this automated segmentation method were compared to those using the manual methods. In addition, the extent and distribution of the surgical parameters associated with the deformation atlas were investigated by a sensitivity analysis using simulation experiments and clinical data. The shift correction results did not change significantly using the automated method (correction of 73±13% ) as compared to the semi-automated method from previous work (correction of 76±13%). The results of the sensitivity analysis show that the atlas could be constructed by coarser sampling (six fold reduction) without substantial degradation in the shift reconstruction, a decrease in preoperative computational time from 13.1±3.5 hours to 2.2±0.6 hours. The automated segmentation technique and the findings of the sensitivity study have significant impact on the reduction of pre-operative computational time, improving the utility of the atlas-based method. The work in this paper suggests that the atlas-based technique can become a 'time of surgery' setup procedure rather than a pre-operative computing strategy

Diffusion MRI for characterising childhood brain tumours

Magnetic resonance imaging (MRI) is widely used both in the clinic and as a research tool in the management of brain tumours. While most studies focus on adult tumours, which have a higher incidence than those in children, paediatric brain tumours differ widely in terms of biology and treatment management. Furthermore, as a non-invasive and non-ionising imaging tool, MRI is used in the diagnosis, prognosis and assessment of treatment response of such tumours. This work focuses on diffusion MRI to study childhood brain tumours. The thesis is divided into three main parts: a reproducibility study of diffusion MRI parameters in order to answer the question of whether clinical imaging may be used interchangeably across multiple-centres to combine data from different institutions; a study on a tumour border diffusion measure as a prognostic biomarker in children with embryonal brain tumours – the apparent transient coefficient in tumour (ATCT); and a study analysing the functional diffusion map (fDM) as a tool for assessing treatment response in paediatric brain tumours. Diffusion MRI has been shown to have a good reproducibility and thus data from multiple centres and scanners can be combined in order to analyse clinical data for patients treated at different institutions; particularly where data for specific tumour types would otherwise be limited. In addition, ATCT has been shown to be a useful prognostic biomarker in children with embryonal brain tumours. Finally, while the fDM may be beneficial in assessing treatment response, the underlying biology of both tumour and healthy tissue needs to be carefully considered, and in particular, areas of necrosis, tumour grade and change in tumour size need to be taken into account. In conclusion, diffusion MRI is a valuable tool in the management of childhood brain tumours, with multi-centre studies paving the way for further research and validation of biomarkers

Brain tumor detection from 3D magnetic resonance images

Master'sMASTER OF SCIENC

Apprentissages procéduraux perceptivo-moteurs dans la neurofibromatose de type 1 et suite à une tumeur de la fosse postérieure pédiatrique irradiée ou non irradiée : études comportementales et en IRM fonctionnelle de repos

L'acquisition de nouvelles habiletés motrices, associée à la pratique ou à l'expérience, est fondamentale dans le développement psychomoteur de l'enfant. Ces mécanismes d'apprentissage procéduraux impliquent l'apprentissage de séquence, sous-tendu principalement par le striatum et les circuits cortico-striataux ; et l'adaptation motrice, sous-tendu par le cervelet et les circuits cortico-cérébelleux. Les études qui composent cette thèse avaient pour objectif principal de caractériser les capacités d'apprentissage procédural moteur et leurs substrats en imagerie fonctionnelle de repos dans deux populations cliniques, la neurofibromatose de type 1 (NF1) et suite à une tumeur de la fosse postérieure (TFP) pédiatrique. La première partie de ce travail explore l'apprentissage de séquence motrice, à l'aide de la tâche de temps de réaction sériels, chez des enfants NF1. A l'échelle du groupe cet apprentissage est préservé, mais à l'échelle individuelle la présence d'objets brillants non identifiés (OBNI), témoins d'anomalies sous-corticales de la myélinisation, caractéristiques de la NF1, semble associée à une altération de l'apprentissage de séquence. Une hyperconnectivité de repos dans les circuits pariéto-striataux, en lien avec les habiletés motrices globales telles que mesurées à la batterie d'évaluation des mouvements de l'enfant (M-ABC), est retrouvée de façon relativement similaire à ce qui a été montré chez les enfants porteurs de trouble du développement de la coordination. La deuxième partie de ce travail explore l'apprentissage de séquence motrice à l'aide de la même tâche, ainsi que l'adaptation motrice à l'aide d'une tâche d'écriture en sens non conventionnel chez des participants guéris d'une TFP pédiatrique. La prise en charge des TFP varie selon le type histologique incluant une chirurgie d'exérèse pour les astrocytomes pilocytiques, une chirurgie et une irradiation focale pour les épendymomes et l'association de chirurgie, radiothérapie et chimiothérapie pour les médulloblastomes. La radiothérapie est un facteur de risque cognitif maintenant bien établi chez les enfants suite à la prise en charge d'une tumeur cérébrale. L'objectif était d'évaluer l'impact de la tumeur et de sa chirurgie ainsi que celui de l'irradiation cérébrale des structures cérébelleuses et striatales sur les apprentissages procéduraux moteurs. L'adaptation motrice est altérée suite à une TFP, et des atypies dans la connectivité fonctionnelle de repos dans les réseaux cortico-cérébelleux de repos sont retrouvées en faveur de séquelle de la tumeur et de sa chirurgie. Un tiers des participants avec TFP irradiés présentent une altération de l'apprentissage de séquence motrice. Des atypies dans les réseaux cortico-striataux de repos sont retrouvées chez les participants avec TFP irradiés, à type d'hyperconnectivité dans les régions motrices, corrélées à l'apprentissage spécifique de séquence, et d'hypoconnectivité dans les régions frontales et précunéales dépendant de la dose d'irradiation aux structures striatales. En résumé, les études comprises dans la présente thèse ont approfondi nos connaissances des capacités d'apprentissage moteur dans les contextes d'une pathologie génétique, modèle de trouble du neurodéveloppement, la NF1 et d'une atteinte lésionnelle tumorale de la fosse postérieure pédiatrique. Les atteintes de la substance blanche dans les régions sous-corticales, dont les OBNI sont le témoin chez les NF1, et secondaires à l'irradiation cérébrale pourraient être une explication commune des mécanismes d'altération des apprentissages moteurs sériels.The acquisition of new motor skills, associated with practice or experience, is fundamental to the psychomotor development of the child. These procedural learning mechanisms include sequence learning, involving mainly striatum and cortico-striatal circuits; and motor adaptation, involving cerebellum and cortico-cerebellar circuits. The main objective of this thesis was to characterize motor procedural learning abilities and their substrates in resting-state functional imaging in two clinical populations, neurofibromatosis type 1 (NF1) and following a pediatric posterior fossa tumor (PFT). The first part of this work explores motor sequence learning, using the serial reaction time task, in NF1 children. At the group level this learning is preserved, but at the individual level the presence of unidentified bright objects (UBOs), indicative of subcortical myelination abnormalities, characteristic of NF1, seems to be associated with impaired sequence learning. Resting hyperconnectivity in parieto-striatal circuits, in relation to gross motor skills assessed using M-ABC, is found to be relatively similar to what has been shown in children with developmental coordination disorders. The second part of this work explores motor sequence learning using the same task, as well as motor adaptation using a non-conventional writing task in participants recovered from pediatric PFT. The management of FPT varies according to histological type, including surgery for pilocytic astrocytomas, surgery and focal irradiation for ependymomas and a combination of surgery, radiotherapy and chemotherapy for medulloblastomas. Radiotherapy is now a well-established cognitive risk factor in children after a brain tumor. The aim was to evaluate the impact of the tumor and its surgery as well as the impact of brain irradiation of cerebellar and striatal structures on motor procedural learning. Motor adaptation is impaired following PFT, and atypical functional resting connectivities in the cortico-cerebellar networks are found in favor of sequelae of the tumor and its surgery. One third of the participants with irradiated PFT had impaired motor sequence learning. Atypical resting cortical-striatal connectivities were found in participants with irradiated PFT: hyperconnectivity in motor regions, correlated with sequence-specific learning, and hypoconnectivity in frontal and precuneal regions, depending on the dose of irradiation to striatal structures. In summary, the studies included in this thesis have furthered our knowledge of motor learning abilities in the contexts of a genetic pathology, a model of neurodevelopmental disorder, that is NF1, and a pediatric PFT lesion. White matter damage in subcortical regions, reflected by OBNI in NF1 and secondary to brain irradiation, could be a common explanation for the mechanisms of impairment of serial motor learning