Automatic signal and image-based assessments of spinal cord injury and treatments.

Spinal cord injury (SCI) is one of the most common sources of motor disabilities in humans that often deeply impact the quality of life in individuals with severe and chronic SCI. In this dissertation, we have developed advanced engineering tools to address three distinct problems that researchers, clinicians and patients are facing in SCI research. Particularly, we have proposed a fully automated stochastic framework to quantify the effects of SCI on muscle size and adipose tissue distribution in skeletal muscles by volumetric segmentation of 3-D MRI scans in individuals with chronic SCI as well as non-disabled individuals. We also developed a novel framework for robust and automatic activation detection, feature extraction and visualization of the spinal cord epidural stimulation (scES) effects across a high number of scES parameters to build individualized-maps of muscle recruitment patterns of scES. Finally, in the last part of this dissertation, we introduced an EMG time-frequency analysis framework that implements EMG spectral analysis and machine learning tools to characterize EMG patterns resulting in independent or assisted standing enabled by scES, and identify the stimulation parameters that promote muscle activation patterns more effective for standing. The neurotechnological advancements proposed in this dissertation have greatly benefited SCI research by accelerating the efforts to quantify the effects of SCI on muscle size and functionality, expanding the knowledge regarding the neurophysiological mechanisms involved in re-enabling motor function with epidural stimulation and the selection of stimulation parameters and helping the patients with complete paralysis to achieve faster motor recovery

Artificial Intelligence, Mathematical Modeling and Magnetic Resonance Imaging for Precision Medicine in Neurology and Neuroradiology

La tesi affronta la possibilità di utilizzare metodi matematici, tecniche di simulazione, teorie fisiche riadattate e algoritmi di intelligenza artificiale per soddisfare le esigenze cliniche in neuroradiologia e neurologia al fine di descrivere e prevedere i patterns e l’evoluzione temporale di una malattia, nonché di supportare il processo decisionale clinico. La tesi è suddivisa in tre parti. La prima parte riguarda lo sviluppo di un workflow radiomico combinato con algoritmi di Machine Learning al fine di prevedere parametri che favoriscono la descrizione quantitativa dei cambiamenti anatomici e del coinvolgimento muscolare nei disordini neuromuscolari, con particolare attenzione alla distrofia facioscapolo-omerale. Il workflow proposto si basa su sequenze di risonanza magnetica convenzionali disponibili nella maggior parte dei centri neuromuscolari e, dunque, può essere utilizzato come strumento non invasivo per monitorare anche i più piccoli cambiamenti nei disturbi neuromuscolari oltre che per la valutazione della progressione della malattia nel tempo. La seconda parte riguarda l’utilizzo di un modello cinetico per descrivere la crescita tumorale basato sugli strumenti della meccanica statistica per sistemi multi-agente e che tiene in considerazione gli effetti delle incertezze cliniche legate alla variabilità della progressione tumorale nei diversi pazienti. L'azione dei protocolli terapeutici è modellata come controllo che agisce a livello microscopico modificando la natura della distribuzione risultante. Viene mostrato come lo scenario controllato permetta di smorzare le incertezze associate alla variabilità della dinamica tumorale. Inoltre, sono stati introdotti metodi di simulazione numerica basati sulla formulazione stochastic Galerkin del modello cinetico sviluppato. La terza parte si riferisce ad un progetto ancora in corso che tenta di descrivere una porzione di cervello attraverso la teoria quantistica dei campi e di simularne il comportamento attraverso l'implementazione di una rete neurale con una funzione di attivazione costruita ad hoc e che simula la funzione di risposta del modello biologico neuronale. E’ stato ottenuto che, nelle condizioni studiate, l'attività della porzione di cervello può essere descritta fino a O(6), i.e, considerando l’interazione fino a sei campi, come un processo gaussiano. Il framework quantistico definito può essere esteso anche al caso di un processo non gaussiano, ovvero al caso di una teoria di campo quantistico interagente utilizzando l’approccio della teoria wilsoniana di campo efficace.The thesis addresses the possibility of using mathematical methods, simulation techniques, repurposed physical theories and artificial intelligence algorithms to fulfill clinical needs in neuroradiology and neurology. The aim is to describe and to predict disease patterns and its evolution over time as well as to support clinical decision-making processes. The thesis is divided into three parts. Part 1 is related to the development of a Radiomic workflow combined with Machine Learning algorithms in order to predict parameters that quantify muscular anatomical involvement in neuromuscular diseases, with special focus on Facioscapulohumeral dystrophy. The proposed workflow relies on conventional Magnetic Resonance Imaging sequences available in most neuromuscular centers and it can be used as a non-invasive tool to monitor even fine change in neuromuscular disorders and to evaluate longitudinal diseases’ progression over time. Part 2 is about the description of a kinetic model for tumor growth by means of classical tools of statistical mechanics for many-agent systems also taking into account the effects of clinical uncertainties related to patients’ variability in tumor progression. The action of therapeutic protocols is modeled as feedback control at the microscopic level. The controlled scenario allows the dumping of uncertainties associated with the variability in tumors’ dynamics. Suitable numerical methods, based on Stochastic Galerkin formulation of the derived kinetic model, are introduced. Part 3 refers to a still-on going project that attempts to describe a brain portion through a quantum field theory and to simulate its behavior through the implementation of a neural network with an ad-hoc activation function mimicking the biological neuron model response function. Under considered conditions, the brain portion activity can be expressed up to O(6), i.e., up to six fields interaction, as a Gaussian Process. The defined quantum field framework may also be extended to the case of a Non-Gaussian Process behavior, or rather to an interacting quantum field theory in a Wilsonian Effective Field theory approach

Deep Anatomical Federated Network (Dafne): an open client/server framework for the continuous collaborative improvement of deep-learning-based medical image segmentation

Semantic segmentation is a crucial step to extract quantitative information from medical (and, specifically, radiological) images to aid the diagnostic process, clinical follow-up. and to generate biomarkers for clinical research. In recent years, machine learning algorithms have become the primary tool for this task. However, its real-world performance is heavily reliant on the comprehensiveness of training data. Dafne is the first decentralized, collaborative solution that implements continuously evolving deep learning models exploiting the collective knowledge of the users of the system. In the Dafne workflow, the result of each automated segmentation is refined by the user through an integrated interface, so that the new information is used to continuously expand the training pool via federated incremental learning. The models deployed through Dafne are able to improve their performance over time and to generalize to data types not seen in the training sets, thus becoming a viable and practical solution for real-life medical segmentation tasks.Comment: 10 pages (main body), 5 figures. Work partially presented at the 2021 RSNA conference and at the 2023 ISMRM conference In this new version: added author and change in the acknowledgmen

Multi-component MRI transverse-relaxation parameter estimation to detect and monitor neuromuscular disease

We aimed to optimise the estimation of skeletal muscle-water spin-spin relaxation time (T2m), and fat fraction estimated from multi-echo MRI, as potential biomarkers, by accounting for instrumental factors such as B1 errors, non-Gaussian noise and non-ideal echo train evolution. A multi-component slice-profile-compensated extended phase graph (sEPG) model for multi-echo Carr-Purcell-Meiboom-Gill (CPMG) spin-echo sequence signals was implemented, modelling the fat signal as two empirically calibrated sEPG components with fixed parameters, and the remaining unknown parameters (B1 field factor, T2m, fat fraction (ffa), global amplitude and Rician noise SD) determined by maximum likelihood estimation. After validation using a calibrated test object the algorithm was used to analyse clinical muscle study data from patient groups with amyotrophic lateral sclerosis (ALS), Kennedy’s disease (KD) and Duchenne muscular dystrophy (DMD) and matched healthy controls. Parameter maps were generated using quality control steps to reject pixels failing fit quality or physical meaningfulness criteria. Muscle fat-fraction was also determined independently by 3-point Dixon MRI (ffd). In ALS and KD median T2m were significantly elevated compared with healthy controls in varied patterns and time courses, whereas it was decreased in DMD; other T2m distribution histogram metrics such as the skewness and full width at quarter maximum also differed significantly between patients and healthy volunteers. Quantitative comparison of ffa and ffd in the same muscles revealed a monotonic relationship deviating from linearity due to differing deviations from the assumed ideal signal behaviour in each method. Finally, the effects upon estimation accuracy and precision of practically realisable pulse sequence parameter choices were explored in simulations and with real data. Recommendations are presented for optimal choices. Clinically practical conventional CPMG sequences, combined with an appropriate signal model and parameter estimation method can provide robust T2m and ffa measures which change in disease and may sensitively reflect different aspects of neuromuscular pathology

ROLE OF FAT CONTENT ON THE STRUCTURE AND FUNCTION OF HUMAN SKELETAL MUSCLE

Muscle size does not fully explain variations in muscle strength. Fat content has been implicated in muscle weakness, though this relationship remains unclear. The relationship between fat and strength may vary between scales (e.g., cellular, organ, and organism). The goal of this dissertation was to clarify the role of fat in the structure and function of muscle using in vitro and in vivo techniques across multiple scales in adults 21-45 years old. Study 1 tested the agreement of intramyocellular lipid (IMCL) content between oil red o (ORO) and magnetic resonance spectroscopy (MRS) techniques. These measures of IMCL were also compared to measures of quadriceps fat content (fat fraction, FF) by magnetic resonance imaging (MRI). Results showed that fat by ORO, MRS, nor MRI were related. This suggests that extracellular lipid contributes to IMCL by MRS, and that fat is not a primarily storage location within muscle cells. Study 2 quantified the relationships between FF, architecture, and strength in vivo using MRI, diffusion tensor imaging (DTI), and isokinetic dynamometry. There was a relationship between FF and fascicle length. However, FF was not related to measures of muscle strength. This suggests that fat may be related to shorter fascicles, but does not impair maximal strength. Muscle curvature and pennation angle were related to muscle strength, suggesting that they may be additional contributors to strength. Study 3 compared measures of single fiber function to whole muscle strength. The relationship between IMCL and single fiber function was also quantified. Measures of IMCL, FF, and BMI were not related, suggesting that IMCL does not contribute to fat t measured at the whole muscle or whole body levels. Measures of IMCL were also not related to single fiber function, indicating that greater levels of lipid accumulation may be necessary for fat-induced impairment of single fiber function. Collectively, the findings of this dissertation indicate that fat and mechanical function must be evaluated at the same anatomical scale for clear interpretations of their relationship. Additionally, this work suggests that fat may have a relationship with muscle structure, but not does have a direct effect on strength

Automating the multimodal analysis of musculoskeletal imaging in the presence of hip implants

In patients treated with hip arthroplasty, the muscular condition and presence of inflammatory reactions are assessed using magnetic resonance imaging (MRI). As MRI lacks contrast for bony structures, computed tomography (CT) is preferred for clinical evaluation of bone tissue and orthopaedic surgical planning. Combining the complementary information of MRI and CT could improve current clinical practice for diagnosis, monitoring and treatment planning. In particular, the different contrast of these modalities could help better quantify the presence of fatty infiltration to characterise muscular condition after hip replacement. In this thesis, I developed automated processing tools for the joint analysis of CT and MR images of patients with hip implants. In order to combine the multimodal information, a novel nonlinear registration algorithm was introduced, which imposes rigidity constraints on bony structures to ensure realistic deformation. I implemented and thoroughly validated a fully automated framework for the multimodal segmentation of healthy and pathological musculoskeletal structures, as well as implants. This framework combines the proposed registration algorithm with tailored image quality enhancement techniques and a multi-atlas-based segmentation approach, providing robustness against the large population anatomical variability and the presence of noise and artefacts in the images. The automation of muscle segmentation enabled the derivation of a measure of fatty infiltration, the Intramuscular Fat Fraction, useful to characterise the presence of muscle atrophy. The proposed imaging biomarker was shown to strongly correlate with the atrophy radiological score currently used in clinical practice. Finally, a preliminary work on multimodal metal artefact reduction, using an unsupervised deep learning strategy, showed promise for improving the postprocessing of CT and MR images heavily corrupted by metal artefact. This work represents a step forward towards the automation of image analysis in hip arthroplasty, supporting and quantitatively informing the decision-making process about patient’s management

Automatic segmentation of the human thigh muscles in magnetic resonance imaging

Advances in magnetic resonance imaging (MRI) and analysis techniques have improved diagnosis and patient treatment pathways. Typically, image analysis requires substantial technical and medical expertise and MR images can su↵er from artefacts, echo and intensity inhomogeneity due to gradient pulse eddy currents and inherent e↵ects of pulse radiation on MRI radio frequency (RF) coils that complicates the analysis. Processing and analysing serial sections of MRI scans to measure tissue volume is an additional challenge as the shapes and the borders between neighbouring tissues change significantly by anatomical location. Medical imaging solutions are needed to avoid laborious manual segmentation of specified regions of interest (ROI) and operator errors. The work set out in this thesis has addressed this challenge with a specific focus on skeletal muscle segmentation of the thigh. The aim was to develop an MRI segmentation framework for the quadriceps muscles, femur and bone marrow. Four contributions of this research include: (1) the development of a semi-automatic segmentation framework for a single transverse-plane image; (2) automatic segmentation of a single transverseplane image; (3) the automatic segmentation of multiple contiguous transverse-plane images from a full MRI thigh scan; and (4) the use of deep learning for MRI thigh quadriceps segmentation. Novel image processing, statistical analysis and machine learning algorithms were developed for all solutions and they were compared against current gold-standard manual segmentation. Frameworks (1) and (3) require minimal input from the user to delineate the muscle border. Overall, the frameworks in (1), (2) and (3) o↵er very good output performance, with respective framework’s mean segmentation accuracy by JSI and processing time of: (1) 0.95 and 17 sec; (2) 0.85 and 22 sec; and (3) 0.93 and 3 sec. For the framework in (4), the ImageNet trained model was customized by replacing the fully-connected layers in its architecture to convolutional layers (hence the name of Fully Convolutional Network (FCN)) and the pre-trained model was transferred for the ROI segmentation task. With the implementation of post-processing for image filtering and morphology to the segmented ROI, we have successfully accomplished a new benchmark for thigh MRI analysis. The mean accuracy and processing time with this framework are 0.9502 (by JSI ) and 0.117 sec per image, respectively

Assessment of body composition in spinal cord injury: A scoping review.

The objective of this scoping review was to map the evidence on measurement properties of body composition tools to assess whole-body and regional fat and fat-free mass in adults with SCI, and to identify research gaps in order to set future research priorities. Electronic databases of PubMed, EMBASE and the Cochrane library were searched up to April 2020. Included studies employed assessments related to whole-body or regional fat and/or fat-free mass and provided data to quantify measurement properties that involved adults with SCI. All searches and data extractions were conducted by two independent reviewers. The scoping review was designed and conducted together with an expert panel (n = 8) that represented research, clinical, nutritional and lived SCI experience. The panel collaboratively determined the scope and design of the review and interpreted its findings. Additionally, the expert panel reached out to their professional networks to gain further stakeholder feedback via interactive practitioner surveys and workshops with people with SCI. The research gaps identified by the review, together with discussions among the expert panel including consideration of the survey and workshop feedback, informed the formulation of future research priorities. A total of 42 eligible articles were identified (1,011 males and 143 females). The only tool supported by studies showing both acceptable test-retest reliability and convergent validity was whole-body dual-energy x-ray absorptiometry (DXA). The survey/workshop participants considered the measurement burden of DXA acceptable as long as it was reliable, valid and would do no harm (e.g. radiation, skin damage). Practitioners considered cost and accessibility of DXA major barriers in applied settings. The survey/workshop participants expressed a preference towards simple tools if they could be confident in their reliability and validity. This review suggests that future research should prioritize reliability and validity studies on: (1) DXA as a surrogate 'gold standard' tool to assess whole-body composition, regional fat and fat-free mass; and (2) skinfold thickness and waist circumference as practical low-cost tools to assess regional fat mass in persons with SCI, and (3) females to explore potential sex differences of body composition assessment tools. Registration review protocol: CRD42018090187 (PROSPERO)