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

Diffusion-tensor MRI methods to study and evaluate muscle architecture

The thesis describes the development of various approaches for measuring muscle architectural parameters using Diffusion Tensor MR Imaging (DTI). It also illustrates how to apply them to study changes in muscle architecture after an injury prevention program.In Chapter 2, because manual segmentation of muscles is cumbersome, we validated a semi-automatic framework for estimating DTI indices in upper leg muscles. This method reduced segmentation time by a factor of three in a cross-sectional study design and can be used fully automatically in a longitudinal assessment of changes in DTI indices.Chapter 3 was a feasibility study measuring fiber orientation changes with DTI in calf muscles and sub-compartments of the Soleus and Tibialis Anterior during plantarflexion and dorsiflexion. Differences in fiber orientations corresponded to the known agonist-antagonist function of the muscles. This shows that DTI can be utilized to assess changes in muscle orientation due to posture or training.In Chapter 4, we compared DTI fiber tractography for Vastus Lateralis fiber architecture assessment with 3D ultrasonography (3D-US). We discovered that both methods have their advantages and disadvantages, with the agreement between the two techniques being moderate.Finally, in Chapter 5, we examined the effects of a hamstring injury prevention exercise on the muscle architectural parameters of basketball players. DTI was employed to quantify changes in fiber orientation and length using tractography and fiber orientation maps. It was observed that the Semitendinosus fascicle length increased after the Nordics exercise, while the Biceps Femoris long head fiber orientation decreased following the Divers intervention

CIR-Myo News: Abstracts of the 2015 Spring Padua Muscle Days

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Resistance training, insulin sensitivity & metabolic health

Skeletal muscle is the largest organ in the human body, comprising 40%-50% of total body weight and more than 600 skeletal muscles in a human body performing common functions such as body movements, maintaining posture, storing protein and glycogen and generating heat. Approximately 0.8% skeletal muscle mass declines per year a process known as sarcopenia. On top of that, ageing also results in a decrease in muscle strength, at a rate of approximately 1-3% per year (Keller & Engelhardt, 2013).Skeletal muscle is the major organ responsible for glucose uptake under insulin stimulated conditions, accounting for ~80% of total glucose disposal and low muscle strength and mass likely contribute to metabolic dysregulation seen in Type 2 diabetes. Research has shown that resistance exercise training can increase strength, muscle size, fat-free mass, connective tissue thickness, decrease body fat, reduce blood pressure and improve insulin sensitivity and VO2max(Croymans et al., 2013; Ozaki et al., 2013;Abdul & Defronzo, 2010). In order to monitor efficacy of such resistance training interventions it is important to be able to accurately quantify skeletal muscle mass and several methods exist for this purpose, although many require expensive equipment making them not always possible to use. The aim of chapter 2 was to investigate the repeatability and validity of a relatively cheap and portable A-mode ultrasound device. This chapter has found that A mode ultrasound is a repeatable measure of muscle thickness (CV of 4.6%) and that both A and B mode ultrasound provide valid measures of muscle volume, as compared to the gold standard MRI (r=0.96). Following this, the aim of chapter 3 wasto determine if this A-mode ultrasound device is able to detect changes in muscle thickness in response to resistance exercise training and to determine its validity. Findings in this Chapter 3 have shown that the A-mode ultrasound can detect increases in muscle thickness of 6.2 ± 5.4%, alongside a 26 ± 7.3% increase in 1RM after 8 weeks of resistance exercise training. However, it was also shown that both A and B mode measures of ultrasound muscle thickness were not valid measures of the resistance exercise induced changes in muscle volume (r=0.30 A-mode & r=0.04 B-mode) Resistance exercise is known as the most efficacious method to increase muscle strength and mass. It has been demonstrated recently that if exercise is performed to volitional failure then gains in muscle mass, and to a lesser extent strength, are similar regardless of the load at which exercise is performed. The aims of chapter 4, were to investigate the effects of 6 weeks of resistance exercise training, comprised of 1 set of each exercise to voluntary failure, on insulin sensitivity and the time-course of adaptations in muscle strength/mass, in overweight men. Results of this chapter have demonstrated that six weeks of resistance exercise, volitional failure of nine exercises – taking 15-20 min per session – undertaken three times per week resulted in a 16% improvement in insulin sensitivity (61.6 ± 18.0 to 71.3 ± 22.9 mg.l2.mmol-2.mU-1.min-1 after the intervention (P<0.05) in healthy overweight men and increases in muscle strength, size and RTD (rate torque development) 50 and 100 were also observed. Several studies have demonstrated that people from South Asia are up to 4-6 times more likely to develop type 2 diabetes than White Europeans. Furthermore, in a recent study from the UK Biobank,grip strength in South-Asian men and women was 5–6 kg lower than in the other ethnic groups and a greater contributor to diabetes prevalence. As resistance exercise is the most effective intervention for increasing muscle mass, strength, and can improve insulin sensitivity, the aim of the Chapter 5 was tocompare the effect of resistance exercise on muscle and metabolic health between South Asians and White Europeans. This chapter has shown that there were no differences in the effect of 12 weeks of resistance exercise training on the majority of the muscle and metabolic outcomes measured, however the increase muscle thickness, 1.2 (95%CI 0.8 to 1.7) mm in South Asians and 2.3 (95%CI 1.8 to 2.9) mm in White Europeans and decrease in systolic blood pressure, 5.1 (95%CI:-7.5 to -2.7) mmHg in White Europeans and a 0.7 (95%CI:-2.4 to 1.0) mmHg in South Asians were attenuated in South Asians. There was also a trend for an attenuated effect of resistance exercise training on VO2max,decrease of 0.7 (95%CI -2.0 to 0.6) ml.kg.min-1 in South Asians. In summary, this thesis has demonstrated that whilst ultrasound measure of muscle thickness is valid at a single time point, this is not the case when evaluating changes with resistance exercise training. Following this we have demonstrated that resistance exercise training, involving a single set of exercise to muscle failure, is effective in inducing short-term improvements in muscle size and strength and also insulin sensitivity in White Europeans, with broadly similar findings in South Asians

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

Performance Benefits of Customised Seating Interfaces for Elite Wheelchair Racing Athletes

The limited customisation in commercially available wheelchairs does not always appropriately accommodate the anthropometric variations resulting from specific impairment. Wheelchair racing athletes demonstrate up to 3.8% total body mass greater in the upper extremities, and up 9.8% total body mass reductions in their lower extremities, and between-limb asymmetries of 62.4%. As a consequence, athletes may not have the stable base of support required for optimal propulsion. The optimisation of an entire wheelchair to match unique athlete geometry is both time consuming and costly, as wheelchairs cost over $2000 each. The use of assistive technology can provide an efficient transition between the commercially available equipment and the unique athlete anthropometry. Customised seating interfaces offer a time and cost effective solution, facilitating regular modifications to satisfy athlete growth. These solutions have been used extensively in clinical applications for enhanced stress distribution and injury prevention at the seating interface; however, they have not yet been applied to sporting contexts. The goal of this research was to investigate the performance impact of customised seating interfaces on wheelchair racing propulsion technique. Supplementary goals included the development of practically viable instrumentation solutions and a musculoskeletal model representative of the unique wheelchair racing athlete anthropometries and physical capabilities to assess injury risk to analyse performance impact holistically. The research was split into four main themes: 1. Verification of the importance of the seating interface relative to other key performance parameters such as aerodynamics and glove selection. 2. Instrumentation of the hand-pushrim and seating interfaces 3. Development of a musculoskeletal model 4. Computational modelling of performance and injury risk Computational modelling was performed in the OpenSim environment which coupled kinematic inputs from 3D motion capture (VICON Bonita V16; Oxford Metrics, Oxford, United Kingdom), with kinetic inputs from a pressure mat at the seating interface (XSensor LX100; Calgary, Alberta, Canada) and inertial measurement units (IMUs) (I Measure U; New Zealand) to estimate the hand-interface interactions. This was achieved using Newton’s Second Law, incorporating athlete-specific mass data (from the analysis DXA scans), and acceleration measured from the IMU. Customised seating interfaces reduced the undesirable peak translations of the knee by up to 41.8% and lateral translation of the spine by 33.4%. These translated towards enhanced performance, with an average performance time reduction of 29.8 s (3.7% race time) in the eight international competitions following the inclusion of the customised seating interface. Additionally, athletes using cushioned seating interfaces had reduced peak pressures at the seating interface as compared to those without the interface. Instrumentation can be used outside the laboratory environments, and can, therefore, be applied in the daily training environment to optimise performance preparation. This research provided foundation work for the use of computational biomechanical analyses for the holistic assessment of wheelchair racing performance. Whilst this research has demonstrated the potential impact computational modelling approaches can have on the performance preparation of athletes, some areas for further refinement have been identified. Future research into the processing of IMU data and the validation of musculoskeletal models for wheelchair racing athletes are the critical areas for improvement. Once achieved, the computational modelling approaches explored in this research can positively impact performance outcome, particularly when coupled with the optimisation of equipment, such as customised seating interfaces.Thesis (Ph.D.) -- University of Adelaide, School of Mechanical Engineering, 201

Neuroprosthetic system to restore locomotion after neuromotor disorder

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with Spinal Cord Injury (SCI) and Parkinson disease. Stimulation parameters are tuned manually and remain constant during motor execution which is suboptimal to mediate maximum therapeutic effects. Here, I present a novel neuroprosthetic system that enabled adaptive changes of neuromodulation parameters during locomotion and allowed to restore high-fidelity control over leg movements in paralyzed rats. Beyond the therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders. Several limitations have restricted the development of neuroprosthetic systems for closed loop neuromodulation. (1) First, it required a mechanistic understanding of the relationships between stimulation features and the recruitment of specific sensorimotor circuits. I found that electrical neuromodulation primarily recruits afferent reflex pathways that lead to coordinated activity of leg muscles during stepping. Moreover, the specific electrode location on the spinal cord could activate distinct reflex pathways and activate specific leg muscle groups of paralyzed rats. These results have been leveraged for the design of flexible and stretchable multi-electrode arrays for electrical and chemical spinal cord stimulation. (2) Second, it was necessary to perform comprehensive mapping experiments to characterize the effect of neuromodulation parameters on hind limb kinematics in order to establish stable and robust feedback signals for real time control. Step height and ground reaction forces emerged as the primary targets for the control of closed loop neuromodulation after spinal cord injury. (3) Third, implementation and optimization of closed-loop neuromodulation strategies necessitated the development of an advanced technological platform that combined feedback and feed-forward loops that match the natural flow of information in the modulated neural systems. These integrated developments allowed animals with complete spinal cord injury to perform over 1000 successive steps without failure, and to climb staircases of various heights and lengths with precision and fluidity. Moreover, the neuroprosthetic system was able to alleviate locomotor deficits in an alpha-synuclein rodent model of Parkinsonâs disease. Current knowledge of human spinal cord properties in response to electrical neuromodulation suggests that the developed control policies can translate into clinical applications to improve neurorehabilitation therapies. Moreover, the developed neuroprosthetic system can readily be interfaced with control signals from the brain to establish cortico-spinal neuroprostheses that are intended to promote activity-dependent plasticity during recovery from spinal cord injury

Characterisation and mechanisms of altered body composition and tissue wasting in cancer cachexia

Cancer cachexia has been defined as a multifactorial syndrome characterised by an ongoing loss of skeletal muscle that cannot be fully reversed by conventional nutritional support. Cachexia affects most patients with advanced cancer and is associated with reductions in treatment tolerance, response to therapy, quality of life, and survival. Thus, amelioration of cachexia would improve both quality of life and clinical outcome. However, the aetiology of cachexia is poorly understood, and there are no agreed diagnostic biomarkers or management strategy for patients with cancer cachexia. Recent advances in the field of cachexia research include the development of diagnostic criteria for cachexia, as well as computed tomography (CT) body composition analysis software, making the ability to detect clinically significant muscle wasting in obese patients in particular more accurate. Although muscle loss appears to be the most important and physiologically relevant event in cachexia, the importance of fat wasting is less understood. During cachexia, different adipose depots around the body demonstrate differential rates of wasting. Furthermore, recent studies from animal models have suggested that adipose tissue may be a key driver of muscle wasting through fat-muscle crosstalk. However, human studies in this area are lacking. The molecular mechanisms driving muscle loss in humans are also poorly understood, and the relationships between muscle and fat wasting, functional impairment and reduced survival are largely unknown. The prognostic significance of adipose wasting and investigations in tissue cross-talk therefore are now becoming more important whilst the quest for a cachexia related biomarker remains at the fore. The main aim of this thesis was to investigate specific mediators, mechanisms and biomarkers of cachexia in robustly phenotyped patients with upper gastrointestinal cancer (UGI) in whom cachexia is known to be prevalent. This thesis is comprised of several projects designed to investigate various areas of cachexia pathophysiology, diagnosis and staging. In order to recruit patients to clinical trials, drive cachexia research and identify those who would benefit from early intervention, it is important to understand how to screen and diagnose patients with cachexia. Many patients present to clinicians with unintentional weight loss (UWL). This can occur in patients with cachexia, sarcopenia and malnutrition. With increasing rates of obesity worldwide, as well as an ageing population, differentiating causes of UWL is difficult. Firstly therefore, in order to investigate the feasibility of screening for UWL a systematic review was undertaken in chapter 3 to determine which screening tools were able to assess cachexia, sarcopenia and malnutrition according to the consensus definitions for each. Each tool was judged against a reference method and psychometric evaluation carried out. No one tool was able to assess all three conditions simultaneously, and out of the 22 tools assessed, only 3 had been validated against the gold standard of CT cross-sectional imaging. Thus, the development of a novel tool that encompasses the consensus definition criteria and directs clinicians towards the underlying diagnosis would likely improve detection and outcomes. Secondly, building upon screening and methods for diagnosing low muscularity, chapter 4 uses CT body composition analysis to determine any age and sex-related variations in patients with UGI cancer. CT-based cut-offs for determining low skeletal muscle volume are sex and body mass index (BMI) specific and have been driven in order to predict mortality in these patients. As discussed above, the prevalence of obesity is increasing and the population is ageing therefore, many patients may be sarcopenic at diagnosis, making the assessment of clinically significant muscle wasting difficult. A retrospective, observational study was carried out on patients who had undergone potentially curative oncological and surgical treatment for oesophageal cancer. Analysis of both staging and post neoadjuvant chemotherapy (NAC) CT was performed in order to assess baseline characteristics and dynamic changes in body composition. Males had higher baseline muscle and visceral fat volume whereas females had higher subcutaneous fat volume. Patients of all ages and both sexes lost muscle volume though there was no difference in rates of wasting between groups. Older patients and females lost significantly more total fat during chemotherapy. This chapter therefore highlights the need for further investigation to define differences in adipose depots during cancer progression and their prognostic value. Chapter 5 showcases the main biological assessment of cancer associated muscle wasting in this thesis. As shown in chapter 4 all patients demonstrated some evidence of muscle wasting. A potential mechanism of this was therefore investigated further by looking at the role of the neuromuscular junction (NMJ). The NMJ provides the link between myelinated motor nerves and skeletal muscle. Very little is known about the structure of the NMJ in human health or in disease. Experimental denervation is a recognised model for studying muscle wasting in vivo, and as a result experimental evidence for the role of the NMJ in cachexia is dependent upon animal models. Recent data, however have shown that rodent and human NMJs are markedly different. NMJ morph, an imageJ-based package was used for morphometric analysis of the NMJ in UGI cancer patients with or without cachexia and non-cancer controls. No significant differences were found between groups in any of the major pre- or post-synaptic variables measured suggesting that the NMJ remains structurally intact in cancer cachexia, and thus, the denervation of skeletal muscle is not a major driver of the disease. Whilst it is recognised that muscle mass plays a significant role in the syndrome of cancer cachexia, as shown in chapter 4 through body composition analysis the importance of fat wasting and the effect of metabolic mediators on fat volume requires attention. In murine tumour models, loss of fat volume may predate the loss of muscle volume. Fatty acids, leptines, cytokines and other adipokines may cause lipotoxic effects in skeletal muscle. Adipokines have been reported to induce insulin resistance, impair muscle development, alter muscle lipid amino acid metabolism and modify signalling thus affecting skeletal muscle volume. Clinical studies have shown that adipokines from murine models are also measurable in patients with cancer cachexia. In chapter 6 through the use of transcriptomics, subcutaneous (SAT) and visceral adipose tissue (VAT) depots were analysed from UGI cancer patients with and without cachexia and healthy controls to elucidate the biochemistry of fat wasting in cancer cachexia. Over 2000 genes differed between cachexia VAT and SAT. The gene that showed the largest difference in expression between cancer VAT and control was Intelectin-1 (ITLN1), a novel adipocytokine. Genes involving inflammation were upregulated in cancer whereas genes involved in energy metabolism and fat browning were down regulated. VAT, therefore, may be a target for therapeutic manipulation in cancer. Further investigation is required in to the role of Intelectin-1 as a biomarker in cachexia. Finally, in previous searches for biomarkers of cancer, likely responsiveness to treatment and the presence of cachexia, plasma has been used as a readily available biofluid for investigation. However, no robust cachexia biomarker has been found. Although as work continues it seems that individual biomarker targets should be replaced by an array of markers. Chapter 7 used liquid chromatography mass spectrometry (LC/MS)-based metabolomics to investigate the metabolic profile of weight loss from plasma samples taken at the time of anaesthesia from patients under-going UGI resectional surgery. This showed two distinct profiles based on percentage weight loss in accordance with the consensus definition. There were 40 metabolites associated with cachexia with six of those being highly discriminative of weight loss. Specifically, a combination profile of LysoPC 18.2, Hexadecanoic acid, Octadecanoic acid, Phenylalanine and LysoPC 16.1 showed close correlation for eight weight-losing samples (≥5% weight loss) and nine weight stable samples (<5% weight loss). In particular ,many of the metabolites discovered were involved in lipid metabolism, lending credence again to the importance of understanding adipose wasting in cachexia. In summary, the role of adipose wasting as investigated through imaging and biochemical results has been shown to be important in the aetiology of cancer cachexia. It has been demonstrated that there is currently no adequate way to screen for conditions which present with UWL and that the adaptation of a tool in order to do this would drive further research and the content of complex interventions. Previously published CT-derived cut points are BMI and sex specific, however, it has been shown that there is a growing need to develop these in order to define patients by age also. In doing so this would define stricter criteria for clinical trials and lead to improved end points. Potential novel biomarkers of lipid wasting have been discovered in this thesis. ITLN1 which has corresponded with weight loss previously in other groups warrants further investigation as it may be a target for future therapeutic manipulation. Those biomarkers discovered in the metabolomics study show that it is possible to separate patients based on weight loss alone. Although this was a pilot study after further investigation and development, biomarkers of lipid wasting may be useful as inclusion criteria or outcome measures in clinical trials. The discoveries of the lack of fat browning and the stability of the NMJ in cachectic patients also importantly highlights the need for patient rather than animal based research