Supervised Partial Volume Effect Unmixing for Brain Tumor Characterization using Multi-voxel MR Spectroscopic Imaging

A major challenge faced by multi-voxel Magnetic Resonance Spectroscopy (MV-MRS) imaging is partial volume effect (PVE), where signals from two or more tissue types may be mixed within a voxel. This problem arises due to the low resolution data acquisition, where the size of a voxel is kept relatively large to improve the signal to noise ratio. We propose a novel supervised Signal Mixture Model (SMM), which characterizes the MV-MRS signal into normal, low grade (infiltrative) and high grade (necrotic) brain tissue types, while accounting for in-type variation. An optimization problem is solved based on differential equations, to unmix the tissue by estimating mixture coefficients corresponding to each tissue type at each voxel. This enables visualization of probability heatmaps, useful for characterizing heterogeneous tumors. Experimental results show an overall accuracy of 91.67% and 88.89% for classifying tumors into either low or high grade against histopathology, and demonstrate the method's potential for non-invasive computer-aided diagnosis

Generating Magnetic Resonance Spectroscopy Imaging Data of Brain Tumours from Linear, Non-Linear and Deep Learning Models.

Magnetic Resonance Spectroscopy (MRS) provides valuable information to help with the identification and understanding of brain tumors, yet MRS is not a widely available medical imaging modality. Aiming to counter this issue, this research draws on the advancements in machine learning techniques in other fields for the generation of artificial data. The generated methods were tested through the evaluation of their output against that of a real-world labelled MRS brain tumor data-set. Furthermore the resultant output from the generative techniques were each used to train separate traditional classifiers which were tested on a subset of the real MRS brain tumor dataset. The results suggest that there exist methods capable of producing accurate, ground truth based MRS voxels. These findings indicate that through generative techniques, large datasets can be made available for training deep, learning models for the use in brain tumor diagnosis

Integration of magnetic resonance spectroscopic imaging into the radiotherapy treatment planning

L'objectif de cette thèse est de proposer de nouveaux algorithmes pour surmonter les limitations actuelles et de relever les défis ouverts dans le traitement de l'imagerie spectroscopique par résonance magnétique (ISRM). L'ISRM est une modalité non invasive capable de fournir la distribution spatiale des composés biochimiques (métabolites) utilisés comme biomarqueurs de la maladie. Les informations fournies par l'ISRM peuvent être utilisées pour le diagnostic, le traitement et le suivi de plusieurs maladies telles que le cancer ou des troubles neurologiques. Cette modalité se montre utile en routine clinique notamment lorsqu'il est possible d'en extraire des informations précises et fiables. Malgré les nombreuses publications sur le sujet, l'interprétation des données d'ISRM est toujours un problème difficile en raison de différents facteurs tels que le faible rapport signal sur bruit des signaux, le chevauchement des raies spectrales ou la présence de signaux de nuisance. Cette thèse aborde le problème de l'interprétation des données d'ISRM et la caractérisation de la rechute des patients souffrant de tumeurs cérébrales. Ces objectifs sont abordés à travers une approche méthodologique intégrant des connaissances a priori sur les données d'ISRM avec une régularisation spatio-spectrale. Concernant le cadre applicatif, cette thèse contribue à l'intégration de l'ISRM dans le workflow de traitement en radiothérapie dans le cadre du projet européen SUMMER (Software for the Use of Multi-Modality images in External Radiotherapy) financé par la Commission européenne (FP7-PEOPLE-ITN).The aim of this thesis is to propose new algorithms to overcome the current limitations and to address the open challenges in the processing of magnetic resonance spectroscopic imaging (MRSI) data. MRSI is a non-invasive modality able to provide the spatial distribution of relevant biochemical compounds (metabolites) commonly used as biomarkers of disease. Information provided by MRSI can be used as a valuable insight for the diagnosis, treatment and follow-up of several diseases such as cancer or neurological disorders. Obtaining accurate and reliable information from in vivo MRSI signals is a crucial requirement for the clinical utility of this technique. Despite the numerous publications on the topic, the interpretation of MRSI data is still a challenging problem due to different factors such as the low signal-to-noise ratio (SNR) of the signals, the overlap of spectral lines or the presence of nuisance components. This thesis addresses the problem of interpreting MRSI data and characterizing recurrence in tumor brain patients. These objectives are addressed through a methodological approach based on novel processing methods that incorporate prior knowledge on the MRSI data using a spatio-spectral regularization. As an application, the thesis addresses the integration of MRSI into the radiotherapy treatment workflow within the context of the European project SUMMER (Software for the Use of Multi-Modality images in External Radiotherapy) founded by the European Commission (FP7-PEOPLE-ITN framework)

Advancing fluorescent contrast agent recovery methods for surgical guidance applications

Fluorescence-guided surgery (FGS) utilizes fluorescent contrast agents and specialized optical instruments to assist surgeons in intraoperatively identifying tissue-specific characteristics, such as perfusion, malignancy, and molecular function. In doing so, FGS represents a powerful surgical navigation tool for solving clinical challenges not easily addressed by other conventional imaging methods. With growing translational efforts, major hurdles within the FGS field include: insufficient tools for understanding contrast agent uptake behaviors, the inability to image tissue beyond a couple millimeters, and lastly, performance limitations of currently-approved contrast agents in accurately and rapidly labeling disease. The developments presented within this thesis aim to address such shortcomings. Current preclinical fluorescence imaging tools often sacrifice either 3D scale or spatial resolution. To address this gap in high-resolution, whole-body preclinical imaging tools available, the crux of this work lays on the development of a hyperspectral cryo-imaging system and image-processing techniques to accurately recapitulate high-resolution, 3D biodistributions in whole-animal experiments. Specifically, the goal is to correct each cryo-imaging dataset such that it becomes a useful reporter for whole-body biodistributions in relevant disease models. To investigate potential benefits of seeing deeper during FGS, we investigated short-wave infrared imaging (SWIR) for recovering fluorescence beyond the conventional top few millimeters. Through phantom, preclinical, and clinical SWIR imaging, we were able to 1) validate the capability of SWIR imaging with conventional NIR-I fluorophores, 2) demonstrate the translational benefits of SWIR-ICG angiography in a large animal model, and 3) detect micro-dose levels of an EGFR-targeted NIR-I probe during a Phase 0 clinical trial. Lastly, we evaluated contrast agent performances for FGS glioma resection and breast cancer margin assessment. To evaluate glioma-labeling performance of untargeted contrast agents, 3D agent biodistributions were compared voxel-by-voxel to gold-standard Gd-MRI and pathology slides. Finally, building on expertise in dual-probe ratiometric imaging at Dartmouth, a 10-pt clinical pilot study was carried out to assess the technique’s efficacy for rapid margin assessment. In summary, this thesis serves to advance FGS by introducing novel fluorescence imaging devices, techniques, and agents which overcome challenges in understanding whole-body agent biodistributions, recovering agent distributions at greater depths, and verifying agents’ performance for specific FGS applications

Embedding MRI information into MRSI data source extraction improves brain tumour delineation in animal models

Glioblastoma is the most frequent malignant intra-cranial tumour. Magnetic resonance imaging is the modality of choice in diagnosis, aggressiveness assessment, and follow-up. However, there are examples where it lacks diagnostic accuracy. Magnetic resonance spectroscopy enables the identification of molecules present in the tissue, providing a precise metabolomic signature. Previous research shows that combining imaging and spectroscopy information results in more accurate outcomes and superior diagnostic value. This study proposes a method to combine them, which builds upon a previous methodology whose main objective is to guide the extraction of sources. To this aim, prior knowledge about class-specific information is integrated into the methodology by setting the metric of a latent variable space where Non-negative Matrix Factorisation is performed. The former methodology, which only used spectroscopy and involved combining spectra from different subjects, was adapted to use selected areas of interest that arise from segmenting the T2-weighted image. Results showed that embedding imaging information into the source extraction (the proposed semi-supervised analysis) improved the quality of the tumour delineation, as compared to those obtained without this information (unsupervised analysis). Both approaches were applied to pre-clinical data, involving thirteen brain tumour-bearing mice, and tested against histopathological data. On results of twenty-eight images, the proposed Semi-Supervised Source Extraction (SSSE) method greatly outperformed the unsupervised one, as well as an alternative semi-supervised approach from the literature, with differences being statistically significant. SSSE has proven successful in the delineation of the tumour, while bringing benefits such as 1) not constricting the metabolomic-based prediction to the image-segmented area, 2) ability to deal with signal-to-noise issues, 3) opportunity to answer specific questions by allowing researchers/radiologists define areas of interest that guide the source extraction, 4) creation of an intra-subject model and avoiding contamination from inter-subject overlaps, and 5) extraction of meaningful, good-quality sources that adds interpretability, conferring validation and better understanding of each case

Frontiers of Cancer Diagnostics: From Photoacoustic Chemical Imaging to Cellular Morphodynamics

While terrific progress has been made over the last century, cancer continues to be a prevalent, lethal disease and is responsible for millions of deaths each year. The advent of personalized medicine has brought great strides in the treatment of cancer, as clinicians are able to select therapeutic courses that have been tailored to patients specific set of biomarkers. This selection, in principle, maximizes the chances of cancer remission while minimizing overall patient harm. In this spirit, we have focused on developing diagnostic techniques for two separate cancer biomarkers: tumor potassium concentration, and cell morphology. We first developed an ionophore-based potassium sensing nanoparticle. The sensor works on the principle of Donnan exclusion in which the overall charge of the carrier remains constant. The hydrophobic interior of the nanoparticle holds a pH-sensitive dye and a potassium ionophore. As the potassium concentrations rise, the ionophore chelates potassium from the solution which results in a proton being removed from the pH dye to maintain charge neutrality. The deprotonation event can be calibrated for quantitative measurement and this sensor was developed for use in diverse imaging modes, which include UV-VIS absorption, fluorescence, and photoacoustics. At physiological pH and in the presence of interfering ions, we were able to quantitatively measure potassium concentrations using each of these readouts. We modified the potassium sensor to enable in vivo measurements of potassium. This formulation makes use of a solvatochromic dye that transitions from the particle's interior to its surface as potassium is chelated, and thus avoids inherent pH-cross sensitivity. Using photoacoustic chemical imaging, we are able to quantitatively measure the potassium concentration in the tumor microenvironment. As predicted, it was shown that the TME is hyperkalemic, having a potassium concentration of 29mM. The results of the in vivo photoacoustic analysis were verified with ICP-MS measurements of TME potassium. Finally, we combined cell magneto-rotation and machine learning to develop a technique to measure the metastatic potential of a cancer cell population. This technique aims at avoiding the use of expensive and difficult to produce biological labels. By magnetically activating cells, we are able to suspend them in an oscillating magnetic field where they are free to explore their morphological shape space. By collecting fluorescence images of these cells, we are able to train a classifier to recognize cells of a given type. A proof of concept for the technique is provided here, where MCF-7 and MDA-MB-231 cells, both breast cancer but of different metastatic potential, were classified. A random forest classifier trained on cell images was able to correctly identify the cell type with 86.9% accuracy.PHDBiophysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163147/1/folzja_1.pd

Quantitative photoacoustic tomography: experimental phantom studies

Photoacoustic tomography (PAT) is a promising non-invasive imaging modality exhibiting high resolution, good contrast and specificity to light-absorbing molecules (chromophores). One of the outstanding challenges the technique faces is that PAT images, though dependent on optical absorption, are not its direct representation because they are coloured by the unknown light fluence. Theoretical studies have succeeded in quantifying optical absorption and chromophore concentration by employing model-based inversions (MBI) that can deal with the non-linearity of the problem and the fluence-related distortion. However, experimental translation has been scarce. The aim was to perform quantitative PAT (qPAT) in a rigorous experimental phantom study to show that highly-resolved 3D estimation of chromophore distributions can be achieved. The first consideration was finding a tissue-relevant and stable matrix material and chromophores. Thermoplastic PVCP was fully assessed. Its stability, intrinsic optical properties, thermoelastic efficiency and low-frequency acoustic properties were suitable. The limitation was the lack of photostability of embedded pigments. Separately, we fully characterised aqueous solutions of sulphate salts and found them to be suitable chromophores for qPAT and potential surrogates for oxy- and deoxyhemoglobin. For a phantom made of sub-mm tubes filled with sulphate solutions in an intralipid-rich background, 3D high resolution estimates of chromophore concentrations were obtained through an efficient diffusion-approximation MBI. Uncertainties in optical inputs of the MBI were tackled by assessing in silico their effect on quantification accuracy and then mitigated in the designed experiment through careful measurements. A faithful representation of the multiwavelength photoacoustic tomography images was sought by employing broadband, near-omnidirectional and high-sensitivity sensors and a detection configuration and reconstruction that overcame the limited-view problem. Estimation of the chromophore ratio, analogous to the much sought-after blood oxygenation, gave a mean absolute error of 3.4 p.p., whilst normalised estimates of the two main chromophore distributions gave errors of 13.2% and 17.2%

Multivariate methods for interpretable analysis of magnetic resonance spectroscopy data in brain tumour diagnosis

Malignant tumours of the brain represent one of the most difficult to treat types of cancer due to the sensitive organ they affect. Clinical management of the pathology becomes even more intricate as the tumour mass increases due to proliferation, suggesting that an early and accurate diagnosis is vital for preventing it from its normal course of development. The standard clinical practise for diagnosis includes invasive techniques that might be harmful for the patient, a fact that has fostered intensive research towards the discovery of alternative non-invasive brain tissue measurement methods, such as nuclear magnetic resonance. One of its variants, magnetic resonance imaging, is already used in a regular basis to locate and bound the brain tumour; but a complementary variant, magnetic resonance spectroscopy, despite its higher spatial resolution and its capability to identify biochemical metabolites that might become biomarkers of tumour within a delimited area, lags behind in terms of clinical use, mainly due to its difficult interpretability. The interpretation of magnetic resonance spectra corresponding to brain tissue thus becomes an interesting field of research for automated methods of knowledge extraction such as machine learning, always understanding its secondary role behind human expert medical decision making. The current thesis aims at contributing to the state of the art in this domain by providing novel techniques for assistance of radiology experts, focusing on complex problems and delivering interpretable solutions. In this respect, an ensemble learning technique to accurately discriminate amongst the most aggressive brain tumours, namely glioblastomas and metastases, has been designed; moreover, a strategy to increase the stability of biomarker identification in the spectra by means of instance weighting is provided. From a different analytical perspective, a tool based on signal source separation, guided by tumour type-specific information has been developed to assess the existence of different tissues in the tumoural mass, quantifying their influence in the vicinity of tumoural areas. This development has led to the derivation of a probabilistic interpretation of some source separation techniques, which provide support for uncertainty handling and strategies for the estimation of the most accurate number of differentiated tissues within the analysed tumour volumes. The provided strategies should assist human experts through the use of automated decision support tools and by tackling interpretability and accuracy from different anglesEls tumors cerebrals malignes representen un dels tipus de càncer més difícils de tractar degut a la sensibilitat de l’òrgan que afecten. La gestió clínica de la patologia esdevé encara més complexa quan la massa tumoral s'incrementa degut a la proliferació incontrolada de cèl·lules; suggerint que una diagnosis precoç i acurada és vital per prevenir el curs natural de desenvolupament. La pràctica clínica estàndard per a la diagnosis inclou la utilització de tècniques invasives que poden arribar a ser molt perjudicials per al pacient, factor que ha fomentat la recerca intensiva cap al descobriment de mètodes alternatius de mesurament dels teixits del cervell, tals com la ressonància magnètica nuclear. Una de les seves variants, la imatge de ressonància magnètica, ja s'està actualment utilitzant de forma regular per localitzar i delimitar el tumor. Així mateix, una variant complementària, la espectroscòpia de ressonància magnètica, malgrat la seva alta resolució espacial i la seva capacitat d'identificar metabòlits bioquímics que poden esdevenir biomarcadors de tumor en una àrea delimitada, està molt per darrera en termes d'ús clínic, principalment per la seva difícil interpretació. Per aquest motiu, la interpretació dels espectres de ressonància magnètica corresponents a teixits del cervell esdevé un interessant camp de recerca en mètodes automàtics d'extracció de coneixement tals com l'aprenentatge automàtic, sempre entesos com a una eina d'ajuda per a la presa de decisions per part d'un metge expert humà. La tesis actual té com a propòsit la contribució a l'estat de l'art en aquest camp mitjançant l'aportació de noves tècniques per a l'assistència d'experts radiòlegs, centrades en problemes complexes i proporcionant solucions interpretables. En aquest sentit, s'ha dissenyat una tècnica basada en comitè d'experts per a una discriminació acurada dels diferents tipus de tumors cerebrals agressius, anomenats glioblastomes i metàstasis; a més, es proporciona una estratègia per a incrementar l'estabilitat en la identificació de biomarcadors presents en un espectre mitjançant una ponderació d'instàncies. Des d'una perspectiva analítica diferent, s'ha desenvolupat una eina basada en la separació de fonts, guiada per informació específica de tipus de tumor per a avaluar l'existència de diferents tipus de teixits existents en una massa tumoral, quantificant-ne la seva influència a les regions tumorals veïnes. Aquest desenvolupament ha portat cap a la derivació d'una interpretació probabilística d'algunes d'aquestes tècniques de separació de fonts, proporcionant suport per a la gestió de la incertesa i estratègies d'estimació del nombre més acurat de teixits diferenciats en cada un dels volums tumorals analitzats. Les estratègies proporcionades haurien d'assistir els experts humans en l'ús d'eines automatitzades de suport a la decisió, donada la interpretabilitat i precisió que presenten des de diferents angles

Intraoperative Quantification of Bone Perfusion in Lower Extremity Injury Surgery

Orthopaedic surgery is one of the most common surgical categories. In particular, lower extremity injuries sustained from trauma can be complex and life-threatening injuries that are addressed through orthopaedic trauma surgery. Timely evaluation and surgical debridement following lower extremity injury is essential, because devitalized bones and tissues will result in high surgical site infection rates. However, the current clinical judgment of what constitutes “devitalized tissue” is subjective and dependent on surgeon experience, so it is necessary to develop imaging techniques for guiding surgical debridement, in order to control infection rates and to improve patient outcome. In this thesis work, computational models of fluorescence-guided debridement in lower extremity injury surgery will be developed, by quantifying bone perfusion intraoperatively using Dynamic contrast-enhanced fluorescence imaging (DCE-FI) system. Perfusion is an important factor of tissue viability, and therefore quantifying perfusion is essential for fluorescence-guided debridement. In Chapters 3-7 of this thesis, we explore the performance of DCE-FI in quantifying perfusion from benchtop to translation: We proposed a modified fluorescent microsphere quantification technique using cryomacrotome in animal model. This technique can measure bone perfusion in periosteal and endosteal separately, and therefore to validate bone perfusion measurements obtained by DCE-FI; We developed pre-clinical rodent contaminated fracture model to correlate DCE-FI with infection risk, and compare with multi-modality scanning; Furthermore in clinical studies, we investigated first-pass kinetic parameters of DCE-FI and arterial input functions for characterization of perfusion changes during lower limb amputation surgery; We conducted the first in-human use of dynamic contrast-enhanced texture analysis for orthopaedic trauma classification, suggesting that spatiotemporal features from DCE-FI can classify bone perfusion intraoperatively with high accuracy and sensitivity; We established clinical machine learning infection risk predictive model on open fracture surgery, where pixel-scaled prediction on infection risk will be accomplished. In conclusion, pharmacokinetic and spatiotemporal patterns of dynamic contrast-enhanced imaging show great potential for quantifying bone perfusion and prognosing bone infection. The thesis work will decrease surgical site infection risk and improve successful rates of lower extremity injury surgery