The current state-of-the-art of spinal cord imaging: methods.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small cross-sectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research

Improvements in the registration of multimodal medical imaging : application to intensity inhomogeneity and partial volume corrections

Alignment or registration of medical images has a relevant role on clinical diagnostic and treatment decisions as well as in research settings. With the advent of new technologies for multimodal imaging, robust registration of functional and anatomical information is still a challenge, particular in small-animal imaging given the lesser structural content of certain anatomical parts, such as the brain, than in humans. Besides, patient-dependent and acquisition artefacts affecting the images information content further complicate registration, as is the case of intensity inhomogeneities (IIH) showing in MRI and the partial volume effect (PVE) attached to PET imaging. Reference methods exist for accurate image registration but their performance is severely deteriorated in situations involving little images Overlap. While several approaches to IIH and PVE correction exist these methods still do not guarantee or rely on robust registration. This Thesis focuses on overcoming current limitations af registration to enable novel IIH and PVE correction methods.El registre d'imatges mèdiques té un paper rellevant en les decisions de diagnòstic i tractament clíniques així com en la recerca. Amb el desenvolupament de noves tecnologies d'imatge multimodal, el registre robust d'informació funcional i anatòmica és encara avui un repte, en particular, en imatge de petit animal amb un menor contingut estructural que en humans de certes parts anatòmiques com el cervell. A més, els artefactes induïts pel propi pacient i per la tècnica d'adquisició que afecten el contingut d'informació de les imatges complica encara més el procés de registre. És el cas de les inhomogeneïtats d'intensitat (IIH) que apareixen a les RM i de l'efecte de volum parcial (PVE) característic en PET. Tot i que existeixen mètodes de referència pel registre acurat d'imatges la seva eficàcia es veu greument minvada en casos de poc solapament entre les imatges. De la mateixa manera, també existeixen mètodes per la correcció d'IIH i de PVE però que no garanteixen o que requereixen un registre robust. Aquesta tesi es centra en superar aquestes limitacions sobre el registre per habilitar nous mètodes per la correcció d'IIH i de PVE

Statistical analysis for longitudinal MR imaging of dementia

Serial Magnetic Resonance (MR) Imaging can reveal structural atrophy in the brains of subjects with neurodegenerative diseases such as Alzheimer’s Disease (AD). Methods of computational neuroanatomy allow the detection of statistically significant patterns of brain change over time and/or over multiple subjects. The focus of this thesis is the development and application of statistical and supporting methodology for the analysis of three-dimensional brain imaging data. There is a particular emphasis on longitudinal data, though much of the statistical methodology is more general. New methods of voxel-based morphometry (VBM) are developed for serial MR data, employing combinations of tissue segmentation and longitudinal non-rigid registration. The methods are evaluated using novel quantitative metrics based on simulated data. Contributions to general aspects of VBM are also made, and include a publication concerning guidelines for reporting VBM studies, and another examining an issue in the selection of which voxels to include in the statistical analysis mask for VBM of atrophic conditions. Research is carried out into the statistical theory of permutation testing for application to multivariate general linear models, and is then used to build software for the analysis of multivariate deformation- and tensor-based morphometry data, efficiently correcting for the multiple comparison problem inherent in voxel-wise analysis of images. Monte Carlo simulation studies extend results available in the literature regarding the different strategies available for permutation testing in the presence of confounds. Theoretical aspects of longitudinal deformation- and tensor-based morphometry are explored, such as the options for combining within- and between-subject deformation fields. Practical investigation of several different methods and variants is performed for a longitudinal AD study

From Diffusion to Tracts

Diffusion of water molecules within the brain tissue can be used to modulate the nuclear magnetic resonance signal that is used to form magnetic resonance images (MRI). As the signal itself can be noisy and its meaning challenging to interpret, mathematical models are generally fitted to these measurements to obtain the more accurate characterization of the brain microstructure. This, of course, requires that the mathematical model itself is sound in respect to the measurement setup. This dissertation focuses on the extensively used tensor models as they have been shown to unravel details of the physical diffusion phenomena along with various applications in the basic neuroscience, the clinical research, and even in the neurosurgery. One of the greatest challenges in the diffusion weighted MRI measurements is subject motion during the image acquisition as that can cause a complete loss of the measurement which is especially highlighted in ill or uncooperative patients studies. Due to the used acquisition technique, this loss extends to multiple measurements simultaneously resulting in an enormous gap in the sampling. Such gaps can be problematic for any model fitting, even for the currently available robust means developed to exclude outlier measurements from affecting the estimate. Hence in this dissertation, a tool coined as SOLID was developed to detect these outliers and to robustly process them during the tensor based model estimation. SOLID was implemented as a part of the widely used ExploreDTI toolbox to allow the rapid international distribution of the tool. Unfortunately, any reduction in the measurement sampling will lead to increasing error propagation during the model estimation. Mathematically this is detailed in terms of a condition number for the matrix inversion in the linear least squares fitting. Previously, the condition number has been used to optimize the diffusion weighted MRI acquisition gradient scheme but in this dissertation it was renovated into a novel quality control tool. The condition number of the matrix inversion that provides the model estimate can be calculated after the outliers are excluded to assess spatially and directionally varying error propagation to obviate any bias in subject or population studies. To motivate the importance of the robust methods and diffusion weighted MRI at large, neurocognitive studies with neonates’ visual abilities and bilinguals’ acquisition age of the second language were conducted as a part of this thesis. The findings in these studies indicated that premature birth affects the white matter structures across the brain whereas the age of acquisition of the second language affects only the speech related brain structures.Aivojen rakenteessa tapahtuvien muutosten mittaaminen on avainasemassa tutkittaessa esimerkiksi keskosena syntyneen lapsen kehitystä tai uusien taitojen, kuten kielten, oppimista. Ihmisaivojen tutkiminen on aiemmin rajoittunut aivojen toiminnan arviointiin aivosähkökäyrän ja neurokognitiivisten testien avulla. Viime vuosikymmenten kehitys magneettikuvaustekniikassa on tuonut mahdollisuuden tutkia kajoamattomasti myös aivojen rakennetta ja jopa seurata sen muutosta lapsen kasvaessa tai ihmisen oppiessa uusia taitoja. Yksi lupaavimmista aivojen tutkimusmenetelmistä on diffuusiopainotettu magneettikuvaus, jolle on löytynyt lukuisia käyttökohteita niin neurotieteessä, lääketieteellisissä tutkimuksissa kuin neurokirurgiassakin. Menetelmä perustuu vesimolekyylien lämpöliikkeen mittaamiseen aivoissa. Molekyylien liike on vapaata muun muassa valkean aineen rakenteiden myötäisesti, mutta lähes mahdotonta kohtisuoraan niiden lävitse. Jäljittämällä nämä reitit voidaan muodostaa tarkka malli aivojen rakenteesta. Mallin pohjalta on mahdollista laskea kuvaavia arvoja, jotka auttavat esimerkiksi määrittämään aivovaurion astetta. Diffuusiopainotetun magneettikuvauksen suurin haaste on menetelmän monimutkaisuus sekä mittauksen että analyysin osalta. Vain hyvin yksinkertaisissa tapauksissa asiantuntija voi arvioida suoraan diffuusiopainotetusta magneettikuvasta poikkeamia aivoissa. Yleensä käytetään matemaattisia menetelmiä kuvan tarkempaan analysointiin. Tällöin keskeistä on inversio-ongelman ratkaisu, missä potilaasta tehdyt mittaukset sovitetaan aivoja kuvaavaan matemaattiseen malliin. Sopivan mallin valinnalla on siis suuri vaikutus lopputuloksen hyödyllisyyteen. Diffuusiopainotettu magneettikuvaus on myös häiriöherkkä ja mittaukset sisältävät luonnostaan paljon kohinaa, jonka vaikutusta vähennetään tekemällä toistomittauksia. Toistomittaukset pidentävät kuvausaikaa, joka puolestaan voi olla haasteellinen potilaalle, koska potilaan pitää olla liikkumatta koko kuvauksen ajan. Potilaan pään pienikin liike voi johtaa huomattaviin mittavirheisiin, koska menetelmällä mitataan vesimolekyylien liikettä, jonka suuruus on vain kymmenien mikrometrien luokkaa. Tässä fysiikan väitöskirjassa keskityttiin diffuusiopainotetun magneettikuvauksen mallintamismenetelmien kehitystyöhön ja niiden käyttöönottoon Helsingin yliopistollisessa sairaalassa. Kehitimme kansainvälistä huomiota herättäneen SOLID-työkalun, jolla voidaan havaita sekä korjata potilaan liikkeestä aiheutuvia virheitä mittaustuloksissa. Tämän lisäksi esitimme laadunvalvonta menetelmän, jolla voidaan arvioida esimerkiksi potilaiden välisten mallinnustulosten vertailukelpoisuutta. Kehitettyjä menetelmiä testattiin ja sovellettiin kahdessa tutkimuksessa: Osoitimme, että vastasyntyneen lapsen kyky seurata katseellaan liikkuvaa kohdetta liittyy laaja-alaisiin muutoksiin aivojen valkean aineen rakenteessa. Lisäksi näytimme, että toisen kielen oppimisajankohta vaikuttaa aivojen puheentuottoon liittyvien aivorakenteiden muodostumiseen

Serial sectioning block-face imaging of post-mortem human brain

No current imaging technology can directly and without significant distortion visualize the defining microscopic features of the human brain. Ex vivo histological techniques yield exquisite planar images, but the cutting, mounting and staining they require induce slice-specific distortions, introducing cross-slice differences that prohibit true 3D analysis. Clearing techniques have proven difficult to apply to large blocks of human tissue and cause dramatic distortions as well. Thus, we have only a poor understanding of human brain structures that occur at a scale of 1–100 μm, in which neurons are organized into functional cohorts. To date, mesoscopic features which are critical components of this spatial context, have only been quantified in studies of 2D histologic images acquired in a small number of subjects and/or over a small region of the brain, typically in the coronal orientation, implying that features that are oblique or orthogonal to the coronal plane are difficult to properly analyze. A serial sectioning optical coherence tomography (OCT) imaging infrastructure will be developed and utilized to obtain images of cyto- and myelo-architectural features and microvasculature network of post-mortem human brain tissue. Our imaging infrastructure integrates vibratome with imaging head along with pre and post processing algorithms to construct volumetric OCT images of cubic centimeters of brain tissue blocks. Imaging is performed on tissue block-face prior to sectioning, which preserves the 3D information. Serial sections cut from the block can be subsequently treated with multiplexed histological staining of multiple molecular markers that will facilitate cellular classification or imaged with high-resolution transmission birefringence microscope. The successful completion of this imaging infrastructure enables the automated reconstruction of undistorted volume of human tissue brain blocks and permits studying the pathological alternations arising from diseases. Specifically, the mesoscopic and microscopic pathological alternations, as well as the optical properties and cortical morphological alternations of the dorsolateral prefrontal cortical region of two difference neurodegeneration diseases, Chronic Traumatic Encephalopathy (CTE) and Alzheimer’s Disease (AD), were evaluated using this imaging infrastructure

Multimodality functional imaging for adpative radiotherapy in cancer

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Radiología y Medicina Física, leída el 23-09-2016Hoy en día, novedosas técnicas radioterápicas como la radioterapia de intensidad modulada (IMRT), la arcoterapia volumétrica modulada (VMAT), la protonterapia y la hadronterapia permiten administrar una alta dosis de cobertura al volumen tumoral evitando el tejido sano circundante. Al mismo tiempo, técnicas de imagen como la tomografía de emisión de positrones-tomografía computarizada (PET/CT) y las imágenes por resonancia magnética (MRI) han madurado permitiendo visualizar un amplio rango de características pato-fisiológicas del tumor, desde el metabolismo a la perfusión. La técnica Diffusion Weighted (DW-) MRI proporciona una estimación de la difusión de las moléculas de agua en tejido a través de la métrica de imagen cuantitativa, coeficiente de difusión aparente (ADC). Dicha métrica proporciona valiosa información tanto acerca de la celularidad del tumor así como un valioso indicador de la respuesta tumoral al tratamiento con radioterapia. Además, la técnica dynamic contrast enhanced (DCE-) MRI proporciona información de la perfusión tumoral utilizando medios de contraste; las métricas derivadas de esta técnica nos permiten evaluar las propiedades vasculares del tejido a través de un medio de contraste basado en gadolinio, estas métricas están también asociadas con la respuesta al tratamiento. Por otro lado, las imágenes de PET/CT dependen de radiotrazadores específicos, siendo 18F-labeled fluorodeoxyglucose (18F-FDG) el más extendido y usado en cáncer. Este radiotrazador puede ser usado para medir las propiedades metabólicas y funcionales de los tumores...Contemporary techniques in radiotherapy (RT), which include intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton and heavy ion therapy, enable the delivery of high dose coverage of tumor volume while sparing healthy surrounding tissue. At the same time, imaging techniques such as positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) have evolved to allow for the visualization of a wide range of pathophysiological characteristics of tumor, from metabolism to perfusion. Diffusion-weighted (DW)-MRI provides an estimate of the diffusivity of water molecules in tissue, with the quantitative imaging metric apparent diffusion coefficient (ADC) providing valuable information about changes in tissue cellularity associated with tumors in addition to predictions of treatment outcomes after RT. Dynamic contrast enhanced (DCE-) MRI provides information on tumor perfusion using contrast agents (CA) to assess the vascular properties of tissue through a gadolinium (Gd)-based CA, also associated with therapy response. On the other hand, PET/CT imaging relies on specific radiotracers, with 18-fluorine fluorodeoxyglucose (18F-FDG) being the most widely used in cancer. This radiotracer can be used to measure metabolic and functional properties of tumors. The combination of functional and molecular information that can be derived from MRI and PET/CT imaging techniques has led to the development of new tools that go beyond uniform dose delivery. Clinical practice in the coming years is expected to progress further down the path of RT treatment adapted to an individualized response - turning from prescribing dose to volume towards prescribing dose to optimizing treatment, minimizing the number of tumoral cells that survive treatment with acceptable comorbidity. This thesis will focus on the building blocks of adaptive RT for Human Papilloma Virus negative (HPV-) Head and Neck Squamous Cell Carcinoma (HNSCC) and Brain Metastases (BM) patients...Depto. de Radiología, Rehabilitación y FisioterapiaFac. de MedicinaTRUEunpu

Magnetic resonance imaging to improve structural localisation in radiotherapy planning

The purpose of this thesis is to develop the role of magnetic resonance imaging (MRI) in the radiotherapy (RT) planning process. This began by assessing a prototype inline three-dimensional distortion correction algorithm. A number of quality assurance tests were conducted using different test objects and the 3D distortion correction algorithm was compared with the standard two-dimensional version available for clinical use on the MRI system. Scanning patients using MRI in the RT position within an immobilisation mask can be problematic, since the multi-channel head coils typically used in diagnostic imaging, are not compatible with the immobilisation mask. To assess the image quality which can be obtained with MR imaging in the RT position, various MRI quality assurance phantoms were positioned within an immobilisation mask and a series of image quality tests were performed on four imaging coils compatible with the immobilisation mask. It was shown that only the 4-channel cardiac coil delivered comparable image quality to a multi-channel head coil. An investigation was performed to demonstrate how MRI patient position protocols influence registration quality in patients with prostate cancer undergoing radical RT. The consequences for target volume definition and dose coverage with RT planning were also assessed. Twenty patients with prostate cancer underwent a computed tomography (CT) scan in the RT position, a diagnostic MRI scan and an MRI scan in the RT position. The CT datasets were independently registered with the two MRI set-ups and the quality of registration was compared. This study demonstrated that registering CT and MR images in the RT position provides a statistically significant improvement in registration quality, target definition and target volume dose coverage for patients with prostate cancer. A similar study was performed on twenty-two patients with oropharyngeal cancer undergoing radical RT. It was shown that when patients with oropharyngeal cancer undergo an MRI in the RT position there are significant improvements in CT-MR image registration, target definition and target volume dose coverage

Application of novel technologies for the development of next generation MR compatible PET inserts

Multimodal imaging integrating Positron Emission Tomography and Magnetic Resonance Imaging (PET/MRI) has professed advantages as compared to other available combinations, allowing both functional and structural information to be acquired with very high precision and repeatability. However, it has yet to be adopted as the standard for experimental and clinical applications, due to a variety of reasons mainly related to system cost and flexibility. A hopeful existing approach of silicon photodetector-based MR compatible PET inserts comprised by very thin PET devices that can be inserted in the MRI bore, has been pioneered, without disrupting the market as expected. Technological solutions that exist and can make this type of inserts lighter, cost-effective and more adaptable to the application need to be researched further. In this context, we expand the study of sub-surface laser engraving (SSLE) for scintillators used for PET. Through acquiring, measuring and calibrating the use of a SSLE setting we study the effect of different engraving configurations on detection characteristics of the scintillation light by the photosensors. We demonstrate that apart from cost-effectiveness and ease of application, SSLE treated scintillators have similar spatial resolution and superior sensitivity and packing fraction as compared to standard pixelated arrays, allowing for shorter crystals to be used. Flexibility of design is benchmarked and adoption of honeycomb architecture due to geometrical advantages is proposed. Furthermore, a variety of depth-of-interaction (DoI) designs are engraved and studied, greatly enhancing applicability in small field-of-view tomographs, such as the intended inserts. To adapt to this need, a novel approach for multi-layer DoI characterization has been developed and is demonstrated. Apart from crystal treatment, considerations on signal transmission and processing are addressed. A double time-over-threshold (ToT) method is proposed, using the statistics of noise in order to enhance precision. This method is tested and linearity results demonstrate applicability for multiplexed readout designs. A study on analog optical wireless communication (aOWC) techniques is also performed and proof of concept results presented. Finally, a ToT readout firmware architecture, intended for low-cost FPGAs, has been developed and is described. By addressing the potential development, applicability and merits of a range of transdisciplinary solutions, we demonstrate that with these techniques it is possible to construct lighter, smaller, lower consumption, cost-effective MRI compatible PET inserts. Those designs can make PET/MRI multimodality the dominant clinical and experimental imaging approach, enhancing researcher and physician insight to the mysteries of life.La combinación multimodal de Tomografía por Emisión de Positrones con la Imagen de Resonancia Magnética (PET/MRI, de sus siglas en inglés) tiene clara ventajas en comparación con otras técnicas multimodales actualmente disponibles, dada su capacidad para registrar información funcional e información estructural con mucha precisión y repetibilidad. Sin embargo, esta técnica no acaba de penetrar en la práctica clínica debido en gran parte a alto coste. Las investigaciones que persiguen mejorar el desarrollo de insertos de PET basados en fotodetectores de silicio y compatibles con MRI, aunque han sido intensas y han generado soluciones ingeniosas, todavía no han conseguido encontrar las soluciones que necesita la industria. Sin embargo, existen opciones todavía sin explorar que podrían ayudar a evolucionar este tipo de insertos consiguiendo dispositivos más ligeros, baratos y con mejores prestaciones. Esta tesis profundiza en el estudio de grabación sub-superficie con láser (SSLE) para el diseño de los cristales centelladores usados en los sistemas PET. Para ello hemos caracterizado, medido y calibrado un procedimiento SSLE, y a continuación hemos estudiado el efecto que tienen sobre las especificaciones del detector las diferentes configuraciones del grabado. Demostramos que además de la rentabilidad y facilidad de uso de esta técnica, los centelladores SSLE tienen resolución espacial equivalente y sensibilidad y fracción de empaquetamiento superiores a las matrices de centelleo convencionales, lo que posibilita utilizar cristales más cortos para conseguir la misma sensibilidad. Estos diseños también permiten medir la profundidad de la interacción (DoI), lo que facilita el uso de estos diseños en tomógrafos de radio pequeño, como pueden ser los sistemas preclínicos, los dedicados (cabeza o mama) o los insertos para MRI. Además de trabajar en el tratamiento de cristal de centelleo, hemos considerado nuevas aproximaciones al procesamiento y transmisión de la señal. Proponemos un método innovador de doble medida de tiempo sobre el umbral (ToT) que integra una evaluación de la estadística del ruido con el propósito de mejorar la precisión. El método se ha validado y los resultados demuestran su viabilidad de uso incluso en conjuntos de señales multiplexadas. Un estudio de las técnicas de comunicación óptica analógica e inalámbrica (aOWC) ha permitido el desarrollo de una nueva propuesta para comunicar las señales del detector PET insertado en el gantry a un el procesador de señal externo, técnica que se ha validado en un demostrador. Finalmente, se ha propuesto y demostrado una nueva arquitectura de análisis de señal ToT implementada en firmware en FPGAs de bajo coste. La concepción y desarrollo de estas ideas, así como la evaluación de los méritos de las diferentes soluciones propuestas, demuestran que con estas técnicas es posible construir insertos de PET compatibles con sistemas MRI, que serán más ligeros y compactos, con un reducido consumo y menor coste. De esta forma se contribuye a que la técnica multimodal PET/MRI pueda penetrar en la clínica, mejorando la comprensión que médicos e investigadores puedan alcanzar en su estudio de los misterios de la vida.Programa Oficial de Doctorado en Ingeniería Eléctrica, Electrónica y AutomáticaPresidente: Andrés Santos Lleó.- Secretario: Luis Hernández Corporales.- Vocal: Giancarlo Sportell